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Electronic structure of sulfur-nitrogen containing compounds : correlations with theory and chemical… Okbinoğlu, Tülin Nesime 2014

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Electronic structure of sulfur-nitrogen containingcompounds: correlations with theory and chemicalreactivitybyTülin Nesime Okbinog˘luB.S., University of Washington, 2003A THESIS SUBMITTED IN PARTIAL FULFILLMENTOF THE REQUIREMENTS FOR THE DEGREE OFDoctor of PhilosophyinTHE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES(Chemistry)The University of British Columbia(Vancouver)September 2014c Tülin Nesime Okbinog˘lu, 2014AbstractMolecules containing sulfur-nitrogen bonds, such as sulfonamides, have longbeen of interest due to their many uses and chemical properties, including thepotential release of nitric oxide and nitroxyl. Understanding the factors thatcause sulfonamide reactivity is crucial, yet their inherent electronic complex-ity have made them difficult to examine. In this thesis, sulfur K-edge x-rayabsorption spectroscopy (XAS) is used in conjunction with density functionaltheory (DFT) to determine the role of electronic transmission effects throughthe sulfur-nitrogen bond. A systematic deconstruction of the elements withinthe sulfonamide moiety is used as an approach to understand critical factorsthat dictate electronic structure.First, the effect of oxidation state changes and variations in R-group insulfenamides, sulfinamides and sulfonamides on intramolecular bonding areexplored. Next, N-hydroxylation of the sulfonamide amide, in both alkyl sulfon-amides and a series of para-substituted aryl sulfonamides with varying Ham-mett para-sigma constants are studied using structure-function relationships,in conjunction with DFT, to understand the role of electron donation and with-drawal to the sulfonamide moiety. The outcome of these modifications on thesulfonamide framework lead to better insight towards directed drug design andits influence on nitroxyl and nitric oxide release.iiPrefaceAll of the DFT calculations in chapters three and five were performed by me us-ing ORCA quantum chemistry program developed by Frank Neese at the Uni-versity of Bonn. Two compounds in chapter three were synthesized in the lab-oratory of Scott Bohle at McGill University: tert-butane sulfinamide and potas-sium dinitrososulfite. The sulfonamides used in chapters three and four werepurchased from Sigma-Aldrich. I synthesized all of the N-hydroxy sulfonamidecompounds used in chapter four and five. The work presented in this thesishas not yet been published but is in preparation.iiiTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ivList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viiList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ixList of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviiiAcknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 X-Ray Absorption Spectroscopy and DensityFunctional Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.1 X-Ray Absorption Spectroscopy (XAS) . . . . . . . . . . . . . . 82.1.1 Sulfur K-Edge X-Ray Absorption Near EdgeStructure (XANES) . . . . . . . . . . . . . . . . . . . . . 132.1.2 Experimental Setup . . . . . . . . . . . . . . . . . . . . 142.1.3 Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . 152.2 Density Functional Theory . . . . . . . . . . . . . . . . . . . . . 152.2.1 Theoretical Simulations of XAS Data . . . . . . . . . . . 17ivxvi3 The Effect of Oxidation on Sulfur-Nitrogen Molecules . . . . . . . 193.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . 213.2.1 XAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213.2.2 DFT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243.3 Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.3.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . 393.3.2 XAS Acquisition and Data Analysis . . . . . . . . . . . . 394 Para-Substituent and Amide Hydroxylation inSulfonamides: Structure-Function Relationships. . . . . . . . . . . 414.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.2.1 XAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.2.2 Structure-Function Relationships . . . . . . . . . . . . . 524.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644.4 Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654.4.1 General Considerations . . . . . . . . . . . . . . . . . . 654.4.2 XAS Acquisition and Data Analysis . . . . . . . . . . . . 695 Computational Analysis of Para-Substituent andAmide Hydroxylation in Sulfonamides . . . . . . . . . . . . . . . . 715.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715.1.1 DFT Calculations . . . . . . . . . . . . . . . . . . . . . . 725.2 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046 Concluding Remarks and Future Directions . . . . . . . . . . . . . 108Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113A Experimental Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124A.1 1H NMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124A.2 ATR-FTIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136A.3 Selected Crystallographic Data . . . . . . . . . . . . . . . . . . 142vB Calculated Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143B.1 DFT Level of Theory Calculations . . . . . . . . . . . . . . . . . 144B.2 Comparison of S K-Edge Spectrum Simulation . . . . . . . . . . 146B.3 DFT Bond Distances for Sulfonamide Compounds . . . . . . . . 158C DFT input files . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160C.1 Selected ORCA Input Files . . . . . . . . . . . . . . . . . . . . . 160viList of Tables4.1 XAS energies of absorption peaks for sulfonamides (a)and N-hydroxy sulfonamides (b). Peak Y arises only withcompounds b and peak X with aryl compounds. Peak Mis the main absorption peak. . . . . . . . . . . . . . . . . . . . . . . 464.2 Hammett constants used in this chapter. p fromreference1 and + and R from reference.2 . . . . . . . . . . . . . . 534.3 Experimental bond lengths and bond angles of 2b, 3b,and 6b. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574.4 Experimental bond lengths of 2a (YIFZAP), 3a (IWEREI),and 6a (XUDTIZ01). . . . . . . . . . . . . . . . . . . . . . . . . . . 604.5 Stretching frequencies for sulfonamides and N-hydroxy sulfonamides. 615.1 Experimental bond distances and angles of 2b,N-hydroxy benzenesulfonamide, from crystal structure,and calculated using BHLYP/def2-TZVP,mPW1PW/def2-TZVP and BP86/TZVP. . . . . . . . . . . . . . . . . 775.2 Experimental bond distances of sulfonamides calculatedusing BP86/TZVP level of theory. . . . . . . . . . . . . . . . . . . . 1005.3 Experimental bond distances N-hydroxy sulfonamidescalculated using BP86/TZVP level of theory. . . . . . . . . . . . . . 100A.1 Selected crystallographic data for compounds 2b, 3b and 6b. . . . . 142B.1 Experimental bond distances of sulfonamides calculatedusing BP86/TZVP level of theory. . . . . . . . . . . . . . . . . . . . 158viiB.2 Experimental bond distances N-hydroxy sulfonamidescalculated using BP86/TZVP level of theory. . . . . . . . . . . . . . 158B.3 Experimental bond distances of sulfonamides calculatedusing BHLYP/Def2-TZVP level of theory. . . . . . . . . . . . . . . . 158B.4 Experimental bond distances N-hydroxy sulfonamidescalculated using BHLYP/Def2-TZVP level of theory. . . . . . . . . . 159B.5 Experimental bond distances of sulfonamides calculatedusing mPW1PW/Def2-TZVP level of theory. . . . . . . . . . . . . . . 159B.6 Experimental bond distances N-hydroxy sulfonamidescalculated using mPW1PW/Def2-TZVP level of theory. . . . . . . . . 159viiiList of Figures1.1 The first sulfonamide antibiotic, prontosil. The activeportion was found to be sulfanilamide. . . . . . . . . . . . . . . . . . 21.2 A pairing of COX-2 inhibitor drugs, celecoxib , Celebrexand rofecoxib, Vioxx.3 Note that rofecoxib lacks asulfonamide functional group. . . . . . . . . . . . . . . . . . . . . . 31.3 Sulfur K-edge XAS data and computational simulation ofsulfur-nitrogen ⇡⇤ character in S-nitrosothiols. reprintedwith permission from.4 Copyright 2008 CanadianScience Publishing or its licensors. . . . . . . . . . . . . . . . . . . 62.1 The incoming photon creates a core hole as the coreelectron is ejected from the 1s orbital. An Auger electronor a fluorescent photon is emitted upon relaxation to fillthe core hole by outer shell electrons. . . . . . . . . . . . . . . . . . 92.2 Bound transitions to empty and partially empty MOs canbe seen in the pre-edge and shoulder while transitions tothe continuum can be seen in edge jump. . . . . . . . . . . . . . . 102.3 X-ray absorption spectrum, shown are the mainabsorption peak with a shoulder and the XANES andEXAFS regions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.4 Experimental setup for transmission and fluorescencesignal detection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.5 Oxidation state changes of sulfur in methionine, reprintedwith permission from.5 Copyright 2009 ACS. . . . . . . . . . . . . . 14ix3.1 The S k-edge XAS spectra of tertbutanesulfinamide (2i),methanesulfonamide (1o), benzenesulfonamide (3o) andpotassium dinitrososulfite (4x). a) Calibrated andnormalized spectra. b) First derivative of all respective spectra. . . . 233.2 Sulfur K-edge XAS spectrum of methanesulfonamide(1o) with simulated S K-edge XAS spectrum overlaid indotted line. The MOs are found along the x-axis as sticks. . . . . . . 243.3 a) Simulated XAS spectrum with MO assignments for thefirst five MOs. b) Energy level diagram ofmethanesulfonamide with assignments and energydensity diagrams. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.4 Methane sulfinated amides, a) Simulated S K-edge XASspectra of 1e, 1i and 1o. b) Energy level diagram of thethree oxidation states of methane sulfinated amide. . . . . . . . . . 283.5 Tertbutanesulfinamide (2i) XAS spectrum and simulatedXAS spectrum overlaid in dotted line with assignmentsfor the first four MOs. The star indicates a feature in theexperimental data which has not yet been explained. . . . . . . . . . 293.6 tert-Butyl sulfinated amides, a) Simulated S K-edge XASspectra of 2e, 2i and 2o. b) Energy level diagram of thethree oxidation states of tert-butyl sulfinated amide. . . . . . . . . . 303.7 Sulfur K-edge XAS spectrum of benzenesulfonamide(3o) with simulated S K-edge XAS spectrum overlaid indotted line. The first seven MOs are found along thebottom as sticks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313.8 Benzene sulfinated amides, a) Simulated S K-edge XASspectra of 3e, 3i and 3o. b) Energy level diagram of thethree oxidation states of benzene sulfinated amide. . . . . . . . . . . 323.9 Example of the equivalent molecular orbitals of the threesulfenamides, sulfur-nitrogen⇤ . . . . . . . . . . . . . . . . . . . . . 343.10 Simulated XAS spectra with similar MOs represented for1e methanesulfenamide (teal), 2e tertbutanesulfenamide(red), and 3e benzenesulfenamide (blue). . . . . . . . . . . . . . . . 35x3.11 Simulated XAS spectra with similar MOs represented for1i methanesulfinamide (teal), 2i (red)tertbutanesulfinamide, and 3i benzenesulfinamide (blue). . . . . . . 363.12 Simulated XAS spectra with similar MOs represented for1o methanesulfonamide (teal), 2o tertbutanesulfonamide(red), and 3o benzenesulfonamide (blue). . . . . . . . . . . . . . . . 374.1 Sulfonamides and N-hydroxysulfonamides investigated inthis chapter and table with shorthand labels. . . . . . . . . . . . . . 434.2 Sulfur K-edge XAS of methanesulfonamide (1a), blackand N-hydroxy methanesulfonamide (1b), red. Theappearance of a new feature at low energy indicates thesignificant impact of the hydroxylation of the amide to thesulfur atom. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444.3 Sulfur K-edge X-ray absorption spectra of a)sulfonamides and b) N-hydroxysulfonamides. The lowestenergy peak is labeled as Y (absent in sulfonamides),the middle energy peak is labeled as X and, the mainabsorption peak will be referred to as peak M. . . . . . . . . . . . . 454.4 Sulfur K-edge X-ray absorption spectrabenzenesulfonamide (2a) andN-hydroxy-p-benzenesulfonamide (2b). 2a displays peakX at 2479.3 eV with the main peak at 2481.4 eV; 2bdisplays peak X at 2478.8 eV with the main peak2481.3 eV, there is an appearance of a new feature, peakY, at 2476.8 eV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.5 Sulfur K-edge X-ray absorption spectrap-methoxybenzene sulfonamide (3a) andN-hydroxy-p-methoxybenzene sulfonamide (3b). 3adisplays peak X at 2479.3 eV with the main peak at2481.2 eV; 3b displays peak X at 2478.9 eV with peak Mat 2481.4 eV, peak Y is seen at 2477.1 eV. . . . . . . . . . . . . . . 47xi4.6 Sulfur K-edge X-ray absorption spectratoluenesulfonamide (4a) andN-hydroxy-p-toluenesulfonamide (4b). 4a displays peakX at 2479.3 eV with the main peak at 2481.6 eV; 4bdisplays peak X at 2478.9 eV with the main peak2481.5 eV, a low intenstiy peak Y is seen at 2476.9 eV. . . . . . . . 474.7 Sulfur K-edge X-ray absorption spectra p-chlorobenzensulfonamide (5a) and N-hydroxy-p-chlorobenzenesulfonamide (5b). 5a exhibits peak X at 2479.3 eV withpeak M at 2481.4 eV; 5b exhibits peak X at 2478.8 eVwith the main peak 2481.4 eV, peak Y is too small to distinguish. . . 484.8 Sulfur K-edge X-ray absorption spectra p-nitrobenzenesulfonamide (6a) and N-hydroxy-p-nitrobenzenesulfonamide (6b). 6a exhibits peak X at 2478.7 eV withthe main peak at 2481.1 eV; 6b exhibits peak X at2478.6 eV with peak M at 2481.3 eV, peak Y is seen at 2477.2 eV. . 484.9 NOHS sulfonamides with para electron donating groups.1b and 2b are included for reference. . . . . . . . . . . . . . . . . . 504.10 NOHS sulfonamides with para electron withdrawinggroups. 1b and 2b are included for reference. . . . . . . . . . . . . . 514.11 1H NMR chemical shift of amide protons versus Hammettp constants, in DMSO. a) Sulfonamide NH2 chemicalshifts (? ? ?). b) N-hydroxy sulfonamide protons: OHproton (⌥ ⌥ ⌥); NH proton (⌥ ⌥ ⌥). . . . . . . . . . . . . . 564.12 Crystal structures of: a) 2b, b) 3b, and c) 6b. . . . . . . . . . . . . . 574.13 Hammett plots of NOHS bond lengths. a) S-N bonddistances vs. p,+,R , b) N-O bond distances vs.p,+,R . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584.14 Hammett plot of ⌫ (SN) vs. p,+,R . . . . . . . . . . . . . . . . . 624.15 Hammett plot of intensities of low energy feature, atapproximately 2477eV, found in N-hydroxysulfonamideXAS spectra vs. p,+,R . . . . . . . . . . . . . . . . . . . . . . . 64xii5.1 BP86/TZVP simulation of experimental S K-edge XASspectum of N-hydroxy methanesulfonamide . . . . . . . . . . . . . . 745.2 BP86/TZVP simulation of experimental S K-edge XASspectum of N-hydroxy benzenesulfonamide. . . . . . . . . . . . . . 755.3 Difference of averaged bond lengths by functional. TheSN, SC and both SO bond distances for each functionalwere averaged and subtracted from the bond lengthsfound using crystallography. Bond distances usingmPW1PW and BHLYP underestimated the experimentalbond lengths while the other functionals overestimated. . . . . . . . 765.4 Difference of bond length, in angstrom, between thefunctional and the crystallographic data, for each bondlength associated with the sulfur and nitrogen atoms inthe sulfonamide moiety. . . . . . . . . . . . . . . . . . . . . . . . . . 765.5 BHLYP/def2-TZVP simulation of experimental S K-edgeXAS spectum of methanesulfonamide. . . . . . . . . . . . . . . . . 795.6 mPW1PW/def2-TZVP simulation of experimental SK-edge XAS spectum of methanesulfonamide. . . . . . . . . . . . . 805.7 BHLYP/def2-TZVP simulation of experimental S K-edgeXAS spectum of N-hydroxy methanesulfonamide. . . . . . . . . . . 815.8 mPW1PW/def2-TZVP simulation of experimental SK-edge XAS spectum of N-hydroxy methanesulfonamide. . . . . . . 825.9 BHLYP/def2-TZVP simulation of experimental S K-edgeXAS spectum of benzenesulfonamide. . . . . . . . . . . . . . . . . 845.10 mPW1PW/def2-TZVP simulation of experimental SK-edge XAS spectum of benzenesulfonamide. . . . . . . . . . . . . 855.11 BHLYP/def2-TZVP simulation of experimental S K-edgeXAS spectum of N-hydroxy benzenesulfonamide. . . . . . . . . . . . 875.12 mPW1PW/def2-TZVP simulation of experimental SK-edge XAS spectum of N-hydroxy benzenesulfonamide. . . . . . . 885.13 MOs for 2b, with energy density diagrams for the MOswhich may designate the shoulder for each functional:BP86, BHLYP and mPW1PW, as a sulfur-nitrogen interaction. . . . . 89xiii5.14 Experimental spectrum of p-Methoxybenzenesulfonamide (3a), in red, calculated XAS 3a spectra indashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905.15 Experimental spectrum of N-hydroxy p-methoxybenzenesulfonamide (3b), in red, calculated 3b XAS spectra indashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.16 Experimental spectrum of p-Toluenebenzenesulfonamide (4a), in red, and calculated 4a XAS spectrain dashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.17 Experimental spectrum of N-hydroxy p-toluenebenzenesulfonamide (4b), in red, and calculated 4b XAS spectrain dashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . 935.18 Experimental spectrum of p-Chlorobenzene sulfonamide(5a), in red, and calculated 5a XAS spectra in dashed blue line. . . . 945.19 Experimental spectrum of N-hydroxy p-chlorobenzenesulfonamide (5b), in red, and calculated 5b XAS spectrain dashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . 955.20 Experimental spectrum of p-Nitrobenzene sulfonamide(6a), in red, and calculated 6a XAS spectra in dashed blue line. . . . 965.21 Experimental spectrum of N-hydroxy p-nitrobenzenesulfonamide (6b), in red, and calculated 6b XAS spectrain dashed blue line. . . . . . . . . . . . . . . . . . . . . . . . . . . . 975.22 MOs for 4b, with energy density diagrams for the MOswhich may designate the shoulder for each functional:BP86, BHLYP and mPW1PW, as a sulfur-nitrogen interaction. . . . . 985.23 MOs for 5b, with energy density diagrams for the MOswhich may designate the shoulder for each functional:BP86, BHLYP and mPW1PW, as a sulfur-nitrogen interaction. . . . . 995.24 Hammett plots of sulfur-carbon bond lengths calculatedat the BP86/TZVP vs. p,+,R . . . . . . . . . . . . . . . . . . . . 1015.25 Hammett plots of sulfur-nitrogen bond lengths calculatedat the BP86/TZVP vs. p,+,R . . . . . . . . . . . . . . . . . . . . 102xiv5.26 Hammett plots of nitrogen-oxygen bond lengths at theBP86/TZVP level of N-Hydroxy sulfonamides vs. p,+,R . . . . . . 1035.27 BHLYP/def2-TZVP XAS spectra. . . . . . . . . . . . . . . . . . . . . 1065.28 mPW1PW/def2-TZVP XAS spectra. . . . . . . . . . . . . . . . . . . 1076.1 Amide substitutions and S K-edge XAS spectra ofBenzenesulfonamide (—), N-CH3 Benzenesulfonamide(– –), N-Ph Benzenesulfonamide (– –), N-OHBenzenesulfonamide (—) and N-OCH3Benzenesulfonamide (—). . . . . . . . . . . . . . . . . . . . . . . . 111A.1 1H NMR spectrum of methanesulfonamide (1a) . . . . . . . . . . . . 124A.2 1H NMR spectrum of N-hydroxy methanesulfonamide (1b) . . . . . . 