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The study of cavitands and carceplexes with C5 symmetry Place, Samuel 2001

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The study of cavitands and carceplexes with C5 symmetry by Samuel Place B.Sc. H o n , University of Aberdeen, Scotland, 1998 A THESIS S U B M I T T E D IN P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F M A S T E R O F S C I E N C E in T H E F A C U L T Y O F G R A D U A T E S T U D I E S (Department of Chemistry) We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y O F BRITISH C O L U M B I A March, 2001 © Samuel Place, 2001 In p r e s e n t i n g this thesis in partial fulfi lment of the r e q u i r e m e n t s for an a d v a n c e d d e g r e e at the University of British C o l u m b i a , I agree that the Library shall m a k e it freely available for reference a n d study. I further agree that p e r m i s s i o n for extensive c o p y i n g of this thesis for scholarly p u r p o s e s may b e g r a n t e d b y the h e a d of m y d e p a r t m e n t or b y his o r her representatives . It is u n d e r s t o o d that c o p y i n g o r p u b l i c a t i o n of this thesis for financial gain shall not b e a l l o w e d w i t h o u t m y writ ten p e r m i s s i o n . T h e Universi ty of British C o l u m b i a V a n c o u v e r , C a n a d a D e p a r t m e n t D a t e DE -6 (2/88) Abstract This thesis presents a study of the synthesis of carceplex 65*2 D M F . [5]cavitand 58 was synthesized and the 2-methyl groups then underwent selective free radical bromination to give Br-[5]cavitand 60, which was converted to SH-[5]cavitand 61. The coupling of two molecules SH-[5]cavitand 61 proved to be successful and led to the formation of carceplex 65*2 D M F which has a C5 symmetry unique to carceplexes as well as hemispheres that are linked by disulfide bonds. N M R data showed carceplex 65 to have encapsulated 2 D M F molecules. M A L D I M S experiments confirmed the correct mass of disulfide carceplex 6 5 » 2 D M F . Carceplex 65*2 D M F is an intriguing system for several reasons: 1) 65*2 D M F is the first ever carceplex that possesses a C5 symmetry 2) 6 5 » 2 D M F is the first carceplex system that has disulfide linkers and 3) 65 has the ability to encapsulate multiple guest molecules (2 D M F ' s ) within its interior. These unique characteristics have been investigated and shall be reported within this thesis. i i Table of Contents Abstract 1 1 Table of Contents . i u List of Figures V 1 List of Schemes viii List of Charts and Tables and Equations. ix List of Abbreviations x Acknowledgements x * Chapter 1. Introduction 1.1 General Introduction • 1 1.2 Cyclodextrins 4 1.3 Calixarenes 6 1.4 Resorcinarenes 8 1.5 Cavitands 12 i . [4] Cavitand enlargement 13 i i . Vases and Kites 14 iii . Capsules-Hosts with a large internal cavity. 16 1.6. Carceplexes 19 i . Templation studies and molecular encapsulation 20 i i . Restricted Motion of Guest in Carceplexes and Capsules 22 iii 1.7. Hemicarceplexes 22 i . Hemicarceplex formation via linker variation 23 1.8. Giant Carceplex entrapping three Organic Molecules 27 1.9. Disulfide Bonds as Linker Units 29 1.10. Project outline and Thesis Goals 31 1.11. References 32 Chapter 2. Formation of Cavitands and Carceplexes with C 5 Symmetry 2.1. Introduction 36 2.2. Results and Discussion 37 i . The synthesis of [5]cavitand 58 37 i i . Selective Functionalization of [5]cavitand 58 41 a) Radical Bromihation of 2-methyl substituent 41 b) Conversion of Br-[5]cavitand 60 to SH-[5]cavitand 61 47 iii . Synthesis of Carceplex 65»guest(s) 49 a) Attempted synthesis of Carceplex 64 •guest(s) 50 b) ' H N M R data 53 c) Verifying Parent Peaks in M S data 55 d) I.R Spectroscopic data 57 iv e) Variable Temperature ! H N M R 62 f) Guest Orientation within the Carceplex Interior 64 g) Computer Simulation of Guest Orientation 66 h) Possible Mechanism for the Formation of Disulfide Carceplex 65»2 D M F 69 2.3 Conclusions • 71 2.4 Future Developments and Applications 72 2.5 Experimental. 74 i . Synthesis of [5]cavitand 58 74 ii . Functionalization of [5]cavitand 58 76 a) Synthesis of Br-[5]cavitand 60 76 b) Synthesis of SH-[5]cavitand 61 76 c) Synthesis of OAc-[5]cavitand 62. 77 d) Synthesis of SAc-[5]cavitand 63 78 iii . Synthesis of carceplex 65«2 D M F 78 2.6 References 80 V List of Figures Chapter 1 Figure 1.1. Pedersen's Crown ethers 2 Figure 1.2. Lehn's Cryptands 4,5 and Cram's Spherands 6,7 3 Figure 1.3. Cyclodextrins: degradation products of starch 5 Figure 1.4. Calix[n]arenes 7 Figure 1.5. The resorcin[4]arene structure 9 Figure 1.6. First generation cavitands 13 Figure 1.7. Enlargement of cavitands. 