125A.3 1H NMR spectrum of benzenesulfonamide (2a) . . . . . . . . . . . . 126A.4 1H NMR spectrum of N-hydroxy benzenesulfonamide (2b) . . . . . . 127A.5 1H NMR spectrum of p-methoxybenzene sulfonamide (3a) . . . . . . 128A.6 1H NMR spectrum of N-hydroxyp-methoxybenzenesulfonamide (3b) . . . . . . . . . . . . . . . . . . 129A.7 1H NMR spectrum of p-toluene sulfonamide (4a) . . . . . . . . . . . 130A.8 1HNMR spectrum of N-hydroxy p-toluene sulfonamide (4b) . . . . . 131A.9 1H NMR spectrum of p-chlorobenzene sulfonamide (5a) . . . . . . . 132A.10 1H NMR spectrum of N-hydroxy p-chlorobenzenesulfonamide (5b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133A.11 1H NMR spectrum of p-nitrobenzene sulfonamide (6a) . . . . . . . . 134A.12 1H NMR spectrum of N-hydroxy p-nitrobenzenesulfonamide (6b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135A.13 IR spectra of methanesulfonamide (blue) and N-hydroxymethanesulfonamide (red). . . . . . . . . . . . . . . . . . . . . . . . 136A.14 IR spectra of benzenesulfonamide (blue) and N-hydroxybenzenesulfonamide (red). . . . . . . . . . . . . . . . . . . . . . . . 137A.15 IR spectra of p-methoxybenzenesulfonamide (blue) andN-hydroxy p-methoxybenzenesulfonamide (red). . . . . . . . . . . . 138xvA.16 IR spectra of toluenesulfonamide (blue) and N-hydroxytoluenesulfonamide (red). . . . . . . . . . . . . . . . . . . . . . . . 139A.17 IR spectra of p-chlorobenzenesulfonamide (blue) andN-hydroxy p-chlorobenzenesulfonamide (red). . . . . . . . . . . . . 140A.18 IR spectra of p-nitrobenzenesulfonamide (blue) andN-hydroxy p-nitrobenzenesulfonamide (red). . . . . . . . . . . . . . 141B.1 Calculated bond lengths of N-hydroxybenzenesulfonamide using sundry functionals and basis sets. . . . . 144B.2 Calculated bond lengths of N-hydroxybenzenesulfonamide using relativistic effects (ZORA) inconjunction to sundry functionals and basis sets. . . . . . . . . . . . 145B.3 Comparison of methane sulfonamide experimental datawith calculated data; BP86, BHLYP, and mPW1PW . . . . . . . . . . 146B.4 Comparison of NOH- methane sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW . . . . . . . 147B.5 Comparison of benzene sulfonamide experimental datawith calculated data; BP86, BHLYP, and mPW1PW . . . . . . . . . . 148B.6 Comparison of NOH- benzenesulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW . . . . . . . 149B.7 Comparison of p- methoxybenzene sulfonamideexperimental data with calculated data; BP86, BHLYP,and mPW1PW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150B.8 Comparison of NOH-p- methoxybenzene sulfonamideexperimental data with calculated data; BP86, BHLYP,and mPW1PW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151B.9 Comparison of toluene sulfonamide experimental datawith calculated data; BP86, BHLYP, and mPW1PW . . . . . . . . . . 152B.10 Comparison of NOH-toluene sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW . . . . . . . 153B.11 Comparison of p-chlorobenzene sulfonamideexperimental data with calculated data; BP86, BHLYP,and mPW1PW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154xviB.12 Comparison of NOH-p- chlorobenzene sulfonamideexperimental data with calculated data; BP86, BHLYP,and mPW1PW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155B.13 Comparison of p- nitrobenzene sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW . . . . . . . 156B.14 Comparison of NOH-p- nitrobenzene sulfonamideexperimental data with calculated data; BP86, BHLYP,and mPW1PW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157xviiList of Schemes3.1 A library of sulfinated amides . . . . . . . . . . . . . . . . . . . . 203.2 Representative compounds selected for XAS analysis. . . . . . . 213.3 Expected resonance structures with the substitutionof an aromatic R-group for sulfinated amides, a)sulfinamides and b) sulfonamides. . . . . . . . . . . . . . . . . . 384.1 Lewis diagrams of sulfonamides with EWG and EDGgroups. Aniline is shown as a comparison. . . . . . . . . . . . . 664.2 Inductions effects of N-hydroxy sulfonamide withEWG and EDG. . . . . . . . . . . . . . . . . . . . . . . . . . . . 66xviiiAcknowledgmentsFirst, I would like to thank Pierre for welcoming me into his group and allowingme to embrace the Wild West spirit to go out there and explore. I’ve learned somuch in the past 5 years, I never expected I’d turn out a real chemist! To myco-supervisor Keng, thank you for always being there when I needed an extralarge brain to figure things out; your advice is priceless. I only wish we couldhave done more work together!To my lab mates, obviously I couldn’t have functioned without you! Wei,our love of food, makeup and clothes has bonded us for life. Thamy, your softspoken patience has been an important part of keeping the sanity in our lab.Insun, your inorganic mind is giant and you helped me learn a whole new side tochemistry. Mario, Anusha, Danielle and Vlad, thank you for paving the path forthe next generation of PK students. To the new additions in our group, Chantaland Shirin, it has been lovely getting to know you. I’ve made so many wonderfulfriends in grad school, you are too many to name but you know who you are,thank you for being there for me and reminding me that ethanol is always asolution. Special thanks to Jen, Amanda and Maria for reading chapters of thisthesis. The Tiki Lounge awaits us.Thanks to the staff at SSRL and CLS, especially Yongfeng at SXRMB, I amgrateful for all your help. Thanks to Brian Patrick for help with crystallographyand Anita Lam for help with the powder diffraction experiments. To the NMRand Mass Spec crew, thank you for helping me with these finicky sulfonamides.I’m sure I owe thanks to many others not listed, please forgive me, I mean well.My deepest gratitude goes to my family, I know I would not have gotten thisfar without your support. Mom, more than anyone else, this is for you. If I growxixup to be half the woman you are, then I will have succeeded in life. Baba, banaverdig˘in hers¸ey için kalbimden tes¸ekkür ederim. My dearest sister, Jasmine,thank you for being the best sister ever, your encouragement means the worldto me. A mi Nani, te quiero mucho. Aunt Dora and Uncle Jan, I finally finished!To the Hoffmans, thank you for being a constant comfort.Finally, I would like to thank the love of my life, Matthew. You’ve alwaysbeen there for me and you help me strive to do my best, even when it drivesme crazy. You are my rock and without you, life and chemistry would be boring;so it is to you I am most grateful. I couldn’t have done it without you.xxChapter 1IntroductionIn the early 1930’s, sulfonamides became a very important class of antibiotics,now known as sulfa drugs. The first of these antibiotics was the dye prontosil,Figure Figure 1.1; the discovery of its antibacterial effect was revolutionary6and earned Gerhard Domagk the 1939 Nobel prize in physiology or medicine.7Prontosil went on to save many lives, and an account in 1936 at VancouverGeneral Hospital8 recounts a trial of a young girl with streptococcal meningitis,“December 22nd — The patient was very irritable and objected tobeing moved. Stiffness of the neck was pronounced. Kernig’s testwas very definitive. ”After the administration of intravenous prontosil,“ December 25th— The patient was very much improved....She feltso well that she sat up and ate a small Christmas dinner of turkey.”8The active portion of prontosil was found to be sulfaniliamide.9 The biologicaleffect of prontosil is generated by competition for p-aminobenzoic acid whichis involved in the synthesis of folate in bacterial cells, but not in human cells,where it is acquired by diet.10,11Today, sulfonamides are found as integral parts of antiviral and anticancerdrugs like Novartis’s LG8X18 (Encorafenib)12 which is an enzyme inhibitor for1Figure 1.1: The first sulfonamide antibiotic, prontosil. The active portionwas found to be sulfanilamide.the treatment of melanoma. Others, like acetazolamide (Diamox)13 and brin-zolamide (Azopt),14 are carbonic anhydrase inhibitors,15,16 used in the treat-ment of epileptic seizures, glaucoma, and macular edema. Sulfonamides arealso found in COX-2 inhibitors17 which are used as anti-inflammatory drugs.The sulfonamide moiety can impart properties not achieved with other func-tional groups, like sulfonyls or carboxamides. For example, the many facetedceleboxib, known on the market as Celebrex, is both a COX-2 and carbonicanhydrase (CA) inhibitor;3,18 an analogous COX-2 inhibitor, the drug rofecoxib(Vioxx), has a methyl sulfone moiety instead,3 and cannot confer CA inhibition,Figure Figure 1.2.The ability to manipulate the sulfur-nitrogen bond in sulfonamides are criti-cal in the release of NO and/or HNO. Studies have shown NO and/or HNO is re-leased by compounds like Angeli’s Salt (Na2N2O3), acyl nitroso containing com-pounds RCONO,19 and—more importantly to this thesis—sulfur-nitrogen bondcontaining compounds such as S-nitrosothiols RSNO20 and sulfonamides. Ni-tric oxide (NO) is a known signaling molecule involved in biochemical, cell bi-ological and physiological processes. Robert F. Furchgott, Ferid Murad andLouis Ignarro earned the Nobel Prize in Physiology or Medicine in 1998 fortheir independent study of the metabolic pathway of nitric oxide in smooth mus-cle vasodilation.21–24 Fukuto and colleagues have reported the closely relatedazanone (HNO) to also elicit vasorelaxation in vivo.25 While very similar, NOand HNO have distinct biochemical pathways of inducing activity in the body;HNO induces venous vasodilation, whereas NO results in arterial vasodila-2Figure 1.2: A pairing of COX-2 inhibitor drugs, celecoxib , Celebrex androfecoxib, Vioxx.3 Note that rofecoxib lacks a sulfonamidefunctional group.tion.26 It has been shown by Miranda et al. that HNO has a longer oxidationlifetime than NO and as such would greatly influence biological effects.27 Bon-ner et al. suggest that N-hydroxy benzenesulfonamide, also known as Piloty’sacid, can release HNO28 and it has been subsequently shown that N-hydroxybenzenesulfonamide derivatives will release azanone at physiological pHs.29Sulfonamides are also advantageous in that its pharmological effects can bemodified via structural changes to the sulfonamide moiety.30 Commonly usedNO/HNO releasing drugs (either directly or via an NO/HNO cascade) are theanti-migraine sumatriptan (Imitrex),31 the anti-hypertensive Indapamide (Lo-zol)32 and the popular muscle relaxer sildenafil (Viagra).33Yet, while we know these molecules play roles in these important pro-cesses, what their reactivities are and how they elicit biological responses re-mains unclear. As a functional group, sulfonamide reactivities have been shownto be very different from structurally similar functional groups. For example, theyare much less electron-withdrawing than their corresponding sulfonate esters,carbonyls or amides. The NH acidities of sulfonamides, pKa 8, are higher3than corresponding amides, pKa 15, but CH acidities are lower than carbonylswhich can make them quite favorable for use in synthesis as protecting groupsdue to the ease of deprotonation in mildly basic environments.10Transmission effects through the sulfur-nitrogen bond have long been ofinterest and have been studied using a variety of techniques. The nature ofthe sulfur-nitrogen bond and its  and/or ⇡ character has been much debated.For example, Raban et al. have shown, using NMR, that sulfenamides (RSNH2)have large rotational barriers which are attributed to nitrogen-sulfur p-d ⇡ bond-ing. As the sulfur undergoes oxidation to sulfinamide and then to sulfonamidethe rotational barrier energy decreases, decreasing the sulfur-nitrogen ⇡ char-acter.34 Yet, according to Lyapkalo et al. N,N-diisopropylnonafluorobutane-1-sulfonamide does exhibit a substantial rotational barrier.35 This is attributedto appreciable sulfur-nitrogen double bond character via p⇡d⇡ bonding due tothe electron-withdrawing effect of the perfluorobutyl substituent. Similarly, Crichand colleagues also found evidence for a rotational barrier in the SN bond insubstituted hexahydropyrrolo inodoles, where an electron donating substituentwill reduce this barrier and electron withdrawing groups will increase the it, in-creasing the sulfur-nitrogen ⇡ bond character.36Other studies have debated the role of sulfur d orbitals and its affect ontransmission through the sulfur-nitrogen bond. NMR studies of arylsulfonamideshave indicated little conjugation involving the arylsulfonamide sulfur d orbitalsand the phenyl p orbitals when an electron donating substituent is present,but larger overlap between the sulfur-nitrogen (p⇡d⇡).37 However, Reed et al.have shown that SN ⇡ bonding occurs not through the involvement of sulfur d-orbitals but through negative hyperconjugation in 32-valence-electron-speciesof X3AY (O3ClF, F3SN, CF4, etc.)38 This is further supported by sulfur K-edgeXAS data and computational work on sulfonyl chlorides which describes hyper-conjugation via mixing of the aryl ⇡-system into the SCl⇤ orbital .39The complex and puzzling nature of the sulfonamide molecule continues inthe measured dipole moments of sulfonamides, which are larger than theoret-ical calculations would suggest.40 This has been interpreted as evidence thatgreater separation of charge will contribute to the stability of the molecule .40Electron-donating phenyl groups were shown to stabilize the sulfonamide more4than electron-withdrawing groups by forming a CS resonance structure witha positive sulfonamide sulfur and a weakened SN. Conversely, electron with-drawing groups strengthen the SN bond and can form a SN double bond.40X-ray crystallography supports this with a trend of SN bond lengths increasingwith electron donating R-groups.41 Again, these data further suggest that mod-ifications of the sulfonamide moiety can manipulate the sulfur-nitrogen bondwhich can be directed toward drug design.Studies on related SN containing molecules, S-nitrosothiols (RSNO), haveprovided interesting insight on the nature of the sulfur-nitrogen bond. X-ray ab-sorption spectroscopy (XAS) of primary and tertiary RSNOs have been shownto exhibit sulfur-nitrogen ⇡⇤ contribution.4,42 In the spectra of these primary andtertiary RNSOs, Figure Figure 1.3, the low energy shoulder has been assignedto the S1s to SN⇡⇤ which is supported by DFT simulations. Significant elec-tron donation from R-groups in tertiary RSNOs lead to a lowering of Zeff whilethe opposite is true in primary RSNOs. This is further bolstered by theoreticalwork done by Timerghazin et al. where a S=N resonance structure is shown toplay an important role in the stabilization of RSNOs.43 Herein, similar methodswill be applied to investigate the stability of the sulfur-nitrogen bond in sulfon-amides, which may orchestrate NO/HNO release.In this thesis, a systematic study of the sulfur-nitrogen bond within sulfon-amides is undertaken so as to understand how the electronic distribution ofsulfinated amides will affect the nature and strength of this bond; particularfocus on the nature of the sulfur-nitrogen bond is important for both the re-lease of azanone as well as structural modifications to the sulfonamide moi-ety and its ramifications on functionality in enzyme inhibition. In Chapter two,an overview of x-ray absorption spectroscopy, sulfur K-edge spectroscopy anddensity functional theory is given. Chapter three introduces systematic modifi-cations to the sulfonamide moiety through the addition of oxygen to the sulfuratom and modifications to the R-group, and how these effect the sulfur-nitrogenbond. In Chapter four, the synthesis of a range of Hammett1 para-substitutedN-hydroxy sulfonamides is discussed and compared to the parent sulfonamidevia structure-function relationships using NMR, IR, crystallography and XAS.The contribution of the electron-withdrawing and electron-donating nature per5(a) S K-edge spectra of (A) S-nitroso- glutathione (dashed), (B) S-nitroso-N-acetylpenicillamine (solid), (C) trityl thionitrite (dotted), and (D) second derivativeof XAS spectra.(b) TD-DFT calculation of S-nitrosothiol, ethyl-S-nitrosothiol.Figure 1.3: Sulfur K-edge XAS data and computational simulation ofsulfur-nitrogen ⇡⇤ character in S-nitrosothiols. reprinted withpermission from.4 Copyright 2008 Canadian Science Publish-ing or its licensors.6substituent to the overall electronic structure is discussed. Chapter five fur-ther delves into a detailed computational assessment and assignment of theXAS transitions for the sulfonamide compounds studied in Chapter four. Fi-nally, Chapter six summarizes the findings of this thesis and future directionsare discussed.7Chapter 2X-Ray AbsorptionSpectroscopy and DensityFunctional Theory2.1 X-Ray Absorption Spectroscopy (XAS)When an x-ray of energy equal to or greater than the binding energy of a coreelectron is absorbed by an atom, that electron is excited. This excitation pro-motes the ejection of an electron with the energy of the incoming photon minusthe electron-binding energy:44Eexcited = ~ !  