13 Figure 1.8. The vase and kite conformers of cavitand 23 16 Figure.1.9. Combination of calixarene and cavitand to create Reinhoudts' holand 31 structure 18 Figure 1.10. The first carceplex 32• Guest 20 Figure 1.11. Disulfide bond between cysteine residues in a peptide chain 29 Figure 1.12 Cavitein 53, a cavitand templated, disulfide linked three helical bundle. ...30 Chapter 2 Figure 2.1 X-ray crystal structure of [5]cavitand 58 38 Figure 2.2. The lH N M R spectrum of [5]cavitand 58 39 Figure 2.3. Schematic representation of the method of measuring the distance of the upper and lower rims of cavitands 57 and 58 41 Figure 2.4. 1H N M R spectrum of Br-[5]cavitand 60 43 Figure 2.5. M A L D I M S spectrum of Br-[5]cavitand 60 44 v i Figure 2.6. ! H N M R spectrum of 0Ac-[5]cavitand 62 46 Figure 2.7. *H N M R spectrum of SH-[5]cavitand 61 48 Figure 2.8. Unsuccessful templates for the formation of sulfide linked carceplex 64«guest(s) 50 Figure 2.9. M A L D I M S of the resulting product from DMF/Benzene carceplex reaction. 52 Figure 2.10. [ H N M R spectrum of carceplex 65»2 D M F 54 Figure 2.11. The M A L D I M S of 65*2 D M F and 65«2 D M A 56 Figure 2.12.1.R. spectrum of carceplex 65»2 D M F 58 Figure 2.13. ' H N M R spectrum of carceplex 65»2 D M F (low temperature) 61 Figure 2.14. High Temperature Variable *H N M R of carceplex 65«2 D M F 63 Figure 2.15. Structural comparison between carceplex 32* D M F , carceplex 52» 3 D M F and carceplex 65*2 D M F 64 Figure 2.16. Computational representation of 65»2 D M F 67 Figure 2.17. Theoretical simulation, showing the 2 D M F molecules orientation within the cavity of 65 68 Figure 2.18. Schematic diagram that shows the calculation of the height and width of carceplex 65»2 D M F 69 Figure 2.19. Proposed oxidative coupling mechanistic representation of the formation of disulfide carceplex 65*2 D M F 70 Figure 2.20. Proposed structure 66 of a [5]cavitand with 5 helical bundles attached via disulfide bonds 72 vi i List of Schemes Schemel.l. Formation of resorcin[n]arene 11 Scheme 1.2. Formation of vase 23 structure by extension of the cavitand walls 15 Scheme 1.3. Gibb's benzyl alcohol coupled host 30 17 Scheme 1.4. Carceplex 34 formation 21 Scheme 1.5. Formation of trimer carceplex 52»3 D M F 28 Scheme 2.1. The formation of resorcin[5]arene 55 developed by Konishi 1 and subsequent formation of [5]cavitand 58 38 Scheme 2.2. The selective functionalization of [5]cavitand 58 to Br-[5]cavitand 60 and SH-[5]cavitand 61. Conversion of [5]cavitand 60 and 61 to the acetylated derivatives 62 and 63 respectively 42 Scheme 2.3. Carceplex 64»guest formation via linking of Br-[5] cavitand 60 with S H -[5]cavitand 61 49 Scheme 2.4. Formation of the disulphide carceplex 65*2 D M F 59 Scheme 2.5. The formation of carceplex 67 via the coupling of cavi[5]tand-OH 68. . . .73 vii i List of Charts, Tables and Equations Chart 1. Hemicarceplex formation from a variety of interhelical bridge moieties 24 Table 1. Shows the effect of varying the linker and how it determines the guest and the rate at which a guest enters the cavity of the host 25 Table 2. M A L D I data performed with /7-nitroanaline as a matrix. Carceplex 65»2 D M F and 65*2 D M A spiked with A g + affording a calculation of the parent peak 65 Equation 1 40 Equation 2 62 ix List of Abbreviations A - angstrom 5 - chemical shift A - change in chemical shift A I B N - 2,2'-Azobisisobutyronitrile C P K - Corey-Pauling-Koltun (models) D M A - A^Af-dimethylacetamide D M F - dimethylformamide H P L C - high pressure liquid chromotography hr - hour I.R. - infrared (spectroscopy) J - coupling constant m/z - mass to charge ratio M A L D I - matrix assisted laser desorption ionization min - minutes N B S - A^bromosuccinimide N F P - 1-formylpiperidine N M P - l-methylpyrrolidin-2-one N M R - nuclear magnetic resonance (spectroscopy) nOe - nuclear Overhauser effect p - para ppm - parts per million rt - room temperature X Acknowledgements I would like to thank Professor John Sherman, my research supervisor, for his, knowledge, encouragement and patience during my stay at UBC. M y thanks to my colleagues in the Sherman research group, especially, Christoph Naumann who has shown the right path to walk and who advise has been superb. To Ayub Jasat, Ashley Causton, Diana Wallhorn, Rajesh Mungaroo, Xuan (Susan) Gui and Darren Makieff thanks for time in proof reading my