Ecore (2.1)where ! is the incoming photon’s energy and Ecore the binding energy of ex-cited core level. The ejected electron, in turn, creates a core hole, which isfilled by the relaxation of outer shell electrons. This relaxation can occur radia-tively or non-radiatively, Figure Figure 2.1, releasing a photon or an electron,respectively. The shell and subshell from which the excited electron originateslends its name to the edge: K edge = 1s; L1 edge = 2s, L2 edge = 2p1/2, L3= 2p3/2, et cetera. The energy of the ejected core electron is characteristic ofthe emitting atom.45 As a result, XAS is an element specific technique, with8well defined binding energies for neighboring atoms. For example, the sulfur1s binding energy is 2472 eV, phosphorous 1s is 2145.5 eV and chlorine 1s is2822.4 eV.46Figure 2.1: The incoming photon creates a core hole as the core electronis ejected from the 1s orbital. An Auger electron or a fluores-cent photon is emitted upon relaxation to fill the core hole byouter shell electrons.X-ray absorption spectroscopy (XAS) involves the excitation of core elec-trons into empty (or partially-empty) bound electronic states, or ionized into thecontinuum as shown in Figure Figure 2.2. The XAS spectrum contains a largeabsorption called the ‘edge jump‘, or ‘white line’, which denotes the ionizationof the core electron to the continuum.The generated XAS spectrum may be split into two regions: the x-ray ab-9Figure 2.2: Bound transitions to empty and partially empty MOs can beseen in the pre-edge and shoulder while transitions to the con-tinuum can be seen in edge jump.sorption near-edge structure (XANES) and the extended fine structure (EX-AFS). The near-edge region begins several eV below the edge jump to 30-50eV past it, while, EXAFS begins at the end of the XANES region to well pastthe white line.47,48 The near edge region arises from bound transitions whichare dominated by electric dipole allowed transitions of ` = ±1 (where ` isthe orbital quantum number) to vacant antibonding molecular orbitals with pcharacter, 1s np .49,50 As the XAS spectrum reflects atoms directly involvedin bonding interactions, the XANES region is very sensitive to oxidation statesand geometries and is a direct probe of covalency.51–53 The intensity of the10transition is dependent on the probability of the transition from the initial stateto the final state based on Fermi’s golden rule.54At energies above the edge are oscillatory structures that correspond to theEXAFS. Here, the electron now possesses kinetic energy above the ionizationthreshold and can interact with its nearest neighbor atoms. These scattering in-teractions lead to constructive and deconstructive interference which correlatesto the local geometry of the absorbing atom and can be used to determine in-teratomic distances and coordination numbers.55,56Figure 2.3: X-ray absorption spectrum, shown are the main absorptionpeak with a shoulder and the XANES and EXAFS regions.Detection of the XAS signal is often achieved in transmission mode. Theintensity of the incoming beam is measured before (Io) and after (I) the sample,as per equation 2.2.Transmittance =✓IIo◆(2.2)The absorbance is dependent on the concentration (c), the molar absorptivity(✏) and pathlength (b) in accordance with Beer’s Law, A = ✏bc. In the case ofa solid sample, as is commonly used at beamlines, the sample thickness (x) is11used in place of pathlength, as in equation 2.3.I = Ioeµx (2.3)Fluorescence detection is also utilized, commonly concurrently with trans-mission detection. The cross-section of fluorescence emission is proportionalto the absorbance. Fluorescence detection can, however, experience satura-tion of the signal if the sample is not dilute as all incoming x-rays that interactwith the sample can contribute to the fluorescence signal. If the sample is tooconcentrated or thick, signal saturation or self-absorption will occur. This self-absorption will decrease and distort signal intensities.47 Total electron yielddetection (TEY) can also be used in conjunction with fluorescence. TEY de-tects all emitted Auger and secondary electrons and has a shallow penetrationdepth which allows for surface analysis and in turn is not susceptible to self-absorption due to thick samples.56,57 In this thesis both fluorescence and TEYXAS data were collected.Figure 2.4: Experimental setup for transmission and fluorescence signaldetection.122.1.1 Sulfur K-Edge X-Ray Absorption Near Edge Structure(XANES)XANES is a particularly useful technique in the study of sulfur containing com-pounds. Sulfur can be a difficult element to study spectroscopically which haslead to its characterization as a ‘spectroscopically silent’ element.48 Insight viaNMR is insufficient due to the absence of 32S nuclear spin; and the use of 33Sis curbed by the expense along with the weak and broad signals obtained. Thisalso means that compounds must be modified and cannot be tested in situ.EPR can also be very useful but only when the sulfur species has an unpairedelectron.S K-edge XAS permits a unique perspective of bonding from the viewpointof the sulfur atom; as absorption occurs from the S 1s core orbital to elec-tric dipole-allowed bound transitions to np molecular orbitals. These are an-tibonding molecular orbitals which are localized around the sulfur and havesubstantial sulfur 3p character. As these MOs are directly involved in bondinginteractions, S K-edge XAS reflects sulfur bonding, and as such are sensitiveto oxidation states and geometries. The sulfur K-edge XAS is advantageousdue to its large span in chemical shift through a range of sulfur oxidation states,Figure Figure 2.5.It has been shown through metal-ligand XAS using metal tetrathiolates thatpre-edges are a direct probe of sulfur covalency.51,58 Since the transitions fromS1s are localized on the ligand, in this case a thiolate, absorption intensity canonly occur if the receiving MO has substantial sulfur 3p character. This ligand3p character, hence, is the result of covalency. As per Hedman et al.:I(S1s !  ⇤) = ↵02I(S1s ! 3p) (2.4)Where I is the intensity of the transition,  ⇤ the transition from 1s to np orbitaland ↵02 represents the amount of sulfur 3p character in the MO.The uncertainty in the pre-edge features are limited by the instrumentalresolution of approximately 0.1eV. The spectra also exhibit relatively sharplinewidths due to the longer core-hole lifetime of the sulfur 1s excitation en-ergy, Et =12~. S K-edge XAS is also an excellent tool for in situ use, as13all manner of sample: amorphous, crystalline, liquid or solution can be tested.Figure 2.5: Oxidation state changes of sulfur in methionine, reprinted withpermission from.5 Copyright 2009 ACS.2.1.2 Experimental SetupSulfur K-edge XAS data were acquired at both Stanford Synchrotron Radia-tion Lightsource (SSRL) and Canadian Light Source (CLS). Fluorescence datawere collected at beamline 4-3 at the Stanford Synchrotron Radiation Light-source (SSRL) under ring conditions of 3GeV and 200-500mA. Solid sampleswere ground finely with 50% boron nitride, to minimize self-absorption, andmounted as a thin layer on sulfur-free Kapton tape at room temperature. Flu-orescence data were acquired using solid state detector at ambient temper-ature and pressure. Energy calibration was carried out using sodium thiosul-fate (Na2S2O3) with the first pre-edge feature being calibrated at 2472.02 eV.59Resolution of incoming beam was approximately 0.1eV. Total electron yield datawere acquired at beamline SXRMB at the CLS under ring conditions of 3 GeVand 180-250mA. Solid samples were ground finely with 50% boron nitride andmounted onto a copper sample holder with carbon tape. Total electron yielddata were acquired under vacuum at ambient temperature. Calibrations wereperformed as above.142.1.3 Data AnalysisRaw data were normalized to incoming beam (Io), calibrated to the first thiosul-fate peak and scans averaged with the Matlab program BlueprintXAS60 pre-fitfunction. Due to sulfur photo-reduction in the fluorescence data, only the firstscans of each run were used for tertbutanesulfinamide and potassium dini-trososulfite in Chapter 3. As TEY does not exhibit such photo-reduction, allscans per run of the rest of the sulfonamide compounds in this thesis wereaveraged for greater signal-to-noise ratio. Background subtraction and normal-ization (where the pre-edge slope is equated to zero and the post-edge to 1) ofthe spectra were achieved using BlueprintXAS.61 For background subtractionand normalization a pre-edge and post-edge slope were estimated and pseudo-Voight peak components added until all peaks in the spectra were represented.Model selection employing the Akaike information criterion (AIC) 62,63 was usedto estimate the optimum number of peaks needed to fit the spectrum properly.The model, for example a 3-peak model versus a 4-peak model, with the low-est AIC was chosen for fitting all spectra. Each parameter input by the useris bound by upper and lower limits; fits were achieved via Monte Carlo basedsearch, chosen from the bounds provided by the user. Fits with smallest sumof squared errors were chosen for background subtraction and normalizationwhich lead to the data shown in this thesis. Energies reported in this thesiswere determined from the inflection point of the first derivative of the spectrumin question.2.2 Density Functional TheoryDensity functional theory (DFT) is commonly used in conjunction with XAS todescribe and model the spectra that are acquired during experimentation. DFTis based on the electron probability density function of a molecule, replacingthe wavefunction based methods of Hartree-Fock and ab initio calculations.The electron density of a molecule is a function only of its position, ⇢(x , y , z).Unlike the wavefunction, electron density is an experimental observable which15can be measured with methods like x-ray diffraction or x-ray fluorescence.64,65DFT stems from Hohenberg and Kohn’s two theorems.66 The first the-orem states that the ground state electron density ⇢(x , y , z) determines allground-state properties.67 Any ground state property is a functional of theof this electron density function; for example the energy would be given asEo = F [⇢o] = E [⇢o].64The second theorem states that the functional F [⇢o] will yield the lowestenergy if and only if the density used is the true ground state electron density.This is DFT equivalent of the wavefunction variation theorem and puts an upperboundary on the true energy.The theorems of Hohenberg and Kohn do not go on to explain how to findthe functional F [⇢o]. Kohn and Sham however, proceed to give us a procedurewhereupon the known quantities can be found with explicit functions and thefunctional can be approximated. In the Kohn-Sham equations, the electronicenergy of the molecule is separated into a portion which can be calculatedaccurately without DFT plus a small term which contains the functional.64 Thefirst term of equation 2.5 integrates the potential energy of each nucleus and⇢o; the second, the non-interacting electrons’ kinetic energy; the third term theelectrostatic repulsion. The only unknown is the electron-electron interactions;the functional of F [⇢o], which is conveniently combined into the final term.E0 =XAZAZ⇢0(r1)r1Adr1122nXi=1h KS1 (1) | r21 |  KS1 (1)i+12ZZ⇢0(r1)⇢0(r2)r12dr1dr2+ EXC [⇢0] (2.5)This equation is exact, so if ⇢0(r1) and the exchange-correlation were known,the exact energy would be found. Since this currently cannot be achieved, ap-proximations are used to improve this exchange-correlation.64 One is the local16density approximation (LDA), in which a uniform electron gas is used a model.65Another is the generalized gradient approximation (GGA) which adds the gra-dient of the charge density to the LDA. Hybrid functionals, a newer approach,add Hartree-Fock exchange to the EXC [⇢0] term of the energy equation.67Basis sets are used to describe atomic orbitals and, by extension, molecularorbitals. A basis set is the linear combination of atomic orbitals to approximatemolecular orbitals. The simplest basis sets consist of only p atomic orbials, likethe simple Hückel basis set. Other basis sets can add polarization functions,allowing the electron density to distort from its ideal symmetry, or diffuse func-tions allowing orbitals to extend in space.64 There are a variety of basis setsthat can be used depending on the molecular system and computational timeframe needed.2.2.1 Theoretical Simulations of XAS DataDFT is to used simulate and model the XAS spectrum of a molecule. XASspectra are excited state spectra and DFT are ground state calculations, sowe must find a way to describe the excited state. This is done by adoptingtime-dependent density functional theory (TD-DFT) to yield the transition en-ergy instead of the excited state energy.67 According to DeBeer and Neese,“one solves the time-dependent linear response equations in the subspace ofparticle-hole pairs that only correspond to excitations from the sulfur 1s-coreorbitals into the empty valence spin-orbitals”.68 This procedure yields error inthe absolute energies, but the relative energies are reproducible and system-atic. Shifting the calculated spectrum a set number of electron-volts, which isdependent on the functional used, leads to proper alignment with experimentaldata; for example BP86 calculated spectra are shifted +76 eV while B3LYP areshifted by 55eV.All calculations within this thesis were performed using the ORCA quantumchemistry program.69 DFT calculations were run with spin-unrestricted Kohn-Sham equations. A variety of functionals and basis were used and will bestated in detail in the following chapters. Relativistic effects (ZORA) were notemployed as the sulfur atom is not a particularly heavy atom and the inclusion of17ZORA did not alter the spectra while requiring more computational time. Geom-etry optimizations were performed and vibrational frequency calculations wereattained using NUMFREQ. Fully optimized geometries showed only positivefrequencies indicating a local minimum was obtained. Single point calculationsfor the excited state spectra were implemented using XES excitation from thesulfur core orbital.18Chapter 3The Effect of Oxidation onSulfur-Nitrogen Molecules3.1 IntroductionThe sulfonamide moiety has been an important motif in many biologically activecompounds and plays a key role in the efficacy of sulfa drugs.10 Sulfonamidesare also found in vivo where they can act as enzyme inhibitors16 and are alsoused in organic synthesis as chiral building blocks70 and protecting groups.71As shown in the introduction, previous work on thioethers and S-nitrosothiols4,5demonstrate that XAS can be a useful tool for the exploration of sulfur contain-ing compounds. Sulfonamides, which consist of similar structural aspects tothioethers and S-nitrosothiols, will undergo analogous XAS analysis and com-parison to DFT calculations.In this chapter, systematic modifications to the R-group and changes to theoxidation states of the sulfur atom will afford a chance at characterizing thisframework, RS(O)nNH2, see Scheme Scheme 3.1. Three oxidation statesof methyl, benzyl and tert-butyl sulfinated amides will be studied: methanesul-fenamide (1e), methanesulfinamide (1i), methanesulfonamide (1o); tertbutane-sulfenamide (2e), tertbutanesulfinamide (2i), tertbutanesulfonamide (2o); ben-19zenesulfenamide (3e), benzenesulfinamide (3i), benzenesulfonamide (3o).1 Potas-sium dinitrososulfite (4x) is used as a representative for a sulfinate compound.R S(O)nH2N R = methyl, tertbutyl and phenyln = 0, 1, 2H3C S NH2 H3C S NH2O H3C S NH2OOS NH2S NH2 S NH2O S NH2OOS NH2O S NH2OOScheme 3.1: A library of sulfinated amidesDue to the complexity involved in the study of sulfonamides, which includestability and reactivity, a systematic approach to the dissection of the sulfon-amide scaffold using DFT will be undertaken. Beginning with the zero oxygensystem— sulfenamides RSNH2— we will directly compare the effects ofchanging a primary alkyl to a tertiary alkyl to an aryl group. Then, we will oxi-dize each sulfenamide to form the sulfinamides RSONH2 and finally we willobserve the changes affected by the second oxidation to form the respectivesulfonamides RS(O)2NH2.1The designations of e, i and o come from the conventional naming of the various sulfonamideoxidation states: e for zero oxygens, i for one oxygen, and o for two.203.2 Results and Discussion3.2.1 XASFour representative compounds were selected for XAS analysis due to stabil-ity and availability: tertbutanesulfinamide (2i), methanesulfonamide (1o), ben-zenesulfonamide (3o) and potassium dinitrososulfite (4x), Scheme Scheme 3.2.Structurally, the representative molecules used for XAS studies are very similar.By making small systematic modifications we can track which, if any, of thesechanges affect the absorption spectrum and, hence, the electronic structure ofthese compounds.The S K-edge XAS spectra of the sulfinated amides are shown in Fig-ure Figure 3.1. The spectra exhibit shifts in energy consistent with changesin oxidation state.47 All four spectra show similarities in their overall shapes,the main feature being a single large absorption band. Both 3o and 4x have anadded feature; 3o displays a prominent shoulder and 4x an additional peak.R S(O)nH2NH3C S NH2 H3C S NH2O H3C S NH2OOS NH2S NH2 S NH2O S NH2OOS NH2O S NH2OOR = methyl, tertbutyl and phenyln = 0, 1, 2S NH2OS NH2OOH3C S NH2OON SOO ON OOK2(CH3)3C-SONH2  tertbutanesulfinamideCH3-SO2NH2  methanesulfonamideC6H5-SO2-NH2   benzenesulfonamideK2 [SO3-N2O2]   potassium dinitrososulfite2-(2i)(1o)(3o)(4x)Scheme 3.2: Representative compounds selected for XAS analysis.21The main absorption peak of 2i is found at 2477 eV; 1o at 2481.1 eV; and3o at 2481.4 eV and with a shoulder at 2479.4 eV. Compound 4x has two peaksfound at 2480.5 eV and 2482.5 eV. The difference in energy between the twosulfonamides, 1o and 3o, is 0.3 eV; a large change in energy would not beexpected for two molecules with similar effective nuclear charge (Zeff ).The energy difference between 2i and 1o/3o is 4.1 eV, whereas; for 1o/3oversus 4x, the difference is 1 eV. The chemical shifts which occur upon oxida-tion directly reflect the Zeff of sulfur; 2i has the least positive core while 4x hasthe most positive, indicating more delocalization of the S electron density.50The pre-edge intensities of ligand-metal XAS spectra correlate to cova-lency.58 A small caveat to mention, however, is the self-absorption that haslikely occurred in the acquisition of the fluorescence data for 2i and 4x. 1oand 3o were acquired via TEY, a process which is not as susceptible to self-absorption, as stated in Chapter two. As such the intensities of 2i and 4x maynot be directly comparable to one another nor to the sulfonamides 1o and 3o,hence, covalency calculations will not be carried out. Be that as it may, thespectra do reflect increased area-under-the-curve-intensities as the moleculesare oxidized due to the creation of more core holes. The increase of the XASintensity also reflects a decrease in electron density in the sulfur atom.As modifications between each compound are small, minimal differences inthe XAS spectra of the compounds are expected, as seen in Figure Figure 3.1.Only upon substitution of an alkyl R-group with an aryl substituent do we seea new feature. It has been shown previously39 that this feature is character-istic of an aryl group bonded to a sulfone. It stands to reason, then, that theshoulder is due to a S1s to SC⇡⇤ transition. Work from Martin-Diaconescu etal. and Karunakaran-Datt et al. 4,5,42 suggest the main absorption peak is dueto transitions from the S1s to SC⇤ and S1s to SO⇤ . Compounds 2i, 1o and3o are then dominated by the ⇤ acceptor states for the SO and SC bond.Further assignments of features are carried out below in conjunction with DFTcalculations and XAS simulations.22Figure 3.1: The S k-edge XAS spectra of tertbutanesulfinamide (2i),methanesulfonamide (1o), benzenesulfonamide (3o) andpotassium dinitrososulfite (4x). a) Calibrated and normalizedspectra. b) First derivative of all respective spectra.233.2.2 DFTAll gas phase DFT calculations were run using ORCA, version 2.9.0,69 usingthe BP86 functional and TZVP basis set. No relativistic effects were added.Excited state calculations and XAS simulations were conducted with TDDFTand XES. The energies calculated for XAS simulations are shifted by +76 eV tomatch with the experimental spectra.68Figure 3.2: Sulfur K-edge XAS spectrum of methanesulfonamide (1o) withsimulated S K-edge XAS spectrum overlaid in dotted line. TheMOs are found along the x-axis as sticks.Comparison of the simulated and experimental XAS spectra of methanesul-fonamide fig. Figure 3.2 are in good agreement; the molecular orbitals—shownalong the bottom as sticks, define the overall shape. The MOs that contributethe most to this shape are the LUMO through LUMO+4. As the XAS spectrumis the visualization of the empty molecular orbitals we will focus on these unoc-cupied molecular orbitals. By using the energy density diagrams as shown in24Figure Figure 3.3 and percent contributions we can gain insight into the elec-tronic structure. The energy level diagram of methanesulfonamide reveals thatthe LUMO is a sulfur-nitrogen⇤ interaction with some sulfur-carbon⇤ . Thecalculated Kohn-Sham LUMO indicates a highly delocalized molecular orbitalwith 12% S3s and 3.8% S3p character. Contributions from the amide nitro-gen have 10.8% N2s character and 6.6% N2p. The methyl carbon contributes5.1% C2s character with 6.1% C3p character. LUMO+1 is predominately sulfur-oxygen⇤ with 31% S3p character (shared, in varying amounts amongst all sur-rounding atoms) and 14.5% O2p character between the two oxygens. LUMO+2is largely sulfur-carbon⇤ , 15.7% S3s character and 21.6% C2p character. InLUMO+3 the electron density on the central sulfur atom is equally distributedamongst all four bonds in a SC⇤ /SN⇤ /SO⇤ type interaction. LUMO+4 is asulfur-nitrogen⇡⇤ , the only MO with ⇡ character that contributes to the shape ofthe spectrum. Overall, the first five MOs indicate that, for methanesulfonamide,bonding within the structure is based on a sigma bond framework, with a fairlyelectronically delocalized sulfur. Bonding to the sulfur is dominated by sigmacontributions with only small S-N⇡⇤ contributions.Calculations of all the oxidations states of methane sulfinated amide showshifts consistent with the changes in the core charge of sulfur, Figure Fig-ure 3.4, methanesulfenamide (1e) having the least positively charged core and1o having the most. As the 1e sulfur is bonded to fewer atoms, it has fewerempty core-holes and thus less intensity in the spectrum. The MOs that con-tribute most to 1e are the LUMO (SN⇤ ) and LUMO+1 (SC⇤ ). Turning to 1i,the LUMO represents SN⇤ , LUMO+1 SO⇤ and SC⇤ , LUMO+2 is equallySN⇤ and SC⇤ and LUMO+3 SC⇤ and SO⇤ . The MOs that contribute mostto the shape of the 1i spectrum are LUMO+2 (SN⇤ and SC⇤ ) and LUMO+3(SC and SO⇤ ). 1o has been discussed above, where LUMO+1 (SO⇤ ) andLUMO+3 (SCON⇤ ) are the main contributors to the peak shape. The twopeaks in 1e merge closer to one another with each addition of oxygen until in1o there only a single peak. This suggests that the addition of oxygen increasesmixing of the electron density of sulfur demonstrated by the decrease in split-ting of the sulfur-nitrogen⇤ MOs and the sulfur-carbon ⇤ MOs as evidencedby the decrease in the energy differences between those MOs.25Figure 3.3: a) Simulated XAS spectrum with MO assignments for the firstfive MOs. b) Energy level diagram of methanesulfonamidewith assignments and energy density diagrams.26The calculated bond lengths of the sulfur-carbon bond vary with each ad-dition of oxygen. 1e has a S-C bond length of 1.832 Å; 1i, 1.850 Å; and1o, 1.817 Å. For the sulfur-nitrogen bond 1e has a bond length of 1.755 Å; 1i,1.763 Å; and 1o is 1.730 Å. The SC and SN both are longest for the sulfinamideand shortest for the sulfonamide.The experimental XAS and simulated spectrum, seen in Figure Figure 3.5of tertbutanesulfinamide also show good agreement, the slight misalignmentbeing due to the +76eV shift used to maintain consistency between all calcula-tions. The molecular orbitals that contribute most to the XAS spectrum are theLUMO and LUMO+1 with some LUMO+3. LUMO is a SN⇤ with SO⇡⇤ , 33%S3p, 15.5% N2p and N2s and 10.3% O2p character combined. LUMO+1 andLUMO+3 are combination SC⇤ with SO⇤ . LUMO+1 has 36.1% S3p, 11.5%C2p and 7.7% O2p. LUMO+3 has 21.6% S3p, 9.9% C2p and 12.2% O2p. ThisMO scheme, as seen in Figure Figure 3.5, is similar to that of 1o, with lower en-ergy MOs being centered around the sulfur-nitrogen⇤ transition and the higherenergy MOs with sulfur-carbon⇤ transitions.The DFT calculations for all the oxidation states of tertbutanesulfinamide,are similar to those of methanesulfonamide and its variants, with the excep-tion of some changes in energies. As a drastic change in R-group has notoccurred, drastic changes in the XAS are not be expected. As the sulfur atomis oxygenated the energy splitting decreases in the MOs for SN⇤ , SO⇤ andSC⇤ so that the features become unresolved in the XAS spectrum. Again, theoxygen additions encourage mixing of the electron density of sulfur amongst itsneighbors.A look at the bond lengths show that for the sulfur-carbon bond, 2e has abond length of 1.885 Å; 2i, 1.927 Å; and 2o, 1.889 Å. For the sulfur-nitrogenbond the bond distances are as follow: 2e, 1.752 Å; 2i 1.764 Å; and 1.737 Å.Similar to the methyl substituent, the SC and SN is longest for the sulfinamide,but the SC is shortest for 2e and the SN is shortest for 2o. This may be due tothe fact that the t-butyl group is more electron donating than the methyl groupand the contraction of the SN bond is an inductive effect mitigated by the twoelectron-withdrawing oxygens.The XAS simulation of benzenesulfonamide is shown in Figure Figure 3.7.27Figure 3.4: Methane sulfinated amides, a) Simulated S K-edge XAS spec-tra of 1e, 1i and 1o. b) Energy level diagram of the three oxi-dation states of methane sulfinated amide.28Figure 3.5: Tertbutanesulfinamide (2i) XAS spectrum and simulated XASspectrum overlaid in dotted line with assignments for the firstfour MOs. The star indicates a feature in the experimentaldata which has not yet been explained.Here, we clearly see the shoulder of the experimental spectrum is predicted inthe simulation. While the intensity and absolute energy are not exactly repro-duced, the overall shape is consistent. The addition of the phenyl group clearlyhas a large impact on the sulfur-carbon bond, which is absent in the alkyl groupsubstituents.The immediately noticeable feature is the LUMO (and to a much smallerextent LUMO+1) which make up the shoulder in the spectrum. LUMO is aSC⇡⇤ with the phenyl ring in a 5 configuration. LUMO+1 has no sulfur contri-bution, the electron density being confined at the 4 of the phenyl group. Thefirst difference between the aryl and alkyl substituents is this ⇡ system that isintroduced.29Figure 3.6: tert-Butyl sulfinated amides, a) Simulated S K-edge XASspectra of 2e, 2i and 2o. b) Energy level diagram of the threeoxidation states of tert-butyl sulfinated amide.30Figure 3.7: Sulfur K-edge XAS spectrum of benzenesulfonamide (3o) withsimulated S K-edge XAS spectrum overlaid in dotted line. Thefirst seven MOs are found along the bottom as sticks.The greatest contributors to the main absorption peak of 3o are LUMO+2through LUMO+5. LUMO+2 exhibits a delocalized sulfur⇤ framework with allfour of the neighboring atoms. LUMO+3 and LUMO+4 are SN⇤ and SO⇤ .The breakdown of the XAS spectrum differs from the previous alkyl sulfinatedamides in that the SN⇤ moves higher in energy while the SC⇤ moves to lowerMO energies.The comparison of all the oxidation states of benzenesulfonamide begin toshow major differences to the previous two compounds. For 3e, the LUMOis the phenyl ring in a 4 configuration with no sulfur contribution and, hence,no contribution to the simulated XAS. LUMO+1 is SN⇤ , similar to the previ-ous compounds. LUMO+2, however, is a SC⇡⇤ which is so close in energy toLUMO+1 that the two are not resolved in the spectrum and contribute almost31Figure 3.8: Benzene sulfinated amides, a) Simulated S K-edge XAS spec-tra of 3e, 3i and 3o. b) Energy level diagram of the three oxi-dation states of benzene sulfinated amide.32equally to the first absorption peak. At LUMO+3 the SC⇤ transition makes upthe second, higher energy, absorption peak.Upon oxygenation, however, the LUMO for 3i is no longer a sulfur-nitrogenMO but a sulfur-carbon⇡⇤ and a 5 MO. LUMO+1 is once again the 4 phenylring, with no sulfur contribution. LUMO+2 is where the SN⇤ MO is found.LUMO+3 is predominately a SO⇤ and the SC⇤ is found at LUMO+4. In 3o, asdiscussed above, the sulfur-carbon⇤ now becomes mixed with the SN⇤ andSO⇤ . LUMO+3 and LUMO+4 are SN⇤ without any contributions from thephenyl ring to the sulfonamide moiety. The sulfur-nitrogen MOs move to higherenergies than seen previously in either 3e or 3i nor in the oxidation states of 1and 2. A ‘pure’ SC⇤ , one that has an electron density diagram like that of 3eLUMO+3, is found at LUMO+6 for 3i and LUMO+7 for 3o.The sulfur-carbon bond distances for the phenyl substituent are as follows:3e, 1.801 Å; 3i, 1.848 Å; and 3o 1.818 Å. For the sulfur-nitrogen: 3e, 1.744 Å;3i, 1.760 Å; and 3o, 1.726 Å. Once again, the longest bond lengths for SC andSN belong to the sulfinamide. The shortest, mirror the t-butyl substituent’s with3e exhibiting the shortest SC and 3o the shortest SN.For another perspective on the overall affects of substituent modifications,Figure Figure 3.10 shows all three of the sulfenamides compounds. The molec-ular orbitals displayed are equivalent, for example; the LUMO of 1e is the sameas LUMO for 2e which is the same as LUMO+1 for 3e, as per Figure Figure 3.9.The sulfur-nitrogen⇤ molecular orbitals for 1e, 2e, and 3e occur at similar en-ergies. This is expected as no modifications to the amide have taken place;and the changes in R group manifest in a small transmission of electronic ef-fect to the sulfur-nitrogen bond. Greater changes are expected, and seen, inthe sulfur-carbon MOs with the substitutions of the different R groups. Theenergies of both SC⇤ and SN⇤ MOs are lowest is 2e, due to the increasedelectron donating nature of the tert-butyl moiety onto the sulfur. This is followedby 1e then 3e, with the electron withdrawing effect of the aryl carbon increasingthe Zeff of the sulfur atom. This order is also reflected in the predicted SC bondlengths: 2e, 1.885 Å; 1e, 1.832 Å; 3e, 1.801 Å.Figure Figure 3.11 shows that the sulfinamides peaks begins to merge toform one peak. A similar comparison to the sulfenamides above shows agree-33        Figure 3.9: Example of the equivalent molecular orbitals of the three sulfe-namides, sulfur-nitrogen⇤ .ment to the sulfur-nitrogen⇤ energies to follow the trend of tertbutane < meth-ane < benzene. The sulfur-carbon⇤ for 1i and 3i this time are much closer toone another, with 2i again at a lower energy than its methyl and phenyl counter-parts. Both the sulfur-carbon and sulfur-nitrogen bond lengths also reproduce asimilar trend to the MOs where 2i is the longest, followed by 1i and the shortestbeing 3i. An interesting feature, the intensities of the SC⇤ MOs are much lowerthan the SN⇤ indicating more electron density around the respective sulfur-carbon bonds. Finally, a comparison of the sulfonamides, Figure Figure 3.12reveals that the ordering of sulfur-nitrogen MOs and the SN bond lengths aresimilar to those of the sulfinamides. A different ordering arises with the sulfur-carbon⇤ MO energies 1o < 2o < 3o. This order is not reflected in the SC bondlengths.Following from the above comparisons, sulfenamides are mostly affected bythe changes in the R-group, R-S-NH2 —especially as the amide remains un-changed. For the sulfinamides, the addition of the oxygen atom overcomes themodifications in R-group and the amide becomes more important electronically,R-SO-NH2. As the oxidation of sulfur increases, increased shielding of coresulfur electrons lead to less electron density for the sulfur-nitrogen⇤ and sulfur-carbon⇤ transitions. If the R-group is aromatic then the sulfur-carbon ⇡ bond34becomes an element to consider in its possible resonance structure,43 whichcan be represented as shown in Figure Scheme 3.3a. For the sulfonamides,there is considerable delocalization of the electron density so that substitutionson either side of the sulfonyl will have an impact on the overall electronic distri-bution of the molecule, R-SO2-NH2. The contribution of the SN⇤ transitionsto the simulated XAS spectral shape are smaller than the SC⇤ indicating theamide is less affected by this second oxygenation and that the SN⇤ is moreelectron rich. For the sulfur-carbon⇤ transition, the XAS intensity increasesindicating a decrease in electron density as the electron withdrawing nature ofthe R-group increases. Again, an aromatic group will impact the resonancestructure as shown in Figure Scheme 3.3b.Figure 3.10: Simulated XAS spectra with similar MOs represented for 1emethanesulfenamide (teal), 2e tertbutanesulfenamide (red),and 3e benzenesulfenamide (blue).35Figure 3.11: Simulated XAS spectra with similar MOs represented for1i methanesulfinamide (teal), 2i (red) tertbutanesulfinamide,and 3i benzenesulfinamide (blue).36Figure 3.12: Simulated XAS spectra with similar MOs represented for 1omethanesulfonamide (teal), 2o tertbutanesulfonamide (red),and 3o benzenesulfonamide (blue).37S NO S NOH H H Ha S NOO S NOOH H H HbScheme 3.3: Expected resonance structures with the substitution of anaromatic R-group for sulfinated amides, a) sulfinamides andb) sulfonamides.383.3 Experimental3.3.1 MaterialsMethanesulfonamide (98% purity) and benzenesulfonamide (98% purity) usedin this study were purchased from Sigma-Aldrich. Methanesulfonamide: 1HNMR (300 MHz, DMSO)  2.91 (s, 3H, CH3),  6.80 (s, 2H, NH2); Benzene-sulfonamide: 1H NMR (300 MHz, DMSO)  7.83 (d, 2H, J=6Hz),  7.58 (m,3H),  7.35 (s, 2H). Potassium dinitrososulfite (Pelouze’s Salt) and tertbutane-sulfinamide (Ellman’s sulfinamide) were synthesized in the laboratory of ScottBohle at McGill University.3.3.2 XAS Acquisition and Data AnalysisSulfur K-edge XAS data for potassium dinitrososulfite and tertbutanesulfinamidewere acquired at Stanford Synchrotron Radiation Lightsource (SSRL). Fluores-cence data were collected at beamline 4-3 at the Stanford Synchrotron Ra-diation Lightsource (SSRL) under ring conditions of 3GeV and 200-500mA.Solid samples were mixed 1:1 with boron nitride, finely ground, to minimizeself-absorption, and mounted as a thin layer on sulfur-free Kapton tape at roomtemperature. Fluorescence data were acquired using solid state detector atambient temperature and pressure. Energy calibration was carried out usingsodium thiosulfate (Na2S2O3) with the first pre-edge feature being calibrated at2472.02 eV.59Sulfur K-edge XAS data for methanesulfonamide and benzenesulfonamidewere acquired at the Canadian Light Source. Total electron yield data wereacquired at beamline SXRMB at the CLS under ring conditions of 3 GeV and180-250mA. Solid samples were mixed 1:1 with boron nitride, finely groundand mounted onto a copper sample holder with carbon tape. Total electronyield data were acquired under vacuum at ambient temperature. Calibrationswere preformed as above.Raw data were normalized to incoming beam (Io), calibrated and averagedwith the BlueprintXAS 60 prefit function. Only the first scans of tertbutanesulfi-namide and potassium dinitrososulfite were used due to sulfur photo-reduction39in the fluorescence data. As TEY does not exhibit such photo-reduction, allscans per run of the two sulfonamides were averaged for greater signal-to-noiseratio. Background subtraction and normalization of the spectra were achievedusing BlueprintXAS.61 The number of components for fits were estimated byemploying the Akaike information criterion (AIC) .62,63 The model with the low-est AIC was chosen for fitting of all spectra; fits with smallest sum of squarederrors were chosen for background subtraction and normalization which lead tothe data shown in this chapter.40Chapter 4Para-Substituent and AmideHydroxylation in Sulfonamides:Structure-FunctionRelationships.4.1 IntroductionAs the prevalence of nitric oxide (NO) and azanone (HNO) signaling in medicineand biochemistry increases, methods of generation become pivotal in drug de-sign. Molecular carriers and releasers of NO/HNO, like azo compounds, S-nitrosothiols, and sulfonamides,19 can be key to directing their storage anddelivery. Transmission effects through sulfur-nitrogen bonds are central to un-derstanding the mechanism of self-decomposition in N-hydroxy sulfonamidesand their subsequent release of NO/HNO.N-hydroxy benzenesulfonamide, known also as Piloty’s acid (PA), was firstsynthesized by Oskar Piloty, in 1896.72 Work done by Angeli,73 postulatedazanone elimination via:C6H5SO2NHO *) C6H5SO2 + HNO (4.1)41Sulfonamides also act as enzyme inhibitors and antibacterials, where elec-tronics and sterics are instrumental to their efficacy,74.3 Many studies of substi-tuted sulfonamides seek structural connections to bacteriostatic activity. Cor-relation analysis using NMR, IR and UV/Vis, 37,75–78 with Hammett parame-ters1,2,79,80 are a favored method of evaluating structural differences with bioac-tivity.In this chapter, the intramolecular structure of sulfonamides and N-hydroxysulfonamides and their potential for NO/HNO release is further studied viastructure-function relationships. The sulfonamido amide nitrogen is hydroxy-lated and compared to the parent sulfonamide, creating an electron withdraw-ing effect away from the nitrogen: CH3O2S!N!O H. Modifications to theR-group are also explored; para-substitutions with a wide range of Hammett constants are used.1 These two modifications on either side of the sulfonamideS-N bond will dictate what governs the electronic structure and to that end,its ramifications on the stability of the S-N bond. As per the previous Chap-ter 3.2.1, sulfur K-edge XAS is used in the same manner and, in Chapter 5, iscorrelated to DFT calculations for further insight.4.2 Results4.2.1 XASThe S K-edge XAS spectra of the simplest system, CH3SO2NH2 methane-sulfonamide (1a) and CH3SO2NHOH N-hydroxymethanesulfonamide (1b) areshown in Figure Figure 4.2. As discussed in the previous chapter and seen inFigure Figure 4.2, 1a has a single broad band at 2481.1 eV, as identified fromthe inflection point of the first derivative spectrum. Upon hydroxylation of theamide, however, a new and very interesting peak appears at 2477.2 eV, whichwill be referred to as peak Y. Recall, this spectrum is seen from the perspectiveof the sulfur atom; this new feature arising from the modification of the neighbor-ing atom must, therefore, directly be influencing the sulfur atom. The nature ofthe sulfur-nitrogen bond, then, must change between the sulfonamide and theN-hydroxy sulfonamide. With the addition of a hydroxy group on the amide, the42S NHOOY X X = H or OHOCH3CH3HClNO2Y =Y Number X = H X = OHmethane 1 a bbenzene 2 a bp-methoxybenzene 3 a bp-toluene 4 a bp-chlorobenzene 5 a bp-nitrobenzene 6 a bFigure 4.1: Sulfonamides and N-hydroxysulfonamides investigated in thischapter and table with shorthand labels.electron withdrawing effect of oxygen could lead the nitrogen to have a partialpositive charge CH3O2S!N+!O–H.Figure Figure 4.3 a) shows spectra for para-substituted aryl sulfonamides:methanesulfonamide (1a), benzenesulfonamide (2a), methoxybenzenesulfon-amide (3a), toluenesulfonamide (4a), chlorobenzenesulfonamide (5a) and nit-robenzenesulfonamide (6a). In the previous chapter, the introduction of an aro-matic group yielded a shoulder in the XAS spectrum, which correlated to theSC⇡⇤ bond. Here, again, all aromatic spectra display a shoulder, shifted tolower energy with respect to the main peak, in the same manner as benzene-sulfonamide in the previous chapter. For the sake of simplicity, this shoulderwill be referred to as peak X.XAS spectra of all the N-hydroxy sulfonamide compounds are shown in Fig-43Figure 4.2: Sulfur K-edge XAS of methanesulfonamide (1a), black and N-hydroxy methanesulfonamide (1b), red. The appearance of anew feature at low energy indicates the significant impact ofthe hydroxylation of the amide to the sulfur atom.ure Figure 4.3 b); the spectra mirror that of the parent compounds but with thenoticeable addition. Akin to the XAS spectrum of 1b, a new feature, peak Y,emerges upon N hydroxylation. If we look at each substituent (Figures Fig-ure 4.2 – Figure 4.8) there is an overall trend whereby the X peaks of all NOHSare shifted to lower energy than their NHS counterparts, i.e. the energy differ-ence between the peak X of 3a and 3b is -0.6 eV. These differences range from-0.3eV to -0.85eV.Visual inspection of the XAS spectra for N-hydroxy sulfonamides with elec-tron donating groups (EDG), Figure Figure 4.9, reveal the lowest energy Ypeaks for 3b and 2b align with the lower energy peak found in 1b, indicativethat this feature does indeed pertain to nitrogen hydroxylation. Peak X for all44(a) Sulfonamides(b) N-hydroxysulfonamidesFigure 4.3: Sulfur K-edge X-ray absorption spectra of a) sulfonamides andb) N-hydroxysulfonamides. The lowest energy peak is labeledas Y (absent in sulfonamides), the middle energy peak is la-beled as X and, the main absorption peak will be referred toas peak M.45Table 4.1: XAS energies of absorption peaks for sulfonamides (a) and N-hydroxy sulfonamides (b). Peak Y arises only with compoundsb and peak X with aryl compounds. Peak M is the main absorp-tion peak.Compound peak Y (eV) peak X (eV) peak M (eV)1a 2481.11b 2477.2 2481.32a 2479.3 2481.42b 2476.8 2478.8 2481.33a 2479.3 2481.23b 2477.1 2478.9 2481.44a 2479.3 2481.64b 2476.9 2478.9 2481.55a 2479.3 2481.45b 2478.8 2481.46a 2478.7 2481.16b 2477.2 2478.6 2481.3(a) S K-edge spectra (b) First derivative of S K-edge spectraFigure 4.4: Sulfur K-edge X-ray absorption spectra benzenesulfonamide(2a) and N-hydroxy-p-benzenesulfonamide (2b). 