thesis and your kind words of encouragement throughout. I wish you well and all the best for the future. This thesis would not have been possible without the assistance from the members of the chemistry department, especially the mass spectrometry and N M R department. I would also like to thank the NIH and NSERC that have funded this research. I am dedicating this thesis to Amanda who has been by my side through every turn. Also to my parents, my brother Ben, my sisters Lucie and Sophie and my late grandparents whose love is there always. Thank you. xi Chapter 1 1.1. General Introduction Molecular recognition and self-assembly are fields of research whose central theme concentrates on specific non-covalent interactions between molecules. The main source of inspiration is found in life, which is almost entirely governed by specific interactions, such as the pairing of complementary nucleoside bases to form the double helix tertiary structure of D N A , and the highly specific substrate recognition by enzymes. One of the aims of supramolecular chemistry is the mimicry of biological processes with synthetic molecules. How molecules organize themselves greatly depends upon the way in which they specifically bind or recognize each other. The necessary information for this organization process is almost entirely present within the individual molecules; the type of atoms present and the way they are connected "tells" the molecule how to interact. Self-assembly is important to biology and material science alike due to its widespread use in the formation of structures such as cell membranes and monolayers. The driving forces behind the formation of a self-assembling structure are a multitude of non-covalent interactions such as hydrogen bonds, van der Waals, electrostatic and K-n interactions, which bring the molecules together in a well defined structure. Numerous one dimensional and two dimensional systems have been recognized, however, self assembly structures that form three dimensional cavities are less well l known, and of these, only a few possess a well defined cavity capable of encapsulating guest molecules.1"4 Following, are a number of self-assembling structures that demonstrate the formation of internal cavities capable of molecular recognition in solution. In 1967, Pedersen synthesized a series of macrocyclic polyethers composed mainly of repeating units of CH2CH2O, known as crown ethers, of which 18-crown-6 is the prototype.5 This molecule strongly binds K + because of the stereoelectronic complementarity between the host and the guest, and also due to the size selectivity of the cavity of the crown ether. The K + guest nests in the center of a wreath-like complex ligated by six oxygens (i.e. 1 in Fig 1.1). Pedersen showed that it was also possible to bind NFLi + and RNH3 + salts (i.e. 2 and 3 respectively in Figure 1.1). Since the discovery by Pedersen that certain crown ethers show a high affinity for alkali-metal cations, 6 ' 7 the field of molecular recognition has developed rapidly. Figure 1.1. Pedersen's Crown ethers Early studies were largely concerned with the complexation of cations based on strong ion-dipole interactions. Two such studies resulted in the introduction of cryptands 1 2 R=H 3 R=Alkyl 2 and spherands9 by Lehn and Cram, respectively. Cryptands were defined as having a three-dimensional cavity whose size would change as the lengths of their bridges were varied; donor sites and substituents can be widely varied. 1 0 ' 1 1 Additional bridges lead to further ligand topologies, such as cylindrical cryptands 4 and the "soccerball cryptand" 5. 1 2 Spherand systems contain ligand donor centers (OCH3, O H , O") which are part o f the intraannular substituents pointing into the interior of a rigid ring (e.g. structures 6 and 7). 6 R = OCH3, OH 7 R = OCH3 Figure 1.2. Lehn's Cryptands 4,5 and Cram's Spherands 6,7. In 1987 Cram, Lehn and Pedersen, were awarded the Nobel Prize for their pioneering work in the field of molecular recognition. Their host-guest compounds have paved the way for a vast amount of research in this area. 3 A n examination of the receptor sites of host-guest molecules found in nature reveals them to have concave surfaces to which substrates with convex surfaces bind. This observation didn't go unnoticed by Cram, who embarked on the study of complexation between synthetic entities that mimic nature's process, at which time he introduced the terms host and guest and the expression host-guest complexation. 1 3" 1 6 In host-guest chemistry, the host molecule contains convergent binding sites and the guest molecule (ion) contains divergent binding sites. The host molecule must recognize, by complexing, those guest molecules that contain the array of binding sites and steric features which complement those of the host. The main binding forces are hydrogen bonding, ion pairing, metal ion to ligand attractions, van der Waals attractive forces and solvent-liberation driving forces. The self-evident postulate that two objects cannot occupy the same space at the same time indicates that host and guest must be compatible with respect to shape if they are to form a complex. 1 4 1.2. Cyclodextrins Cyclodextrins, naturally occurring cyclic oligosaccharides, are one of the most important host components of supramolecular chemistry. The first cyclodextrins were isolated in 1891 by Villiers as degradation products of starch. In 1904, Schardinger characterized them as cyclic oligosaccharides, and in 1938 Freudenberg et al. described them as being macrocyclic compounds built from glucopyranose units linked by a-(l,4)-glycosidic bonds. 1 7 Cyclodextrins can be obtained with the help of cyclodextrin glycosytransferases 4 by enzymatic degradation of starch. The latter is a polysaccharide consisting of a-(l,4)-linked glucose units and is found as a left-handed helix with six units per turn. In this enzyme controlled process, compounds with six to twelve glucopyranose units per ring are produced. The size of the cyclodextrin depends on the enzyme and the reaction conditions, the main products are a, P or y - cyclodextrin (6, 7 and 8 glucopyranose). These compounds adopt a circular, conical conformation, where the height is about 8A o o and the cavity's inner diameter is between 5 A and 8 A wide (compounds 8, 9 and 10 see Figure 1.3). Figure 1.3. Cyclodextrins: degradation products of starch and a schematic representation below demonstrating the size and shape of these compounds. 5 Cyclodextrins contain a hydrophobic cavity which is made water-soluble by the many outward-pointing O H groups. A fascinating- property of cyclodextrins is their ability, to incorporate other organic compounds into their cavity. A primary criterion for the inclusion of guests within the host's cavity is their size selectivity. A n example of a guest inclusion is that of the crown ethers within the well of the y-cyclodextrins with the additional incorporation of a metal ion into the crown ether's interior (similar to the Russian wooden dolls, encased one inside another). 1.3. Calixarenes Cyclic oligomers obtained via the condensation of formaldehyde with para-alkylphenols under alkaline conditions were named calix[n]arenes (e.g 11) by Gutsche; 1 9 the [n] denotes the number of aromatic units. The prefix calix is derived from the Greek word chalice, pertaining to its shape in its most stable conformation (e.g. 12 calix[4]arene). 6 R 11 R = a l k y l 12 R =alkyl n = 4 Figure 1.4. Calix[n]arenes Gutsche et al. found that the amount of catalyst and temperature at which the reaction between />-tert-butylphenol and formaldehyde is carried out determined the ring size of the product. Reactions at high temperatures (220 °C) with catalytic amounts of N a O H , give />-terr-butylcalix[4]arene in 50-60% y i e l d . 2 0 Performing the reaction at a lower temperature (145 °C) produces />-terf-butylcalix[8]arene i n 65% y ie ld , 2 1 p-tert-butylcalix[6]arene can be obtained in 85% yield when K O H (0.5 equivalents) is used instead of N a O H i n boiling xylene. The odd numbered analogs cannot be obtained in high yields; p-tert-butylcalix[5]arene was isolated in a yield of only 15% while p-tert-butylcalix[7]arene could not be obtained i n yields exceeding 6%. 2 3 ' 2 4 One of the most important properties of calixarenes is their ability to include smaller ions and molecules reversibly. The calixarene structure lends itself to the inclusion o f guests either i n the cavity formed by the aryl units, or by modification o f the hydroxyl groups present on the lower r im of the structure. Studies have shown that 25 varying the ring size of the calixarene allows for different ion selectivity. 7 In the case of both calixarenes and cyclodextrins, careful manipulations of the reaction conditions have been shown to have a diverse effect on the size of the macrocyclic product. So far we have presented macrocyclic structures that possess a bowl shaped cavity (calixarenes and cyclodextrins) which enables them to entrap a molecule within their cavity, however, the open-ended nature of these structures allows for the bound molecule to escape from the domains of these cavities. 