2a displayspeak X at 2479.3 eV with the main peak at 2481.4 eV; 2bdisplays peak X at 2478.8 eV with the main peak 2481.3 eV,there is an appearance of a new feature, peak Y, at 2476.8 eV.46(a) S K-edge spectra (b) First derivative of S K-edge spectraFigure 4.5: Sulfur K-edge X-ray absorption spectra p-methoxybenzenesulfonamide (3a) and N-hydroxy-p-methoxybenzene sulfon-amide (3b). 3a displays peak X at 2479.3 eV with the mainpeak at 2481.2 eV; 3b displays peak X at 2478.9 eV with peakM at 2481.4 eV, peak Y is seen at 2477.1 eV.(a) S K-edge spectra (b) First derivative of S K-edge spectraFigure 4.6: Sulfur K-edge X-ray absorption spectra toluenesulfonamide(4a) and N-hydroxy-p-toluenesulfonamide (4b). 4a displayspeak X at 2479.3 eV with the main peak at 2481.6 eV; 4b dis-plays peak X at 2478.9 eV with the main peak 2481.5 eV, alow intenstiy peak Y is seen at 2476.9 eV.47(a) S K-edge spectra (b) First derivative of S K-edge spectraFigure 4.7: Sulfur K-edge X-ray absorption spectra p-chloro benzensul-fonamide (5a) and N-hydroxy-p-chlorobenzene sulfonamide(5b). 5a exhibits peak X at 2479.3 eV with peak M at2481.4 eV; 5b exhibits peak X at 2478.8 eV with the mainpeak 2481.4 eV, peak Y is too small to distinguish.(a) S K-edge spectra (b) First derivative of S K-edge spectraFigure 4.8: Sulfur K-edge X-ray absorption spectra p-nitrobenzene sulfon-amide (6a) and N-hydroxy-p-nitrobenzene sulfonamide (6b).6a exhibits peak X at 2478.7 eV with the main peak at2481.1 eV; 6b exhibits peak X at 2478.6 eV with peak M at2481.3 eV, peak Y is seen at 2477.2 eV.48aromatic NOHS overlap in the same region (absent in the alkyl sulfonamide)which would suggest it is related to the presence of the aromatic ring. Similarlyfor the electron withdrawing groups (EWG) we turn our attention to Figure Fig-ure 4.10. Again, peak X is present only in the aromatic sulfonamides and thelowest energy peak Y corresponds to the nitrogen hydroxylation. The differ-ence between the electron withdrawing and electron donating groups can beseen in this ⇠2477eV Y peak. The intensities are lower for the EWG than theEDG. This points to an overall change in the delocalization of the electron dis-tribution which has a direct impact in the sulfur nitrogen bond character. TheXAS energies where these peaks appear do not exhibit a correlation with Ham-mett  constants; so the affect of these substitutions are more complicatedthan a straightforward explanation of electron donation or withdrawal. Since allcompounds are substituted at the para position, steric hindrance or mesomericdifferences due to ortho/meta placement are not considered. A more detailedanalysis, supported by DFT calculations will be discussed in the following chap-ter.49(a) S K-edge spectra(b) First derivative of S K-edge spectraFigure 4.9: NOHS sulfonamides with para electron donating groups. 1band 2b are included for reference.50(a) S K-edge spectra(b) First derivative of S K-edge spectraFigure 4.10: NOHS sulfonamides with para electron withdrawing groups.1b and 2b are included for reference.514.2.2 Structure-Function RelationshipsThe outcome of small structural changes can be quantified and correlated withkinetic or thermodynamic reactivity via structure-function relationships, alsocalled quantitative structure activity relationships (QSAR) or linear free energyrelationships (LFER) .80,81 Hammett constants were first based on the changesin the ionization equilibrium induced by structural modifications of substitutedbenzoic acids, equation 4.2:XC6H5C(O)OH + H2O *) XC6H5C(O)O + H3O (4.2)A simple formula illustrates how a substituent in the para or meta position ofa phenyl ring can act upon the equilibrium of a reaction in the Hammett equa-tion 4.3:log✓kiko◆= ⇢ (4.3)Where ki is an equilibrium constant or a rate constant of the substituted reac-tant and ko the commensurate quantity of the unsubstituted reactant,  is thesubstituent constant—p for para and m for meta, and ⇢ is the reaction con-stant, which is dependent on the reaction, medium and temperature.1 While anempirical relationship, the use of Hammett parameters makes navigable other-wise quantitatively undefinable attributes in chemical reactions. For example,the 1H NMR chemical shift of amide protons in sulfonamides have been shownto correlate well with Hammett  parameters.75,77,82A myriad of other constants that separate inductive and resonance effectscan be found in the works of Hansch and Taft; Okamoto and Brown; and oth-ers.2,79,83 The separation of inductive and resonance  constants can aid inthe analysis of how a substituent influences a reactive center. For example,constants that stabilize negative charges via resonance find better linear corre-lation with , based upon the ionization of para-substituted phenols. For thosethat stabilize positive charges via resonance, +, is based on the heterolysis ofpara-substituted t-cumyl chlorides.84 For this sulfonamide system, the meansof substituent effects are unknown so it is best to use a range of  constantsto determine which will give the best correlation. In this chapter, the original52Hammett p ; Okamoto and Brown’s + ; and Hansch and Taft’s R (resonanceto negative center), are used for QSAR tests. Values for each substituent canbe found in Table Table 4.2. Simple linear regression analysis will determinewhich para- constant best describes the affect of substituent effects to the sul-fonamide sulfur and nitrogen atoms using NMR, IR, crystallography and XASdata. Intuitively, the R2 score reflects how well a linear regression model fits itsdata. Given data points xi let yi be the observation at that point, fi be the regres-sion prediction at that point, and yˆ be the mean response of all observations.The “goodness-of-fit” can then be written asR2 =Pi (fi  yˆ )2Pi (yi  yˆ )2. (4.4)The numerator represents the amount of the signal explained by the regressionmodel and the denominator can be roughly seen as the total variation in theseobservations. As a result this score can be interpreted as the total amount ofvariation that is explained by the regression model, where scores range be-tween a value of 0 (a poor fit) and 1 (a perfect fit).Table 4.2: Hammett constants used in this chapter. p from reference1and + and R from reference.2Substituent p + ROCH3 -0.27 -0.78 -0.27CH3 -0.17 -0.31 0.03H 0 0 0Cl 0.23 0.11 -0.12NO2 0.78 0.79 0.18531H NMRSulfonamide samples were prepared in a solution of d6-DMSO, peaks obtainedfor the deuterated solvent were used as internal reference points. The sul-fonamide compounds exhibit chemical shifts for the NH2 protons in the 7ppmrange; the amide and hydroxyl protons for the N-hydroxy sulfonamides in the9ppm range (see Appendix A.1 for spectra). Comparison of the amide proton1H NMR chemical shift versus Hammett p results in a linear relationship, Fig-ure Figure 4.11. The sulfonamide amide protons are shifted upfield with elec-tron donating substituents, conversely, electron withdrawing groups are shifteddownfield. This indicates that the EWG inductively causes deshielding of theamide protons. The NOHS amide proton and hydroxy proton also display a lin-ear relationship with the Hammett p constant. We see again EDG are shiftedupfield while EWG shift downfield. As per Davis et al., the slope is a measureof transmission through the sulfur-nitrogen bond. It is stipulated that the 1HNMR chemical shift of the hydroxyl protons in N-arenesulfonamides hydrogenbond with the nitrogen, which in turn is a measure of electron density on nitro-gen. The slope is then considered the equivalent to the reaction constant ⇢ asproposed by the Hammett equation. If we consider hydrogen bonding of sul-fonamides with DMSO we too can extend this interpretation of varying electrondensity on the nitrogen atom.NHS : NH = 0.50 p + 7.34 R2 = 0.999 (4.5)NOHS : OH = 0.44 p + 9.60 R2 = 0.997 (4.6)NOHS : NH = 0.44 p + 9.55 R2 = 0.963 (4.7)The proton NMR data reports excellent correlation The slopes of NHS andNOHS are very similar, equations 4.5, 4.6 and 4.7. The positive slopes ofthe Hammett plots indicate a sensitivity of the proton chemical shifts to EWG.As the electron-withdrawing substituents’ p become more positive, the furtherdownfield the proton will shift. This points to an increase in the acidity of the pro-54tons and, hence, a decrease in the negativity of the nitrogen. The N-hydroxysulfonamide protons are even more acidic, as the intercept is approximately2 ppm higher than that of the sulfonamide. The slightly more positive sulfon-amide slope indicates the substituent changes influence the NHS more thanthe NOHS proton.Sigma constants that express mesomeric interactions R and +p (R2 =0.522 and 0.935 respectively) do not boast as good a fit with the proton chem-ical shift as p (R2 = 0.999) which further indicates that the substituents affectthe sulfonamide moiety by induction rather than mesomeric effects; except inthe case of the N-hydroxy amide proton with is best correlated to resonancewith a positive center.For the amide protons of the sulfonamides:+ : NH = 0.35 + + 7.41 R2 = 0.935 (4.8)R : NH = 0.89 R + 7.43 R2 = 0.522 (4.9)For the hydroxyl proton of the N-hydroxy sulfonamides:+ : OH = 0.30 + + 9.66 R2 = 0.903 (4.10)R : OH = 0.78 R + 9.68 R2 = 0.511 (4.11)For the amide proton of the N-hydroxy sulfonamides:+ : NH = 0.32 + + 9.61 R2 = 0.983 (4.12)R : NH = 0.84 R + 9.63 R2 = 0.570 (4.13)55(a) Sulfonamide NH2 proton.(b) N-hydroxy sulfonamide OH and NH protons.Figure 4.11: 1H NMR chemical shift of amide protons versus Hammettp constants, in DMSO. a) Sulfonamide NH2 chemical shifts(?  ?  ?). b) N-hydroxy sulfonamide protons: OH proton(⌥ ⌥ ⌥); NH proton (⌥ ⌥ ⌥).56X-Ray CrystallographyThree N-hydroxy sulfonamides were crystallized in methanol at room temper-ature Figure 4.12. Table Table 4.3 gives the bond lengths of: N-hydroxy ben-zenesulfonamide (2b), N-hydroxy- p-methoxy benzenesulfonamide (3b) and N-hydroxy- p-nitrobenzene sulfonamide (6b).Table 4.3: Experimental bond lengths and bond angles of 2b, 3b, and 6b.Bond Length Å 3b 2b 6bS-C 1.756 1.752 1.756S-N 1.674 1.655 1.633S-O 1.438 1.439 1.439S-O 1.439 1.436 1.429N-O 1.434 1.429 1.424Bond Angle 3b 2b 6bCSN 108.14 109.14 106.00OSO 119.37 119.63 120.67SNO 109.75 109.50 110.22CSNO 53.97 58.97 58.56Hammett Parameter -0.286 0 0.778O4O5N2S1O3C6 H1oH2n(a) NOH-benzenesulfonamideN2S1H2nH3oO5 O4O3C6C9C13O12(b) NOH-p-methoxy-benzenesulfonamideN2S1H2nH3oO14O19O3C4N10 C9O11O12(c) NOH-p-nitro-benzenesulfonamideFigure 4.12: Crystal structures of: a) 2b, b) 3b, and c) 6b.The sulfur-carbon bond lengths appear unaffected by the changes occur-57(a) S-N bond distances.(b) N-O bond distances.Figure 4.13: Hammett plots of NOHS bond lengths. a) S-N bond dis-tances vs. p,+,R , b) N-O bond distances vs. p,+,R .58ring at the para-position of the phenyl group regardless of ED or EW nature.This is interesting in light of the fact that alterations do occur in the S-N and N-O bond lengths; and these do correlate with p constants, Figure Figure 4.13.The sulfur-nitrogen and nitrogen-oxygen bond lengths contract with electronwithdrawing group. The correlation is further improved when resonance Ham-mett constants are used. The best fits occur when + (R2 = 0.999) is employed.For the sulfur-nitrogen bond distances:S N = 0.036 p + 1.66 R2 = 0.953 (4.14)S N = 0.026 + + 1.65 R2 = 0.998 (4.15)S N = 0.089 R + 1.65 R2 = 0.975 (4.16)For the nitrogen-oxygen bond distances:N O = 0.009 p + 1.43 R2 = 0.933 (4.17)N O = 0.006 + + 1.43 R2 = 0.999 (4.18)N O = 0.022 R + 1.43 R2 = 0.987 (4.19)The bond length of 1.755Å for the sulfur-carbon bond indicates a doublebond81 and this bond length is consistent regardless of the nature of the para-substituent. This suggests that resonance contribution from the substituent hasa small impact on the sulfonamide; instead, the contraction of the nitrogen con-taining bonds are due to induction. This is somewhat contrary to the QSARwhich suggests resonance with a positive center. We can consider the elec-tron poor nitrogen to be more positive, but there is no other justification for aresonance structure with the the nitrogen.Sulfonamide S-N and S-C bond lengths from the literature are reported in59Table Table 4.4 for 2a (YIFZAP), 3a (IWEREI) and 6a (XUDTIZ01), from theCambridge Crystallographic Data Center. Here, we see that the NHS S-Nbonds are slightly shorter than the corresponding NOHS S-N bonds. The S-C bonds show less variation between the NOHS and NHS species. Scholzet al. reported the S-N bond length to be 0.5Å longer in PhSO2NHOH thanPhSO2NH2, which is attributed to a decrease in nitrogen lone pair donation tothe sulfur bonding orbitals.85 In the most electron-donating case (R = methoxy-benzene), the sulfur-nitrogen bond length increases by 0.062Å upon nitrogenhydroxylation; for the most electron-withdrawing (R = nitrobenzene) the differ-ence is +0.024Å.Typical NO bond length is reported at 1.4Å and NO at 1.2Å.86 Our val-ues for N-O fall solidly within the bounds of a single bond. The S-N bond lengthof a similar functional group, S-nitrosothiols, report SN 1.6–1.8Å and SN⇠1.5Å.43,86 These values suggest a single bond between the sulfur-nitrogen,for both NHS and NOHS.Table 4.4: Experimental bond lengths of 2a (YIFZAP), 3a (IWEREI), and6a (XUDTIZ01).Bond Length Å 3a 2a 6aS-C 1.761 1.754 1.770S-N 1.612 1.598 1.609Hammett Parameter -0.286 0 0.778IRInfrared spectroscopy has also been used to evaluate affects of substituents onthe sulfonamide group.77 Solid state samples of all NHS and NOHS were mea-sured using attenutated total reflectance-FTIR, spectra are in Appendix A.2.Characteristic frequencies for sulfonamides are the ⌫(NH2) at 3100–3490 cm1,⌫a(SO2) at 1330–1380 cm1, ⌫s(SO2) at 1140–1170 cm1 and ⌫(SN) at 860–9501 .81,87Table Table 4.5 reports the stretching frequencies for all NHS and NOHS.Vibrational frequencies of the bonds associated with the sulfur and nitrogen60atoms blueshift upon amide hydroxylation, indicating an increase in the strengthof bonds associated with the sulfur and nitrogen atoms. The changes are notsystematic with the substituent effects. The only frequency to show agreementwith p are the NOHS ⌫(SN). Within the NOHS compounds the S-N stretch red-shifts as the substituent becomes more electron withdrawing; which points to aweakening of the sulfur-nitrogen bond. The vibrational data point to the amidesubstitution being the greater contributor to the overall molecular structure thanthe substituents at the para-phenyl position.Table 4.5: Stretching frequencies for sulfonamides and N-hydroxy sulfon-amides.Wavenumber (cm1) ⌫a (NH2) ⌫s (NH2) ⌫a (SO2) ⌫s (SO2) ⌫ (SN) ⌫ (CS)1a 3321 3257 1307 1144 876 7661b 3375 3254 1320 1158 900 7882a 3345 3250 1310 1153 902 7542b 3438 3245 1321 1161 922 7363a 3343 3266 1300 1103 912 8003b 3377 3229 1325 1160 944 7404a 3324 3237 1323 1149 905 8074b 3375 3254 1346 1161 940 7185a 3327 3235 1323 1145 911 7545b 3436 3245 1325 1162 918 7626b 3448 3247 1343 1161 914 742⌫ (SN) = 27.66 p + 930.64 R2 = 0.740 (4.20)⌫ (SN) = 23.33 + + 926.79 R2 = 0.829 (4.21)⌫ (SN) = 46.90 R + 925.91 R2 = 0.343 (4.22)The slopes for ⇢ show poor fit, which is unsurprising as the vibrational fre-quencies are not systematic with Hammett constants. The best fit, however, is61Figure 4.14: Hammett plot of ⌫ (SN) vs. p,+,Rstill given by + with resonance interaction with the sulfonamide moiety.62XASThe energies at which the Y and X peaks appear in the XAS data do not corre-late well with p. We do, however, see an interesting trend with the intensitiesof the low energy feature, see Figure Figure 4.3 b) at ⇠2477eV: 2b at 1.15, 3bat 1.87, 4b at 0.36, 6b at 0.90, and at 5b no peak is seen. These peaks showsigns of correlation to those substituents which have inherent resonance. Themethyl and chloro substituents will not partake in as strong a mesomeric effectwith the phenyl ring as the nitro and methoxy groups will. A comparison of pwith resonance inclusion parameters are seen in Figure Figure 4.15.Intensity at 2477 eV = 0.501 p + 0.913 R2 = 0.083 (4.23)Intensity at 2477 eV = 0.522 + + 0.836 R2 = 0.174 (4.24)Intensity at 2477 eV = 1.560 R + 0.799 R2 = 0.133 (4.25)The poor correlation of the XAS intensities to the inductive parameter isclear (R2 = 0.083); the resonance parameters are little help to the relationship.This is not too surprising as XAS conveys a different perspective. XAS spectrareveal the anti-bonding MOs, whereupon the bonding MOs can be deduced.Induction is not a property that can be seen easily within the MO framework.Resonance factors, though they show poor correlation here, however, can beseen within the MO framework and will be further explored in the followingchapter with DFT calculations. The minimal differences seen between the sub-stituents’ XAS spectra suggest that the substituent effect has a