1.4. Resorcinarenes In 1872, Adolf von Bayer studied the synthesis of phenol based dyes. Several years later Michael determined the correct elemental composition of the sparingly soluble, high melting, crystalline product (Ci3Hio02)n and its acetyl derivative (Ci3rI8(OCOCH3)2)n-27 From this data, he concluded that the product is formed by the combination of ah equal number of benzaldehyde and resorcinol molecules and the loss of an equal number of water molecules. In 1940 Niederl and Vogel studied several condensation products obtained from the reaction between aliphatic aldehydes and resorcinol; based on the molecular weight determinations it was concluded that the ratio between aldehyde and resorcinol in the product should be 1:1. It was proposed that this cyclic tetrameric structure 13 was analogous to cyclic tetrameric structures frequently encountered in nature, e.g. porphyrins. Erdtman and coworkers finally proved the structure in 1968 by a single crystal X-ray analysis.2 8 The structure consisted of four meta linked resorcinol units, forming the cyclic structure 13. 8 R 2 13 R i = aliphatic R 2 = H Figure 1.5. The resorcin[4]arene structure Most resorcinarenes are prepared via a one step acid-catalyzed condensation reaction between resorcinol (in certain cases 2-methylresorcinol or pyragallol (1,2,3-trihydroxybenzene) have been used) 2 9 ' 3 0 and an aliphatic or aromatic aldehyde. Using a derivative of resorcinol expands the versatility of the resorcinarene product, in particular, functional groups may be added. It has been shown that resorcin[4]arene is the thermodynamically favored macrocyclic product in the acid catalyzed condensation reaction. Precipitation of the least soluble resorcin[4]arene 13 (all cis isomer), serves as a thermodynamic sink, which drives the reaction towards formation of one macrocyclic product.3 1 Thus, the creation of a resorcinarene consisting of more than 4 aryl units proves quite challenging. Konishi et al. studied the condensation of 2-alkyresorcinols with formaldehyde and its equivalents, producing cyclic tetramer 15 in high y i e l d . 2 9 ' 3 2 However, when the reaction was stopped prematurely, the cyclic pentamer and cyclic hexamer were isolated 9 from the reaction mixture.33 The reaction solution was extracted in diethyl ether and tetramer 15 was removed as insoluble material when triturated with methanol. The resulting material was suspended in diethyl ether allowing for the separation of the insoluble hexamer 17, and leaving pentamer 16. The yield of cyclic oligomers is dependent on the reaction conditions such as temperature, time, solvent and condensation agent. In order to clarify the formation pathway, the acid catalyzed reaction of 2-propylresorcinol with formaldehyde diethyl acetal was examined by H P L C and ' H N M R spectroscopy. Two new cyclic oligomers, resorcin[5]arene 16 and resorcin[6]arene 17 were reported. Examination of the reaction progress showed that, after 15 min, a decrease in 14 and the appearance of many linear oligomers was observed. At 30 min, three major products were detected, which were identified as the cyclic tetramer 15, the cyclic pentamer 16 and the cyclic hexamer 17. At this time the composition of the three products was found to be 17>16>15. After the reaction had run for 2 h, 15 was the predominant product, and after 6 h the yield of 15 was nearly quantitative. 10 H O ^ O H C 2 H 5 ( X C 2H 5 0' ;CH2 HCI/ EtOH 14 R = n-Pr, Me R OH HO R 15 16 17 Schemel.l Formation of resorcin[n]arene The pathways for the formation of the cyclic oligomers and the ring contraction and enlargement are explained as follows. During the initial stage, the acid-catalyzed reaction of 14 with a bridging agent rapidly produces linear oligomers, which readily polymerize or depolymerize to the linear tetramer, pentamer or hexamer, and these oligomers cyclize to the corresponding resorcin[n]arene. After consumption of 14, the reconstruction of 16 and 17 is predominant. Ring opening of these cyclic oligomers results in linear oligomers, that are precursors for the cyclic tetramer 15. In conclusion, the selective formation of the cyclic tetramer 15 is attributable to its ultimate thermodynamic stability. 