smaller impactto the bonding framework than the amide hydroxylation.63Figure 4.15: Hammett plot of intensities of low energy feature, at approxi-mately 2477eV, found in N-hydroxysulfonamide XAS spectravs. p,+,R .4.3 DiscussionThe structure-function relationships shown using NMR, IR, X-ray crystallogra-phy and XAS point to a system where induction and resonance effects work in acomplicated manner. The NMR chemical shift and crystallography bond lengthscorrelate well with Hammett parameters and indicate that the substituents doaffect the framework of the molecular bonding. The structure parameters whichinclude resonance with the sulfonamide center increase corollary relationships;however, a lack of correlation with substituent in the vibrational and absorptionspectra suggests the hydroxylation of the amide as far more important than thesubstituent effect. The greater changes in the crystallography, IR and XAS arealways connected to the amide substitution, not the R-group modifications.It has been noted that the reactivity of the primary amino group is most im-64portant for sulfonamide activity,76 which supports the QSAR data shown in thisthesis. NMR studies of anilines and carboxamides agree with the NMR datashown here82,88 and can be used to draw parallels. The comparison of ani-line NMR QSAR shows a similar plot, of differing ⇢ value,88 where the anilineprotons are shifted most downfield with electron-withdrawing groups, implyinga decrease in the nitrogen negativity; the addition of a hydroxyl group on theamide further pulls electron density away from the nitrogen, perturbing the bondbetween the sulfur and nitrogen. This is consistent with the contraction of bondlength seen in the crystallography. For the sulfonamides, the crystallographyand XAS data imply a sulfur-carbon double bond for both EWG and EDG, how-ever, Lewis diagrams do not support this, Scheme Scheme 4.1.The general good fit for + within the QSAR tests indicate EDGs at the paraposition will stabilize the electron poor nitrogen, and EWG will destabilize thisbond leading to potential cleavage of S-N; this affect may not be strictly due toresonance affects as implied by +, or Scheme Scheme 4.1. Anecdotally, theonly compound for which IR was not acquired was for 6a (nitrobenzenesulfon-amide) as it had already decomposed to a sulfoxide. This affect may be morepronounced in the sulfonamides, as they are without the stabilizing EWG of thehydroxyl oxygen. What is made clear from the QSAR is that the substituenteffect is small and non-systematic and that the amide hydroxylation is muchmore important to the bonding framework, as seen in Scheme Scheme 4.2.According to calculations in the previous chapter and the low energy fea-ture found in XAS spectra this points to further evidence that there is somebond multiplicity occurring within the sulfonamide S-N. DFT calculations in thefollowing chapter will elaborate on this statement.4.4 Experimental4.4.1 General ConsiderationsSulfonamides used in this study were purchased from Sigma-Aldrich (98-99%purity). 1H NMR spectra were collected on a Bruker Avance 300 MHz or400MHz spectrometer at ambient temperature. 1H NMR chemical shifts are65Scheme 4.1: Lewis diagrams of sulfonamides with EWG and EDG groups.Aniline is shown as a comparison.Scheme 4.2: Inductions effects of N-hydroxy sulfonamide with EWG andEDG.66reported in ppm versus residual protons in deuterated solvents as follows: 2.50, DMSO-d6 and 3.33, water. ATR-FTIR were performed on solid sam-ples using PerkinElmer Frontier FT-IR spectrometer. Mass spectrometry wasperformed using electron impact ionization mass spectrometer Kratos MS-50.CHN Elemental analysis were performed using a Carlo Erba EA1108 elementalanalyzer. Diffraction measurements for X-ray crystallography were made on aBruker X8 APEX II diffraction with graphite monochromated Mo-K↵ radiation.The structures were solved by direct methods and refined by full-matrix least-squares using the SHELXTL crystallographic software of Bruker-AXS. Unlessspecified, all non-hydrogens were refined with anisotropic displacement pa-rameters, and all hydrogen atoms were constrained to geometrically calculatedpositions but were not refined.Synthesis of N-hydroxy-benzenesulfonamide (2b). N-hydroxy benzene-sulfonamide was prepared as reported in literature,89 .90 Hydroxylamine hy-drochloride (1.44g, 20mmol) in 10mL MeOH-H2O (3:2) was treated with MgO(0.68g, 8.6mmol). A solution of sulfonyl chloride (8.6mmol) in THF (60mL) wasthen added and mixed vigorously. A second batch of MgO (0.34g, 4.3mmol)was added and the reaction was vigorously stirred for 12-18h at RT. TLC (EtOAc-hexane, 2:1) was used to confirm the disappearance of the sulfonyl chloridestarting material, the mixture was then filtered through Whatman paper, con-centrated and purified using Silicycle TLC prep plates with EtOAc-hexane, 2:1,eluent. high conversion, low purification. The band corresponding to the N-hydroxysulfonamide was extracted from silica with 80-20% MeOH:DCM, filteredand evaporated to dryness. A white solid was collected. Crude material wasrecrystallized in methanol at RT to yield white crystals. 1H NMR (300 MHz,DMSO)  9.59 (m, 2H), 7.84 (d, 2H, J=9Hz), 7.63 (m, 3H, J=13Hz). IR (ATR-FTIR) ⌫(OH) 3438 cm1, ⌫(NH) 3245 cm1, ⌫(SO)a 1321 cm1, ⌫(SO)s 1161 cm1,⌫(SN) 922 cm1. LRMS (EI): m/z Calculated: 173, Obtained: 173. ElementalAnalysis calculated for (C6H7NO3S ⇤ 0.3C4H8O2 ⇤ 0.1CH2Cl2): C, 42.13; H,4.65; N, 6.73. Obtained: C, 41.95; H, 4.32; N, 6.44.Synthesis of N-hydroxy-p-methoxybenzenesulfonamide (3b). N-hydroxyp-methoxybenzenesulfonamide was prepared as described for (2b). A white67solid was collected. The crude material was recrystallized in methanol at RT toyield white crystals. 1H NMR (300 MHz, DMSO)  9.53 (s, 1H), 9.48 (s, 1H),7.72 (d, 2H, J=9Hz), 7.42 (d, 2H, J=9Hz), 2.40 (s, 3H). IR (ATR-FTIR) ⌫(OH)3375 cm1, ⌫(NH) 3354 cm1, ⌫(SO)a 1346 cm1, ⌫(SO)s 1161 cm1, ⌫(SN) 940cm1. LRMS (ESI): m/z [M+Na+] 226.2; (EI) Calculated: 203, Obtained: 203.Elemental Analysis calculated for (C7H9NO4S ⇤ 1.45C4H8O2 ⇤ 0.8CH2Cl2): C,40.95; H, 5.61; N, 3.51. Obtained: C, 41.47 ; H, 4.98 ; N, 2.87. EA does not hit,due to apparent hydrolysis during analysis.Synthesis of N-hydroxy-toluenesulfonamide (4b). N-hydroxy toluene-sulfonamide was prepared as described for (2b). A white solid was collected.1H NMR (300 MHz, DMSO)  9.49 (s, 1H), 9.38 (s, 1H), 7.76 (d, 2H, J=9Hz),7.14 (d, 2H, J=9Hz), 3.85 (s, 3H). IR (ATR-FTIR) ⌫(OH) 3375 cm1, ⌫(NH) 3354cm1, ⌫(SO)a 1346 cm1, ⌫(SO)s 1161 cm1, ⌫(SN) 940 cm1. LRMS (ESI): m/z[M+Na+] 209.9; (EI) Calculated: 187, Obtained: 187. Elemental Analysis cal-culated for (C7H9NO3S): C, 44.91; H, 4.85; N, 7.48. Obtained: C, 44.90; H,4.87; N, 7.24.Synthesis of N-hydroxy-p-chlorobenzenesulfonamide (5b). N-hydroxyp- chlorobenzenesulfonamide was prepared as described for (2b). A white solidwas collected. 1H NMR (300 MHz, DMSO)  9.69 (s, 1H), 9.67 (s, 1H), 7.84(d, 2H, J=9Hz), 7.72 (d, 2H, J=9Hz). LRMS (EI): m/z Calculated: 207, Ob-tained: 207. Elemental Analysis calculated for (C6H6NO3SCl ⇤ 0.15C4H8O2 ⇤0.15CH2Cl2): C, 34.71; H, 3.24; N, 6. Obtained: C, 34.81; H, 3.06; N, 5.87.Synthesis of N-hydroxy-p-nitrobenzenesulfonamide (6b). N-hydroxy p-nitrobenzenesulfonamide was prepared as described for (2b). A yellowish-white solid was collected. The crude material was recrystallized in methanolat RT to yield white crystals. 1H NMR (300 MHz, DMSO)  9.95 (s, 1H),9.87 (s, 1H), 8.46 (d, 2H, J=9Hz), 8.09 (d, 2H, J=9Hz). IR (ATR-FTIR) ⌫(OH)3448 cm1, ⌫(NH) 3247 cm1, ⌫(SO)a 1343 cm1, ⌫(SO)s 1161 cm1, ⌫(SN) 914cm1. LRMS (EI): m/z Calculated: 218, Obtained: 218. Elemental Analysis for(C6H6N2O5S ⇤ 0.25C4H8O2 ⇤ 0.1CH2Cl2): C, 34.29; H, 3.22; N, 11.26. Ob-68tained: C 34.34, H 3.26, N 11.26.Synthesis of N-hydroxy-methylsulfonamide (1b). N-hydroxy methylsul-fonamide was prepared as described for (2b). A white solid was collected. 1HNMR (300 MHz, DMSO)  9.56 (s, 1H), 9.03 (s, 1H), 2.92 (s, 3H). LRMS (ESI):m/z [M+Na+] 134. Elemental Analysis calculated for (CH5NO3S⇤0.05C4H8O2⇤0.05CH2Cl2): C, 12.54; H, 4.63; N, 11.69. Obtained: C, 12.37; H, 4.53; N,11.59.4.4.2 XAS Acquisition and Data AnalysisSulfur K-edge XAS data for potassium dinitrososulfite and tertbutanesulfinamidewere acquired at Stanford Synchrotron Radiation Lightsource (SSRL). Fluores-cence data were collected at beamline 4-3 at the Stanford Synchrotron Radi-ation Lightsource (SSRL) under ring conditions of 3GeV and 60-100mA. Solidsamples were ground finely with 50% boron nitride, to minimize self-absorption,and mounted as a thin layer on sulfur-free Kapton tape at room temperature.Fluorescence data were acquired using solid state detector at ambient temper-ature and pressure. Energy calibration was carried out using sodium thiosulfate(Na2S2O3) with the first pre-edge feature being calibrated at 2472.02 eV.Sulfur K-edge XAS data for methanesulfonamide and benzenesulfonamidewere acquired at the Canadian Light Source. Total electron yield data were ac-quired at beamline SXRMB at the CLS under ring conditions of 3 GeV and 180-250mA. Solid samples were ground finely with 50% boron nitride and mountedonto a copper sample holder with carbon tape. Total electron yield data wereacquired under vacuum at ambient temperature. Calibrations were preformedas above.Raw data were normalized to incoming beam (Io), calibrated and averagedwith the BlueprintXAS 60 prefit function. Due to sulfur self-absorption in fluores-cence data, only the first scans of each run were used for tertbutanesulfinamideand potassium dinitrososulfite. As TEY does not exhibit such self-absorption,all scans per run of the two sulfonamides were averaged for greater signal-69to-noise ratio. Background subtraction and normalization of the spectra wereachieved using BlueprintXAS.61 The number of components for fits were es-timated by employing the Akaike information criterion (AIC) .62,63 The modelwith the lowest AIC was chosen for fitting of all spectra; fits with smallest sumof squared errors were chosen for background subtraction and normalizationwhich lead to the data shown in this thesis.70Chapter 5Computational Analysis ofPara-Substituent and AmideHydroxylation in Sulfonamides5.1 IntroductionIt has been previously shown that simulated DFT sulfur K-edge XAS spectrafor sulfur containing molecules like sulfonates and thiols agree well with exper-imental XAS data.91–93 In the work of Martin-Diaconescu et al., the XAS spec-trum of p-toluene sulfonic acid exhibits a main absorption peak at 2481.7eV anda shoulder at 2479.9eV. TD-DFT calculations assigned the shoulder transitionto be a SOH⇤ with a 5⇡⇤ contribution and the main peak to be a SO/SC⇤ tran-sition.39Good agreement between DFT calculations and experimental spectra havebeen established for S-nitrosothiols (RSNO), similar to sulfonamides. Szilagyiet al. show that for S-nitroso-N-acetylpenicillamine and S-nitroso-glutathione,the shoulder at ⇠2471 is due to the ON-S⇡⇤ interaction, the main peak at2473eV to the ON-S⇤ transition.42As sulfonamides and N-hydroxysulfonamides bear similarities to these com-pounds, a reasonable description of the electronic distribution of sulfonamides71and the affects of substituent changes and amide hydroxylation should be at-tained. DFT calculations of all the compounds used in Chapter 4 are used toreconstruct the XAS data and to interpret the spectra.5.1.1 DFT CalculationsAs described in Chapter 3.2.2 of this thesis, XAS simulations are calculatedusing TD-DFT excitation at the BP86/TZVP level of theory using ORCA, ver-sion 2.9.0.69 Simulated spectra for 1a and 2a, are shown in Figures Figure 3.2and Figure 3.7, respectively. The simulated spectra present satisfactory agree-ment to the experimental data. Using the same parameters, N-hydroxy meth-anesulfonamide (1b) and N-hydroxy benzenesulfonamide (2b) undergo similartreatment.Figure Figure 5.1 shows the simulated sulfur K-edge XAS spectrum of1b. Intriguingly, the prominent low energy feature is not reproduced in thecalculated spectrum. The calculated Kohn-Sham LUMO for 1b indicates aSN⇤ molecular orbital with 10.1% S3p and 15.3% N2p character, this is differ-ent from 1a LUMO in that the sulfur no longer shares electron density with themethyl carbon, instead directing its electron density directly along the sulfur-nitrogen bond. The LUMO+1 to be a SN⇡⇤ with 14.5% S3p and 13.2% N2pcharacter. LUMO+2 is SC⇤ with 18.4% C2p and 6.3%S 3p, LUMO+3 has16.8% O 2p and 24.9% S3p shared in a SO⇡⇤ with some SC⇤ . This break-down of 1b is not so different to the assessment of 1a, with the exception ofthe sulfur-nitrogen transitions moving to lower MOs; which suggests that thehydroxylation of the amide has small impact on the DFT calculation of the elec-tronic contribution.Using 2b as a model for the aryl NOHS, see Figure Figure 5.2; the LUMO isa SC⇡⇤ with 20.6% C2p and 5.6% S3p contribution to the MO. LUMO+1 has nosulfur interactions but a 4 contribution from the phenyl ring. LUMO+2 displaysSCNO⇤ where the electron density of the sulfur atom is shared amongst itsneighbors almost equally. The LUMO+3 SN⇡⇤ and NO⇤ . Once again, thisis similar to the result of 2a. The DFT calculations fall short of predicting thechanges that occur upon hydroxylation and downplays the importance of the72added amide hydroxyl. Herein, lies a very interesting point, until now DFTcalculations using the BP86/TZVP level of theory have satisfactorily describedexperimental XAS data4,39,54 and yet, now fails to include the impact of the -OH on the sulfonamide as is seen in the experimental data. Is this occurringbecause there are shortcomings in the calculations? Or are we misattributingthe appearance of this new peak to the wrong moiety?In order to rule out a flaw through the usage of a too small basis set oran incompatible functional, a thorough test was conducted. Geometry opti-mizations were performed on N-hydroxybenzenesulfonamide (2b) with eight ofthe most commonly used functionals: BP86,94,95 B3LYP,96,97 PW91,98 mP-WPW,99 mPW1PW,99 BHLYP,100 B2PLYP-D101 and mPW2PLYP-D.99,101 Anarray of def2 Ahlrichs group basis sets were also used with each functional:def2-SVP, def2-TZVP, def2-TZVPP, def2-aug-TZVPP and def2-QZVPP.102 Eachset of functional/basis set combinations were run once with and once withoutrelativistic effects using ZORA. Bond distances from the optimized geometriesfor each functional/basis set were then compared to the crystal structure of 2b,see Figure Figure 4.12. The functional/basis set combination that reproducedthe bond lengths most accurately and within a reasonable computational timeframe were selected for use.The def2-TZVP basis set returned the most reasonable geometry opti-mizations per each functional without adding extended computational time.The bond length differences of all sulfur containing bond distances from eachfunctional are shown in Figure Figure 5.3. The geometry optimizations frommPW1PW/def2-TZVP, B3LYP/def2-TZVP, BHLYP/def2-TZVP and mPW2PLYPD/def2-TZVP levels of theory produced the smallest differences in the sulfur bond dis-tances with mPW1PW and BHLYP underestimating, and B3LYP and mPW2PLYPD overestimating the bond lengths. While approximating the bond dis-tances best, mPW2PLYPD was not used in further calculations as the compu-tational time for this geometry optimization ran for approximately 28 days; incontrast the geometry optimization using BHLYP took approximately 10 hours.The sulfur-carbon, sulfur-nitrogen, sulfur-oxygen and nitrogen-oxygen bonds,Figure Figure 5.4, were best reproduced with BHLYP followed by mPW1PW.As a result, BHLYP and mPW1PW were used for further DFT analysis. The73(a) Comparison of experimental and DFT simulated spectra of 1b.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals.Figure 5.1: BP86/TZVP simulation of experimental S K-edge XAS spec-tum of N-hydroxy methanesulfonamide74(a) Comparison of experimental and DFT simulated spectra of 2b.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 2b.Figure 5.2: BP86/TZVP simulation of experimental S K-edge XAS spec-tum of N-hydroxy benzenesulfonamide.75Figure 5.3: Difference of averaged bond lengths by functional. The SN,SC and both SO bond distances for each functional were aver-aged and subtracted from the bond lengths found using crys-tallography. Bond distances using mPW1PW and BHLYP un-derestimated the experimental bond lengths while the otherfunctionals overestimated.Figure 5.4: Difference of bond length, in angstrom, between the functionaland the crystallographic data, for each bond length associatedwith the sulfur and nitrogen atoms in the sulfonamide moiety.76inclusion of relativistic effects did not improve the geometries while extendingthe computational time, as such, ZORA was not used in further calculations.For a complete table of bond lengths via functional and basis set, please seeAppendix B.1.Table 5.1: Experimental bond distances and angles of 2b, N-hydroxy ben-zenesulfonamide, from crystal structure, and calculated usingBHLYP/def2-TZVP, mPW1PW/def2-TZVP and BP86/TZVP.Bond Length (Å) XTAL BHLYP mPW1PW BP86S-C 1.752 1.756 1.763 1.786S-N 1.655 1.661 1.678 1.724S-O 1.439 1.417 1.429 1.451S-O 1.436 1.415 1.427 1.449N-O 1.429 1.390 1.399 1.433Bond Angle () XTAL BHLYP mPW1PW BP86CSN 109.14 106.95 107.11 103.02OSO 119.63 122.48 122.78 122.45SNO 109.50 112.78 112.71 110.72CSNO 58.97 56.73 57.17 86.22The BHLYP and mPW1PW functionals (both with def2-TZVP basis, hence-forth, this will be assumed for all BHLYP and mPW1PW calculations that follow)best approximated the crystal structure of 2b and, hence, were chosen to carryout XAS spectroscopic simulation. Reassessment of 1a (methanesulfonam-ide), 1b (N-hydroxy methanesulfonamide), 2a (benzenesulfonamide) and 2b(N-hydroxy benzenesulfonamide) were carried out with both functionals. Ex-cited state calculations and XAS simulations were conducted with TDDFT andXES. The energies calculated for XAS were shifted by +49.5 eV and +20.5 eVfor mPW1PW and BHLYP, respectively, to match with the experimental spec-tra68 and are shown in Figures Figure 5.5 – Figure 5.12. Since the main reasonfor these calculations is the reproduction of the peak at 2477eV, only the firstfive MOs and their contributions to the shape of the simulated spectrum will bediscussed.77The spectra for 1a, Figures Figure 5.5 and Figure 5.6, with both functionalslook similar to the BP86/TZVP level calculated spectra and show fair agree-ment with the experimental data, see Appendix B.2 for comparative spectra.Upon examination of the BHLYP MO representations, we see the LUMO andLUMO+1 have a small contribution to the shape of the spectrum. The greatercontributors LUMO+2 and LUMO+3 are the SN⇡⇤ and SN⇤ , and LUMO+4 andLUMO+5 represent SC⇡⇤ and SC⇤ transitions, respectively. Similar results areattained for the MO descriptions with the mPW1PW functional but with smallerenergy differences between the sulfur-nitrogen and sulfur-carbon transitions.These predictions resemble those made by the BP86 functional, so in the caseof methanesulfonamide the use of different functionals do not lead to disparitiesin the description of the electronic structure.Upon hydroxylation of the methanesulfonamide nitrogen, the XAS clearlyexhibits a new feature, which must directly relate to this modification. Will thechange in functionals help describe this peak? Figures Figure 5.5 and Fig-ure 5.6 show the results of the amended calculations; the peak at ⇠2477 is notreproduced with either of the functionals but an assessment of the MOs couldstill describe the what is seen in the experimental spectrum. Interestingly, thesimilarities that arose in the functionals for the 1a calculations now begin todiverge. The BHLYP excited state MO calculations show that the LUMO hasalmost no contribution to the simulated XAS shape; LUMO+4, LUMO+6 andLUMO+7 are the greater contributors. LUMO+1 has transitions to a SO⇤ andNO⇤ , LUMO+4 is a SC⇤ transition, LUMO+6 is the SN⇤ , and LUMO+7a SO⇡⇤ with a bit of SN⇤ . For mPW1PW the LUMO is now a SN⇡⇤ , andLUMO+1 is SO⇤ and NO⇤ , again these first two MOs do not contributegreatly to the overall shape, but if they were to be shifted to lower energy, couldbe seen as reproducing the lower edge feature. LUMOs 2–5 make up the mainpeak and are: LUMO+2 SO⇡⇤ and a small SC⇤ , LUMO+4 an SC⇤ alongthe sulfur-carbon bond axis and LUMO+4 is predominately SN⇤ with somesulfur-oxygen mixing.For the alkylsulfonamides the effect of the different functionals on the N-hydroxy produced mixed results. How much of a difference will there be inthe case of the the arylsulfonamides? In the BP86 calculations for both 2a78(a) Comparison of experimental and DFT simulated spectra of 1a.