11 1.5. Cavitands In 1982 Cram coined the word cavitand for a class of organic compounds that contain an enforced concave cavity large enough to accommodate other molecules or ions. 3 5 a The concave surface permits substrate binding through non-covalent interactions between the substrate and the different functional groups located inside the cavity. Cavitands have elicited much attention as their rigid hemispherical cavities lend themselves to significant further development, such as the creation of a spherical host by the coupling of two cavitands. First generation cavitands 18 were prepared by Cram from Hogberg's resorcin[4]arene (octol) 19 through alkylidene and dialkylsilicon bridging of neighboring 3135 3135 phenol groups. ' While their complexation properties have been studied in detail, ' their depth, a mere 3.3-4.2 A , limited the types of molecules that they were able to bind. For example, in solution, only weak affinity towards small organic molecules (CD2CI2, C D 3 C N , C S 2 , CD3NO2 and C 6 D 5 C D 3 , etc.) was detected, 3 5 e thus the host guest properties are clearly dependent on the dimensions of the cavities. Several studies have examined the possibility of extending the cavitands and deepening the cavitands in an attempt to create a larger cavity. 12 R = alkyl, Ar X = (Cry, SiRj 18 Figure 1.6. F i r s t g e n e r a t i o n c a v i t a n d s 1.5.L [4]Cavitand enlargement T h e p r e p a r a t i o n o f c a v i t a n d f r o m the r e s o r c i n [ 4 ] a r e n e ( o c t o l ) 19 i n w h i c h f o u r sets o f O H h y d r o g e n s a r e b r i d g e d b y CH2, CH2CH2 a n d CH2CH2CH2 y i e l d i n g s t r u c t u r e s 20, 21 a n d 22 r e s p e c t i v e l y . 3 5 b Me Me Me Me n=1,20 n=2, 21 n=3, 22 R = H, CH3, Br Figure 1.7. E n l a r g e m e n t o f c a v i t a n d s 13 These cavitands (20, 21 and 22) are all generally conical with the cone supported on a square framework of four methyl "feet" located at the bottom of the bowl. The variation of the 0 - 0 distances with n in the ArO-(CH2) n -OAr provides a good measure of the relative openness of the cavity on its rim. When n =1 the 0 -0 distance is 2.34 A , n = 2, the 0 - 0 distance is 2.93 A , when n = 3, the O-O distance is 3.16 A. In all cases, the orbitals of the unshared electron pairs on the oxygen diverge from the cavity, and the (CH2) n groups generally point upward, increasing the depth of the cavity. Examination of the crystal structures shows that in 20«CFi2Cl2, the CH2 inserts into the cavity whereas in 21«CHCi3 one CI and part of a second occupy the cavity. This suggests that the host with the larger cavities is able to complex the larger solvent molecules, or larger parts of the guest. 1.5JL Vases and Kites A n alternate way of creating large cavitands, is by increasing the height of the "walls" of the cavity and thus deepening the cavitand's internal cavity. Deep cavities represent unique species of molecular containers, distinct not only from the covalently sealed hosts, but also from the open cavity macrocycles. These cavities are open-ended, with slow guest inclusion on the N M R timescale. Both covalent bonds and non-covalent interactions can be utilized to control the size and shape of the cavities. This is achieved by varying the solvent polarity and/or temperature. The uptake and release of guests may, in some cases, involve the folding and unfolding of the host. 14 A s part of the search for easily made cavitands possessing a large internal volume, Cram et al. reported the preparation of the vase (four quinoxaline flaps axial, or aaaa conformation) and kite (four quinoxaline flaps equatorial, or eeee conformation) structures 23.37a The bridging of the four sets of hydrogen bonded hydroxyls by the reaction of octols 19 with 4 equivalents of diazines 24 produces 23. The synthesis of 23, when conducted in dry (CH3) 2 SO-CsHC03 with 3 equivalents of 24, gave an easily separable mixture of 23 (30%) and 25 (40%). Thus, it appears that the first three bridges are formed faster than the fourth, likely due to steric reasons. 24 23 25 R = alkyl, Ar Scheme 1.2. Formation of Vase 23 structure by extension of the cavitand walls. The ' H N M R spectra of cavitand 23, taken in different solvents and at different temperatures, proved useful in identifying the structures of the vase and kite conformers. Cavitand 23 in 1:1 CDCI3-CS2 (v/v) appears to exist only in the vase form at temperatures of 45 °C and above and only in the kite form at temperatures below -62 °C. 15 In the ' H N M R spectrum of 23 from 45-70 °C, all the protons exhibit sharp signals consistent with C^v symmetry. Vase 23 is capable of entrapping a whole CH2CI2 molecule. The crystal structure of 23 showed that the guest molecule lies in the lower part of the vase, thus signifying that a larger and deeper cavitand has been formed. 