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 1a.Figure 5.5: BHLYP/def2-TZVP simulation of experimental S K-edge XASspectum of methanesulfonamide.79(a) Comparison of experimental and DFT simulated spectra of 1a.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 1a.Figure 5.6: mPW1PW/def2-TZVP simulation of experimental S K-edgeXAS spectum of methanesulfonamide.80(a) Comparison of experimental and DFT simulated spectra of 1a.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 1b.Figure 5.7: BHLYP/def2-TZVP simulation of experimental S K-edge XASspectum of N-hydroxy methanesulfonamide.81(a) Comparison of experimental and DFT simulated spectra of 1b.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 1b.Figure 5.8: mPW1PW/def2-TZVP simulation of experimental S K-edgeXAS spectum of N-hydroxy methanesulfonamide.82and 2b, the LUMO was a sulfur-carbon⇡⇤ mixed with electron density about thephenyl ring, the LUMO+1 had no sulfur contribution, all of the electron densitybeing centralized on the ring, as seen in Figure 5.2. The first three MOs ofbenzenesulfonamide using BP86, BHLYP, and mPW1PW are the same, thoughtheir respective contributions to the spectrum vary. The similarities go furtherfor both BHLYP and mPW1PW as the first five MOs are the same. For BHLYPLUMO (SC⇡⇤ ), LUMO+6 (SO⇤ ), LUMO+9 (SN) and LUMO+11 (SN and SOmixing) make up the shoulder and main peak of 2a. For mPW1PW: LUMO(SC⇡⇤ ), LUMO+5 (SN⇡⇤ ) and LUMO+8 (SN and SO mixing) are the importantMOs. Again, for a sulfonamide the differences in functional do not cause greatdeviations in description of the XAS spectrum.The addition of the hydroxyl group to benzenesulfonamide results in an ad-ditional shoulder to the sulfur K-edge XAS, will BHLYP or mPW1PW accuratelyreproduce these features? Once more, the first two MOs of all three functionalsare the same: LUMO is a sulfur-carbon⇡⇤ and LUMO+1 a 5 configuration. Asit was in the case of 2a, the first four MOs are the same for both BHLYP andmPW1PW, and in neither is the new shoulder replicated. The major contribu-tors for BHLYP, Figure Figure 5.9, are LUMO, LUMO+6 (SNO⇤ ) and LUMO+10(SNO mixing). Major contributors for mPW1PW, Figure Figure 5.10 are LUMO,LUMO+4 (NO⇤ , with the amide oxygen), LUMO+9 (SCN⇤ ) and LUMO+11(CSON⇤ ). It is clear that one of these lower energy features represent thesulfur-carbon ⇡⇤ interaction introduced with the aryl substituent. The XAS datasuggest the shoulder to be this sulfur-carbon ⇡⇤, Figure Figure 4.3a. What theother feature is, however, is still debatable. As seen in Figure Figure 4.3b thepeak at 2477eV is consistent through all of the N-hydroxysulfonamides, alkyland aryl. This feature should pertain not to the SC⇡⇤ but to some sulfur-nitrogeninteraction. Perhaps, then, we could surmise that the first “high intensity” MO—after LUMO— represents the electron density configuration for this featurebut at the wrong energy. For BP86 and BHLYP these would be LUMO+3 andLUMO+6, respectively, which happen to be very similar: a sulfur-nitrogen ⇡⇤and nitrogen-amide oxygen ⇤. For mPW1PW it is a mixing of sulfur-nitrogen-amide oxygen ⇤ in LUMO+4, Figure Figure 5.13. That these MOs would rep-resent sulfur-nitrogen interactions is logical as the added hydroxyl group should83(a) Comparison of experimental and DFT simulated spectra of 1a.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 2a.Figure 5.9: BHLYP/def2-TZVP simulation of experimental S K-edge XASspectum of benzenesulfonamide.84(a) Comparison of experimental and DFT simulated spectra of 2a.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 2a.Figure 5.10: mPW1PW/def2-TZVP simulation of experimental S K-edgeXAS spectum of benzenesulfonamide.85directly affect these atoms.The calculations with both functionals for the remaining compounds (bysubstituent: p- methoxybenzene (3), p- toluene (4), p- chlorobenzene (5), p-nitrobenzene (6)) are shown in Figures Figure 5.14– Figure 5.21. For all com-pounds, both sulfonamide and N-hydroxysulfonamide, EWG or EDG substituent,regardless of functional, the first two MOs are the same as for 2a and 2b. LUMOis a sulfur-carbon⇡⇤ with the phenyl ring in a 4 configuration and LUMO+1a 5 configuration. This time, however, substituent effects begin to changethe shape of the simulated spectra, and some agree reasonably well. Furtherinspection into the calculations for N-hydroxy-p- toluenesulfonamide (4b) andN-hydroxy-p- chlorobenzenesulfonamide (5b), mPW1PW in particular, follows.An assessment of 4b-BHLYP, Figure Figure 5.17a), shows LUMO and LUMO+7to be the largest contributors to the shape of the lower energy peak and shoul-der. The LUMO+7 for 4b is the same as the MO for 2b-BHLYP (LUMO+6),which is a sulfur-nitrogen ⇡⇤ and nitrogen-amide oxygen ⇤. The largest tran-sition in the main peak is LUMO+14 which is a SC⇤ .An initial look at the calculations for 4b-mPW1PW, Figure Figure 5.17b),yields a very promising match to the experimental spectrum. The main donorsto the lower energy lineshape of the spectrum are LUMO and LUMO+6. Oncemore, the same electron distribution seen for 2b-BHLYP (LUMO+6), 4b-BHLYP(LUMO+7) occurs for 4b-mPW1PW in LUMO+6.The calculations for 5b with BHLYP and mPW1PW are consistent with theprevious assessments. The MOs in the energy range for the shoulder contribu-tion for both BHLYP (LUMO+7) and mPW1PW (LUMO+5) are similar to eachother and with 2b and 4b. The main absorption peak are equivalent SC⇤ con-tributions for 5b-mPW1PW, 4b-BHLYP and 4b-mPW1PW; in 5b-BHLYP, this MOis a nitrogen-sulfur-oxygen ⇤ interaction. Figures Figure 5.22 and Figure 5.23display the equivalent MOs for the shoulder transition.A comparison of the bond lengths calculated for all sulfonamides and N-hydroxyl sulfonamides with BP86/TZVP (Figure Table 5.2, Table 5.3), BHLYP/def2-TZVP and mPW1PW/def2-TZVP levels of theory indicate small variations withineach level of theory. For both the sulfonamide and N-hydroxy sulfonamide thesulfur-carbon bond exhibited a variation of 0.02Å through the range of Ham-86(a) Comparison of experimental and DFT simulated spectra of 2b.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 2b.Figure 5.11: BHLYP/def2-TZVP simulation of experimental S K-edge XASspectum of N-hydroxy benzenesulfonamide.87(a) Comparison of experimental and DFT simulated spectra of 2b.(b) Calculated energy levels and electron density diagrams for the first six molecularorbitals of 2b.Figure 5.12: mPW1PW/def2-TZVP simulation of experimental S K-edgeXAS spectum of N-hydroxy benzenesulfonamide.88Figure 5.13: MOs for 2b, with energy density diagrams for the MOs whichmay designate the shoulder for each functional: BP86, BH-LYP and mPW1PW, as a sulfur-nitrogen interaction.mett substituent. The consistency in S-C bond length, with varying Hammettparameter, is echoed in the crystal structures. The predicted sulfur-nitrogenbond lengths exhibit a small contraction with increasing electron withdrawingcharacter in both the sulfonamides and N-hydroxy sulfonamides; but not to theextent seen in the NOH crystal structures. The bond length that displayed thegreatest variation in the crystal structures, the nitrogen-hydroxyl oxygen, variesthe least in the calculations. Once again, this echoes the problems in predictingthe lower edge XAS feature which arises with amide hydroxylation. For com-plete tables of all substituent predicted bond lengths at various levels of theory,see Appendix B.3.The predicted bond distances of alkyl and aryl sulfonamides are not shownto differ greatly. According to the predictions for the sulfonamides, the R-group— be it alkyl, aryl, electron donating or electron withdrawing— seemsto have a small impact on the overall bonding structure. However, in the case89(a) Comparison of 3a experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 3a experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.14: Experimental spectrum of p-Methoxybenzene sulfonamide(3a), in red, calculated XAS 3a spectra in dashed blue line.90(a) Comparison of 3b experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 3b experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.15: Experimental spectrum of N-hydroxy p-methoxybenzene sul-fonamide (3b), in red, calculated 3b XAS spectra in dashedblue line.91(a) Comparison of 4a experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 4a experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.16: Experimental spectrum of p-Toluenebenzene sulfonamide(4a), in red, and calculated 4a XAS spectra in dashed blueline.92(a) Comparison of 4b experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 4b experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.17: Experimental spectrum of N-hydroxy p-toluenebenzene sul-fonamide (4b), in red, and calculated 4b XAS spectra indashed blue line.93(a) Comparison of 5a experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 5a experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.18: Experimental spectrum of p-Chlorobenzene sulfonamide(5a), in red, and calculated 5a XAS spectra in dashed blueline.94(a) Comparison of 5b experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 5b experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.19: Experimental spectrum of N-hydroxy p-chlorobenzene sul-fonamide (5b), in red, and calculated 5b XAS spectra indashed blue line.95(a) Comparison of 6a experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 6a experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.20: Experimental spectrum of p-Nitrobenzene sulfonamide (6a),in red, and calculated 6a XAS spectra in dashed blue line.96(a) Comparison of 6b experimental and BHLYP/def2-TZVP simulated spectra.(b) Comparison of 6b experimental and mPW1PW/def2-TZVP simulated spectra.Figure 5.21: Experimental spectrum of N-hydroxy p-nitrobenzene sulfon-amide (6b), in red, and calculated 6b XAS spectra in dashedblue line.97Figure 5.22: MOs for 4b, with energy density diagrams for the MOs whichmay designate the shoulder for each functional: BP86, BH-LYP and mPW1PW, as a sulfur-nitrogen interaction.98Figure 5.23: MOs for 5b, with energy density diagrams for the MOs whichmay designate the shoulder for each functional: BP86, BH-LYP and mPW1PW, as a sulfur-nitrogen interaction.99Table 5.2: Experimental bond distances of sulfonamides calculated usingBP86/TZVP level of theory.Bond Length (Å) 1a 3a 4a 2a 5a 6aS-C 1.817 1.807 1.813 1.817 1.815 1.832S-N 1.729 1.733 1.729 1.726 1.724 1.704S-O 1.487 1.490 1.489 1.488 1.488 1.481S-O 1.487 1.487 1.488 1.488 1.487 1.481Table 5.3: Experimental bond distances N-hydroxy sulfonamides calcu-lated using BP86/TZVP level of theory.Bond Length (Å) 1b 3b 4b 2b 5b 6bS-C 1.821 1.793 1.801 1.806 1.804 1.814S-N 1.804 1.784 1.781 1.780 1.778 1.775S-O 1.478 1.487 1.487 1.487 1.486 1.485S-O 1.497 1.497 1.496 1.495 1.494 1.492N-O 1.422 1.425 1.425 1.424 1.423 1.420of the N-hydroxy alkylsulfonamide, both the sulfur-carbon and sulfur-nitrogenbond distance are elongated, compared to the N-hydroxy arylsulfonamides.Could this lead to the assumption that both the sulfur-carbon and the sulfur-nitrogen bonds are weaker for alkyl substitutions? If we apply the trends givenin the aryl sulfonamides, to a view of the sulfur from the alkyl perspective,the elongation of the SC bond indicates an electron withdrawing nature of themethyl group; from the nitroxyl side of the sulfur, an electron donating nature.It is clear that the sulfone oxygens create areas of delocalized electron densitywhich may stabilize this counterintuitive development. The NO bond length,again, shows little change within R-group variance; and it is likely that a bet-ter description of this electron rich area would allay the behavior seen in thesimulations.Hammett plots for the sulfur-nitrogen, sulfur-carbon and nitrogen-hydroxyloxygen are show in Figures Figure 5.24. The calculations and assessments tofollow will be using BP86/TZVP level of theory.100(a) Sulfonamides.(b) N-hydroxy sulfonamides.Figure 5.24: Hammett plots of sulfur-carbon bond lengths calculated atthe BP86/TZVP vs. p,+,R .101(a) Sulfonamides.(b) N-hydroxy sulfonamides.Figure 5.25: Hammett plots of sulfur-nitrogen bond lengths calculated atthe BP86/TZVP vs. p,+,R .102Figure 5.26: Hammett plots of nitrogen-oxygen bond lengths at theBP86/TZVP level of N-Hydroxy sulfonamides vs. p,+,R .The geometry predicted with BP86/TZVP gives rise to the following Ham-mett equations:For the NOHS sulfur-carbon bond distances:S C = 0.017 p + 1.80 R2 = 0.813 (5.1)S C = 0.013 + + 1.80 R2 = 0.961 (5.2)S C = 0.044 R + 1.81 R2 = 0.950 (5.3)For the NOHS sulfur-nitrogen bond distances:S N = 0.008 p + 1.78 R2 = 0.951 (5.4)103S N = 0.006 + + 1.78 R2 = 0.980 (5.5)S N = 0.020 R + 1.78 R2 = 0.956 (5.6)The best fit for both SC and SN bond distances once again occurs with +.The trends for the SN agrees with that of the equations found for the NOHScrystal structure. The contraction of the sulfur-nitrogen bond with EWG is con-sistent with the idea that the bond is stabilized between two electron denseareas. This does not necessarily correlate to the strength of the bond. As seenin Scheme Scheme 4.2 this contraction could occur due to electrostatics, anEWG will destabilize this bond leading to cleavage of S-N.5.2 ConclusionThe DFT calculations lead to very interesting results. The XAS spectra forthe unsubstituted amide sulfonamide compounds were successfully simulatedusing BP86/TZVP level of theory. To recap, the XAS data for methanesulfon-amide shows a single absorption peak, which corresponds to a ⇤ frameworkthrough the carbon-sulfur-nitrogen bonds. Experimentally, the introduction ofan aryl group produced a shoulder (peak X), at approximately 2478eV, whichcomputationally was shown to correspond to the sulfur-carbon ⇡⇤. Upon amidehydroxylation of methane sulfonamide, a new feature emerges in the XAS ataround 2477eV (peak Y), due to a perturbation in the nature of the sulfur-nitrogen bond. This feature is also seen in the aryl N-hydroxy sulfonamides,at similar energies; these aryl compounds present both a shoulder due to theSC⇡⇤ (peak X) and a peak due to sulfur-nitrogen interaction (peak Y). The sim-ulated spectra for these N-hydroxy compounds, however, no longer faithfullyreproduce the experimental data. The use of a variety of functionals and ba-sis sets still fall short of explaining the peak at 2477eV. The experimental dataclearly indicate that the hydroxyl substitution to the nitrogen has a far greater104impact on the sulfonamide moiety than the calculations suggest. Substituenteffects also do not exhibit a large affect on the outcome of the simulated spec-tra regardless of functional, as seen in Figures Figure 5.27 and Figure 5.28.The only noticeable difference is a shift in the SC⇡⇤ peak at 2477eV to approxi-mately 0.5eV higher for the nitrobenzene species. This is somewhat consistentto the experimental data, where the greater differences are seen to occur withchanges at the nitrogen as opposed to changes at the R-group.Why is it, then, that with satisfactory descriptions of molecules like sulfonicacids and s-nitrosothiols are we no longer able to describe N-hydroxy sulfon-amides and its seemingly small modification? An explanation could lie in the in-congruity of predicting an excited state model, using a ground state calculation.X-ray absorption spectroscopy is an excited state description of a moleculewhile DFT is based on a ground state model. The application TD-DFT to excitethe S1s core electron and the subsequent relaxation of the remaining electronsto fill said core hole may not accurately reflect the actual electronic structure ofsulfonamides, and hence, would not accurately predict how the hydroxylationwould affect its structure. There is also the possibility that the sulfur-nitrogen⇤ ,which appears at higher energy—at approximately 2480eV—represents the lowenergy peak but simply appears at the wrong energies in the calculations. Cal-culated transitions from the sulfur 1s to SC MOs and SN MOs would occur atsimilar energies and it is possible with BHLYP or mPW1PW functionals the SNtransitions are overestimated and may in reality be lower.We can arrive at the conclusion that regardless of the incomplete descrip-tion of the sulfonamide moiety, a new perspective is revealed with the sulfurK-edge data. It is interesting to see that small modifications can have an suchan impact not only on the XAS spectra but also on our ability to describe theelectronic structure of sulfonamides using standard DFT methods. Undoubt-edly, XAS/DFT of other small organic molecules will show some disparity orperhaps, even, suggest a better model from which the electronic structure ofsulfonamides can be better understood.105(a) Sulfonamides.(b) N-hydroxy sulfonamides.Figure 5.27: BHLYP/def2-TZVP XAS spectra.106(a) Sulfonamides.