23-vase aaaa conformation R=alkyl, Ar 23-kite eeee conformation Figure 1.8. The vase and kite conformers of cavitand 23 1.5.UL Capsules - Hosts with a large internal cavity o In a recent study, Gibb et al., reported the assembly of benzyl alcohol derived deep-cavity cavitands (DCC) 27, as a highly efficient moiety for irreversible assembly.36 They demonstrated the stereoselective bridging of resorcinarenes with benzal dibromide, 16 a process which provided access to a new series of deep-cavity cavitands 26/' The cavitand 26 with an upper rim functional group could be further derivatized. The bromo derivative 27 was used as an entry point for the synthesis of DCCs 28 and 29, with a suitable structure that would allow the formation of host 30 (Scheme 1.4). Conclusive evidence for the formation of 30 was derived from an X-ray o crystallographic determination. The cavity was calculated to be approximately 19 x 15 A . Due to the size of the cavity, they were unable to find a suitable, molecular template. 30 Scheme 1.3. Gibb's benzyl alcohol coupled host 30 The synthesis of receptor molecules with large cavities generally tends to be problematic as a result of the inherent flexibility of large organic molecules. However, work by Reinhoudt 3 8 demonstrates a new approach to the synthesis of large receptor 17 molecules by the combination of building blocks already possessing a cavity, namely calix[4]arenes and resorcinol based [4] cavitands. The assembly of the cyclic array provided a convergent route for the synthesis of holand 31, a rigid host molecule in which the cavities of the four components form a cage of nanoscale dimensions. According to o o C P K modeling, the axes are about 15 A and 20 A long, with a calculated internal volume of approximately 1.0 nm 3 (1000 A 3 ) . A systematic search for suitable guest molecules for holand 31, using the computer simulation program D O C K 1 4 , 3 9 showed that steroids are a suitable class of guest compounds. As yet no complexation has been found by holand 31, likely due to the guests ability to escape from the confines of the cavity as a result of the open structure of holand 31. Figure.1.9. Combination of calixarene and cavitand to create Reinhoudts' holand 31 structure 18 1.6. Carceplexes Two cavitand hemispheres can be combined by spacers to create carcerands. Carcerands are closed-surface, globular shaped molecules with enforced hollow interiors large enough to incarcerate simple organic molecules, inorganic ions or both. When a carcerand cavity is occupied by a guest molecule, the complex is called a carceplex. The guest cannot escape their molecular cells without breaking covalent bonds between atoms that block their escape. The cavity of a carcerand has been called a 'new phase of matter' by Cram et a l ; 4 0 the inner phases are not bulk-phase dependent, the properties of the molecules are different inside a carcerand than when in the bulk solvent. The formation of a carcerand without a guest entrapped within the interior is highly unlikely, because this phenomenon is entropically unfavorable. That is, a vacuum (empty interior) the size of the carcerand interior would be created. The first synthesis of a carcerand (32) by the reaction of a tetrakis(mercaptomethyl)cavitand and a tetrakis(chloromethyl)cavitand in D M F using CS2CO3 as a base was reported by Cram 4 0 According to Cram, stabilization of the S N2 transition state during the closure of the bridges by one (or more) guest molecules led to the permanent incarceration of these molecules. However, due to severe solubility problems full characterization of carceplex 32 was not achieved. The solubility of the carcerand 32 was enhanced by using different pendant groups which facilitate the purification and characterization of the carceplexes 4 1 19 32»Guest R = CH3 Figure 1.10. The original carceplex 32 1.6.L Templation studies and molecular encapsulation Chapman et al. performed an in depth study on the templation effect in carceplex formation.42 The authors showed that the formation of carceplex 34 occurs due to the two bowl shaped molecules (tetrol 33) wrapping around a guest/template (Scheme 1.4), and that these bowls get sewn together by an irreversible formation of OCH2O bridges. The reaction only worked i f a suitable template molecule was present, and the ability of template molecules to form this carceplex was found to vary by 10 6 -fold. 4 3 ' 4 4 The results showed that the templating