(b) N-hydroxy sulfonamides.Figure 5.28: mPW1PW/def2-TZVP XAS spectra.107Chapter 6Concluding Remarks andFuture DirectionsIn this thesis, the electronic structure of sulfonamides and its affects on thesulfur-nitrogen bond have been investigated. Factors that govern transmissioneffects through this bond are important in understanding the sulfur-nitrogenbond, which is a crucial aspect in determining NO and HNO release. Variousmodifications to the sulfonamide moiety have illustrated that small changes canlead to large perturbations in the electronic distribution of the molecule. The useof sulfur K-edge x-ray absorption spectroscopy has allowed a unique view ofthe outcomes of these modifications on the sulfur atom and, hence, the sulfur-nitrogen bond.In Chapter three the effect of changes in R-group and oxidation state on thesulfonamide moiety were explored. XAS data show that each addition of oxy-gen shifts the sulfur Zeff to higher energies. Methanesulfonamide and tert-butylsulfinamide exhibit similarly shaped absorption peaks, each with a single mainabsorption peak. DFT calculations show that the LUMO for both are a mixedsulfur-nitrogen-sulfone oxygen⇤ framework. The alteration of an alkyl R-groupto an aryl substituent, as in benzene sulfonamide, displays an additional lowenergy shoulder to the main absorption peak. This shoulder was confirmed viaDFT as the sulfur-carbon⇡⇤ . DFT calculations of sulfinated amides also indi-cate a more delocalized sigma framework with each addition of oxygen which108is consistent with the idea that, as a functional group the sulfinamido groupis least electron withdrawing of carbonyl compounds, sulfones and sulfonateesters.10Chapter four investigates modifications of the sulfonamide R-group withHammett parameters. Substituent effects do not exhibit a straight-forward trendin the N-hydroxy sulfonamide and parent sulfonamide XAS spectra; where thechanges in the R-group are largely overshadowed by the amide hydroxylation,further cementing the complex nature of the sulfonamide moiety. To furtherparse the effects of these modifications, more traditional spectroscopic tech-niques were used in conjunction with quantitative structure activity relation-ships. QSAR studies showed NMR and x-ray crystallographic data correlatedwell with Hammett parameters and that for the sulfonamide nitrogen, electron-withdrawing groups would lead to a more positive nitrogen. The bond lengthdata trend is also supported by Sirsalmath et al.,29 where substituents withEWG groups have shorter NO bond lengths, and is interpreted to mean thata shorter NO bond length would facilitate the formation of HNO, which woulddestabilize the sulfur-nitrogen bond. IR stretching frequencies for sulfonamidesblueshifted upon hydroxylation for the ⌫ sulfur-nitrogen and ⌫nitrogen-oxygenstretching frequencies; however, the most redshifted of these were the electron-withdrawing substituents for the N-hydroxy sulfonamides, again pointing to adestabilization of the S-N bond. Mainly, substituent effects by R-group weremostly inductive with some potential for stabilization by resonance, yet substi-tutions at the amide had a far larger impact on the QSAR and XAS studies.In Chapter five DFT calculations of the sulfonamides and N-hydroxy sulfon-amides, used in Chapter four, were carried out to further examine and simulatethe XAS spectra. For the parent sulfonamides, reasonable DFT estimates andspectral simulations were achieved. DFT calculations fell short, however, whenreproducing the lower edge XAS feature which arises upon amide hydroxyla-tion. A thorough test of various functionals and basis sets resulted in the selec-tion of mPW1PW and BHLYP as functionals to be used for the XAS simulationof sulfonamides. The low energy feature was still not faithfully reproduced, butthe simulated spectra were much more closely emulated. It is possible thatthe calculated transition energies for SC⇤ and SN⇤ are very close and the109functionals may transpose the energies for these two transitions.It has been shown that bacteriostatic activity in sulfonamides are very de-pendent on variations of the N atom of the sulfonamido group.41,76 We haveseen that an alteration from a proton to a hydroxyl group pulls electron densityaway from the nitrogen perturbing the bond between the sulfur and nitrogen.Immediate future work will center on exploring how further substitutions on theamide, see Figure Figure 6.1, will affect the sulfonamido moiety. XAS data hasbeen acquired and initial data analysis indicates that a methoxy substituenton the amide nitrogen has a similar effect as the hydroxyl substituent on theXAS spectra; whereas, phenyl or methyl substitution does not exhibit the lowerenergy peak Y. QSAR and DFT calculations will be undertaken to further inves-tigate these modifications.Though this body of work has focused on utilizing XAS for sulfonamides assmall organic molecules, the use of sulfonamides as ligands to metal centerswould allow a glimpse of these molecules in a different electronic environment.Further work on nitric oxide and azanone release could be based on usingsulfonamides as ligands for coordination to metal centers. For example, bio-logically some tissues contain both HNO and NO. As the two species exhibitdifferent behavior biochemically in vasodilation processes, a selective trap forone will enable the other to complete its dilatory function. Ferric porphyrins withN-hydroxy sulfonamide ligands have been shown to trap NO, yielding ferrousnitrosyl compounds.103 Mn(III) porphyrins with N-hydroxyl sulfonamide ligands,on the other hand, have been shown to trap HNO.104 The selectivity of NOand HNO to the different metal centered porphyrins would be an interestingcandidate for metal-sulfur ligand XAS.Another interesting line of sulfonamide research would be in the structure-activity of carbonic anhydrase. Carbonic anhydrase (CA) is a well studied zincmetalloenzyme which is strongly inhibited when bound to sulfonamides. Thereare an array of CA isozymes in a plethora of tissue and cells, but there arefew specific isozyme inhibitors.15,105 CA inhibitors can be prone to side-effectswhen used as drugs so specificity of inhibition would greatly enhance the useof sulfonamides as drugs. The use of metal-sulfonamide ligand XAS and DFTcould explain how CAs bind so strongly to the sulfonamides by revealing the110Figure 6.1: Amide substitutions and S K-edge XAS spectra of Benzene-sulfonamide (—), N-CH3 Benzenesulfonamide (– –), N-PhBenzenesulfonamide (– –), N-OH Benzenesulfonamide (—)and N-OCH3 Benzenesulfonamide (—).111electronic framework. Subsequent work could then be focused on enhancingspecific aspects of this Zn(II)-sulfonamide bond to target inhibition of specificisozymes.Overall, this thesis has shown that S K-edge XAS has proven a very ef-fective tool for the study of small molecules. We have found evidence for aninteresting electronic structure for sulfonamides which has not been seen withother methods of analysis. 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Journal of BiologicalInorganic Chemistry 2009, 14, 935–945.123Appendix AExperimental DataA.1 1H NMRVerticalScaleFactor=11o_2013.001.esp12 11 10 9 8 7 6 5 4 3 2 1 0ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.001.94NH2CH3WaterDMSO2.482.492.492.903.316.79Figure A.1: 1H NMR spectrum of methanesulfonamide (1a)124VerticalScaleFactor=11xo2013t2.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.000.820.88OHNHH2OCH3DMSO2.492.49 2.502.913.319.039.56Figure A.2: 1H NMR spectrum of N-hydroxy methanesulfonamide (1b)125VerticalScaleFactor=16o_DMSO.001.esp131211109876543210-1ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity1.855.01H2ODMSONH2Ph2.502.503.337.35 7.577.597.82 7.84Figure A.3: 1H NMR spectrum of benzenesulfonamide (2a)126VerticalScaleFactor=16xodmso1.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity5.001.73H2ODMSOOH/NHPh1.242.492.50 2.51 2.513.327.607.627.647.687.707.827.837.859.579.589.599.60Figure A.4: 1H NMR spectrum of N-hydroxy benzenesulfonamide (2b)127VerticalScaleFactor=18o_2013.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.002.001.841.87OCH3H2ODMSO-d6NH2PhPh2.50 2.513.323.827.077.107.207.737.76Figure A.5: 1H NMR spectrum of p-methoxybenzene sulfonamide (3a)128VerticalScaleFactor=18xo_2013_1.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.003.970.57OCH3H2ODMSOOH/NHPh1.242.502.51 2.513.163.183.333.733.753.857.127.157.747.779.409.50Figure A.6: 1H NMR spectrum of N-hydroxy p-methoxybenzenesulfonamide (3b)129VerticalScaleFactor=14o_2013.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.001.833.97DMSOCH3NH2H2OPh2.372.50 2.513.327.267.387.69 7.72Figure A.7: 1H NMR spectrum of p-toluene sulfonamide (4a)130VerticalScaleFactor=14xo_2013.002.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity3.003.711.75OH/NHH2ODMSO CH3Ph2.402.50 2.513.327.407.437.707.739.489.53Figure A.8: 1HNMR spectrum of N-hydroxy p-toluene sulfonamide (4b)131VerticalScaleFactor=15odmso.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity2.004.42NH2H2ODMSOPh2.503.327.467.647.677.81 7.84Figure A.9: 1H NMR spectrum of p-chlorobenzene sulfonamide (5a)132VerticalScaleFactor=15xo_june2013.002.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity4.001.90H2ODMSOOH/NHPh2.492.50 2.513.327.707.737.82 7.859.679.69Figure A.10: 1H NMR spectrum of N-hydroxy p-chlorobenzene sulfon-amide (5b)133VerticalScaleFactor=17o_2013.001.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity1.954.00NH2H2ODMSOPh2.50 2.503.327.738.058.088.40 8.43Figure A.11: 1H NMR spectrum of p-nitrobenzene sulfonamide (6a)134VerticalScaleFactor=17xo_2013.003.esp1211109876543210ChemicalShift(ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00NormalizedIntensity1.952.002.01H2ODMSOOH/NHPh1.242.492.50 2.513.328.078.108.448.479.879.95Figure A.12: 1H NMR spectrum of N-hydroxy p-nitrobenzene sulfonamide(6b)135A.2 ATR-FTIRFigure A.13: IR spectra of methanesulfonamide (blue) and N-hydroxymethanesulfonamide (red).136Figure A.14: IR spectra of benzenesulfonamide (blue) and N-hydroxybenzenesulfonamide (red).137Figure A.15: IR spectra of p-methoxybenzenesulfonamide (blue) and N-hydroxy p-methoxybenzenesulfonamide (red).138Figure A.16: IR spectra of toluenesulfonamide (blue) and N-hydroxy tolu-enesulfonamide (red).139Figure A.17: IR spectra of p-chlorobenzenesulfonamide (blue) and N-hydroxy p-chlorobenzenesulfonamide (red).140Figure A.18: IR spectra of p-nitrobenzenesulfonamide (blue) and N-hydroxy p-nitrobenzenesulfonamide (red).141A.3 Selected Crystallographic DataTable A.1: Selected crystallographic data for compounds 2b, 3b and 6b.2b 3b 6bChem. Formula C6H7SNO3 C7H9SNO4 C6H6SN2O5FW 173.19 203.21 218.19T (K) 100 100 90.0a (Å) 16.889(3) 6.9725(5) 10.0873(4)b (Å) 4.9434(8) 10.2563(7) 7.2208(3)c (Å) 8.6310(14) 11.8863(8) 12.1744(5)↵ (deg) 90.00 88.443(3) 90.00 (deg) 90.00 83.466(3) 109.225(2) (deg) 90.00 85.485(3) 90.00volume (Å) 720.6(2) 841.73(10) 837.31(6)crystal system orthorhombic triclinic monoclinicspace group Pna21 P-1 P2(1)/n142Appendix BCalculated Data143B.1 DFT Level of Theory CalculationsFunctional Def2-SVP Def2-TZVP Def2-TZVPP Def2-aug-TZVPP Def2-QZVPPSC 1.804 1.786 1.786 1.787 1.786SN 1.762 1.724 1.732 1.722 1.722BP86 SO 1.476 1.451 1.451 1.448 1.446SO 1.477 1.449 1.449 1.452 1.449NO 1.417 1.433 1.433 1.432 1.433SC 1.794 1.778 1.778 1.779 1.778SN 1.727 1.698 1.698 1.698 1.697B3LYP SO 1.462 1.437 1.437 1.437 1.434SO 1.461 1.434 1.434 1.434 1.431NO 1.405 1.418 1.418 1.417 1.417SC 1.799 1.781 1.781 1.782 1.781SN 1.755 1.718 1.718 1.717 1.716PW91 SO 1.474 1.447 1.449 1.45 1.444SO 1.474 1.449 1.447 1.446 1.447NO 1.413 1.429 1.428 1.427 1.428SC 1.778 1.763 1.763 1.764 1.763SN 1.703 1.678 1.678 1.678 1.677mPW1PW SO 1.453 1.429 1.429 1.430 1.427SO 1.452 1.427 1.427 1.427 1.424NO 1.387 1.399 1.399 1.398 1.399SC 1.769 1.756 1.756 1.756 1.756SN 1.683 1.661 1.661 1.661 1.660BHLYP SO 1.441 1.417 1.417 1.417 1.414SO 1.439 1.415 1.415 1.415 1.412NO 1.380 1.390 1.390 1.389 1.389SC 1.784SN 1.717B2LYP SO 1.461SO 1.460NO 1.406SC 1.784SN 1.721mPWPW SO 1.450SO 1.478NO 1.430SC 1.762SN 1.682mPW2PLYPD SO 1.431SO 1.429NO 1.413Basis Set!Figure B.1: Calculated bond lengths of N-hydroxy benzenesulfonamideusing sundry functionals and basis sets.144Functional Def2-SVP Def2-TZVP Def2-TZVPP Def2-aug-TZVPP Def2-QZVPPSC 1.805 1.786 1.786 1.787SN 1.766 1.726 1.726 1.725BP86 SO 1.478 1.451 1.451 1.449ZORA SO 1.477 1.449 1.448 1.446NO 1.419 1.433 1.434 1.433SC 1.795 1.778SN 1.731 1.700B3LYP SO 1.463 1.436ZORA SO 1.462 1.434NO 1.406 1.419SC 1.800 1.781 1.781 1.782SN 1.759 1.720 1.720 1.719PW91 SO 1.475 1.449 1.449 1.447ZORA SO 1.475 1.447 1.446 1.445NO 1.414 1.430 1.429 1.429SC 1.779 1.763 1.764SN 1.704 1.679 1.679mPW1PW SO 1.455 1.43 1.429ZORA SO 1.454 1.427 1.427NO 1.386 1.4 1.400SC 1.770 1.751SN 1.684 1.656BHLYP SO 1.442 1.439ZORA SO 1.441 1.436NO 1.379 1.430SC 1.782SN 1.716B2LYP SO 1.46ZORA SO 1.459NO 1.407SC 1.785SN 1.724mPWPW SO 1.450ZORA SO 1.448NO 1.431SC 1.787SN 1.726BP86 RIJCOSX SO 1.452ZORA SO 1.449NO 1.434SC 1.763SN 1.684mPW2PLYP-D SO 1.429ZORA SO 1.431NO 1.414Basis Set!Figure B.2: Calculated bond lengths of N-hydroxy benzenesulfonamideusing relativistic effects (ZORA) in conjunction to sundry func-tionals and basis sets.145B.2 Comparison of S K-Edge Spectrum SimulationFigure B.3: Comparison of methane sulfonamide experimental data withcalculated data; BP86, BHLYP, and mPW1PW146Figure B.4: Comparison of NOH- methane sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW147Figure B.5: Comparison of benzene sulfonamide experimental data withcalculated data; BP86, BHLYP, and mPW1PW148Figure B.6: Comparison of NOH- benzenesulfonamide experimental datawith calculated data; BP86, BHLYP, and mPW1PW149Figure B.7: Comparison of p- methoxybenzene sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW150Figure B.8: Comparison of NOH-p- methoxybenzene sulfonamide ex-perimental data with calculated data; BP86, BHLYP, andmPW1PW151Figure B.9: Comparison of toluene sulfonamide experimental data withcalculated data; BP86, BHLYP, and mPW1PW152Figure B.10: Comparison of NOH-toluene sulfonamide experimental datawith calculated data; BP86, BHLYP, and mPW1PW153Figure B.11: Comparison of p-chlorobenzene sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW154Figure B.12: Comparison of NOH-p- chlorobenzene sulfonamide exper-imental data with calculated data; BP86, BHLYP, andmPW1PW155Figure B.13: Comparison of p- nitrobenzene sulfonamide experimentaldata with calculated data; BP86, BHLYP, and mPW1PW156Figure B.14: Comparison of NOH-p- nitrobenzene sulfonamide exper-imental data with calculated data; BP86, BHLYP, andmPW1PW157B.3 DFT Bond Distances for Sulfonamide CompoundsTable B.1: Experimental bond distances of sulfonamides calculated usingBP86/TZVP level of theory.Bond Length (Å) 1a 3a 4a 2a 5a 6aS-C 1.817 1.807 1.813 1.817 1.815 1.832S-N 1.729 1.733 1.729 1.726 1.724 1.704S-O 1.487 1.490 1.489 1.488 1.488 1.481S-O 1.487 1.487 1.488 1.488 1.487 1.481Table B.2: Experimental bond distances N-hydroxy sulfonamides calcu-lated using BP86/TZVP level of theory.Bond Length (Å) 1b 3b 4b 2b 5b 6bS-C 1.821 1.793 1.801 1.806 1.804 1.814S-N 1.804 1.784 1.781 1.780 1.778 1.775S-O 1.478 1.487 1.487 1.487 1.486 1.485S-O 1.497 1.497 1.496 1.495 1.494 1.492N-O 1.422 1.425 1.425 1.424 1.423 1.420Table B.3: Experimental bond distances of sulfonamides calculated usingBHLYP/Def2-TZVP level of theory.Bond Length (Å) 1a 3a 4a 2a 5a 6aS-C 1.757 1.751 1.756 1.760 1.759 1.772S-N 1.635 1.636 1.634 1.632 1.631 1.616S-O 1.419 1.420 1.419 1.419 1.418 1.414S-O 1.419 1.420 1.419 1.419 1.418 1.414158Table B.4: Experimental bond distances N-hydroxy sulfonamides calcu-lated using BHLYP/Def2-TZVP level of theory.Bond Length (Å) 1b 3b 4b 2b 5b 6bS-C 1.756 1.739 1.745 1.749 1.748 1.757S-N 1.676 1.663 1.661 1.660 1.658 1.654S-O 1.412 1.418 1.417 1.417 1.417 1.415S-O 1.425 1.424 1.424 1.423 1.422 1.420N-O 1.389 1.384 1.384 1.384 1.383 1.381Table B.5: Experimental bond distances of sulfonamides calculated usingmPW1PW/Def2-TZVP level of theory.Bond Length (Å) 1a 3a 4a 2a 5a 6aS-C 1.765 1.758 1.763 1.768 1.766 1.779S-N 1.649 1.650 1.648 1.646 1.644 1.631S-O 1.431 1.432 1.431 1.431 1.430 1.426S-O 1.431 1.432 1.431 1.431 1.430 1.426Table B.6: Experimental bond distances N-hydroxy sulfonamides calcu-lated using mPW1PW/Def2-TZVP level of theory.Bond Length (Å) 1b 3b 4b 2b 5b 6bS-C 1.764 1.746 1.752 1.756 1.755 1.764S-N 1.695 1.679 1.677 1.676 1.674 1.669S-O 1.424 1.430 1.430 1.429 1.429 1.428S-O 1.439 1.438 1.437 1.436 1.436 1.434N-O 1.397 1.393 1.393 1.392 1.392 1.390159Appendix CDFT input filesC.1 Selected ORCA Input Files#2a, benzenesulfonamide#Geometry optimization! UKS BP86 RI TZVP TightSCF SlowConv SCFConv7 OPT NumFreq*xyz 0 1S -0.120179 1.583225 -0.173336N -0.004535 1.540635 -1.894918O 1.217804 1.222062 0.370497O -0.821307 2.849209 0.173753C -1.250781 0.208274 0.194786C -0.717309 -1.054805 0.458683C -1.592332 -2.106312 0.745858C -2.973371 -1.884647 0.773721C -3.487836 -0.608183 0.519113C -2.625339 0.452170 0.228519H -0.286265 2.455532 -2.256584H 0.962827 1.328791 -2.152212H 0.363226 -1.202579 0.452272H -1.191675 -3.098742 0.958182H -3.651604 -2.708506 1.002341H -4.564602 -0.433207 0.554824H -3.005960 1.457083 0.044500*$new_job! UKS BP86 RI TZVP TightSCF SlowConv SCFConv7%base "2a_xes"160%xes Coreorb 0,0OrbOp 0,1end*xyzfile 0 1 2a.xyz$new_job! UKS BP86 RI TZVP TightSCF SlowConv SCFConv7%base "2a_tddft"%tddft OrbWin[0] = 0,0,-1,-1OrbWin[1] = 0,0,-1,-1nroots 200maxdim 40000triplets trueDoQuad trueend*xyzfile 0 1 2a.xyz!normalprint!grid4 nofinalgrid#2a, benzenesulfonamide! UKS BHLYP NORI Def2-TZVP TightSCF SlowConv SCFConv7 OPT*xyz 0 1S -0.120179 1.583225 -0.173336N -0.004535 1.540635 -1.894918O 1.217804 1.222062 0.370497O -0.821307 2.849209 0.173753C -1.250781 0.208274 0.194786C -0.717309 -1.054805 0.458683C -1.592332 -2.106312 0.745858C -2.973371 -1.884647 0.773721C -3.487836 -0.608183 0.519113C -2.625339 0.452170 0.228519H -0.286265 2.455532 -2.256584H 0.962827 1.328791 -2.152212H 0.363226 -1.202579 0.452272H -1.191675 -3.098742 0.958182H -3.651604 -2.708506 1.002341H -4.564602 -0.433207 0.554824H -3.005960 1.457083 0.044500*#XES161! UKS BHLYP NORI Def2-TZVP TightSCF SlowConv SCFConv7%base "xes_2abh"%xes Coreorb 0,0OrbOp 0,1end*xyzfile 0 1 2a_bhlyp.xyz#TDDFT! UKS BHLYP NORI Def2-TZVP TightSCF SlowConv SCFConv7%base "tddft_2abh"%tddft OrbWin[0] = 0,0,-1,-1OrbWin[1] = 0,0,-1,-1nroots 200maxdim 40000triplets trueDoQuad trueend*xyzfile 0 1 2a_bhlyp.xyz#peripheral information!normalprint!grid4 nofinalgrid#2a, benzenesulfonamide! UKS mPW1PW NORI Def2-TZVP TightSCF SlowConv SCFConv7 OPT*xyz 0 1S -0.120179 1.583225 -0.173336N -0.004535 1.540635 -1.894918O 1.217804 1.222062 0.370497O -0.821307 2.849209 0.173753C -1.250781 0.208274 0.194786C -0.717309 -1.054805 0.458683C -1.592332 -2.106312 0.745858C -2.973371 -1.884647 0.773721C -3.487836 -0.608183 0.519113C -2.625339 0.452170 0.228519H -0.286265 2.455532 -2.256584H 0.962827 1.328791 -2.152212H 0.363226 -1.202579 0.452272H -1.191675 -3.098742 0.958182H -3.651604 -2.708506 1.002341H -4.564602 -0.433207 0.554824H -3.005960 1.457083 0.044500*162#XES! UKS mPW1PW NORI Def2-TZVP TightSCF SlowConv SCFConv7%base "xes_2ampw"%xes Coreorb 0,0OrbOp 0,1end*xyzfile 0 1 2a_mpw.xyz#TDDFT! UKS mPW1PW NORI Def2-TZVP TightSCF SlowConv SCFConv7%base "tddft_2ampw"%tddft OrbWin[0] = 0,0,-1,-1OrbWin[1] = 0,0,-1,-1nroots 200maxdim 40000triplets trueDoQuad trueend*xyzfile 0 1 2a_mpw.xyz#peripheral information!normalprint!grid4 nofinalgrid163

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