ability of one guest over another guest was related to their ability to form the OCH2O bridges between the two bowls. Since this reaction is irreversible, there must be a key bridge that locks the guest within the capsule with respect to the time scale of the experiment. This particular bridge formation would be considered the guest determining step (GDS), 4 4 the step beyond which the guest 20 becomes entrapped and does not exchange between the interior of the host and the exterior environment. The template with the faster G D S is therefore more suited to the interior of the forming carceplex through non-covalent interaction. S c h e m e 1.4. Carceplex 3 4 formation. The mechanism for the formation of carceplex 34 is understood as follows: Complex 35» guest forms, followed by the formation of the first OCH2O bridge, with the guest still in fast exchange. The formation of the second bridge was found to be the G D S . The host species formed during the transition-state of this step is highly rigid and binds strongly with high selectivity to suitable guests. The most stable complexes (i.e. those containing the best template molecule) form the second bridge the fastest. Subsequent bridging leads to the product. 4 3 21 1.6. U Restricted Motion of Guest in Carceplexes and Capsules J H N M R spectroscopy can determine whether a guest molecule has been encapsulated within the host's interior due to an upfield shift in signal for the guest molecule. The upfield shift for the encapsulated guest molecule results from the shielding effect of the arene-lined interior of the host. Guest orientation within carceplexes and capsules can be determined qualitatively from N M R data, and the molecular mobility of the guest can be determined by dynamic *H N M R experiments, for instance, via coalescence of ' H N M R signals. 4 5 In the ' H N M R spectra, A8 (8 of free guest - 5 encapsulated guest) values for the guest protons indicate the proximity of these moieties to the arenes lining the top and bottom of the hosts' cavities. Generally, A5 values over 4 ppm indicate a close proximity to the arenes, while A5 values of less than 2 ppm indicate positioning near the host's equator. 1.7. Hemicarceplexes Hemicarceplexes are like carceplexes, but contain small portals in their shells through which a guest can enter and depart the inner cavity upon sufficient heating, without breaking any covalent bonds. There are two strategies to synthesizing hemicarceplexes. One strategy is to omit one (or more) of the bridging units used to 22 connect the two hemispheres, providing a portal which connects the interior with the medium in which the complex is dissolved. The dimensions of the omitted bridging unit determine those of the portal, which is likely to expand at higher temperatures and contract at lower ones. In a second approach (which will be discussed in further detail), the equatorial linking groups which connect two rigid hemispherical cavitands are long and flexible enough to co-operatively adopt conformations which generate temporary portals large enough for appropriately sized molecules to depart or enter host interiors at appropriate temperatures. /. 7.i Hemicarceplex formation via linker variation Cram and co-workers have extensively investigated the linker units between the hemispherical cavitand moieties.46 Using this approach they found that by varying the interhemispherical linkers promoted formation of a hemicarceplex, thereby creating a slot type structure with four portals equally spaced throughout the lengthwise axis of the shell. The cavity shape and size are unique to each hemicarceplex depending on the linking units. The synthetic strategy was the same as that used for the carceplex formation, with tetrol 33 as the building block for a large number of hemicarceplexes. The versatility of this approach is evident by the large variety of hemicarceplexes and hemicarcerands (i.e., 36-49) reported to date (summarized in Chart 1 ) . 4 6 - 5 7 The ability of a guest to exit or enter the host cavity, is an important characteristic of hemicarceplexes. The rate of decomplexation can be measured by ' H N M R , 23 monitoring the signals of the host and guest and determining the rate with which the guest escapes the host interior. A selection of interhemispherical linkers are compared (see Table 1), to demonstrate how the different linkers can effect the rate at which guests acceptably enter or escape the cavity. X x Guesl x x Chart 1. Hemicarceplex formation from a variety of interhemispherical bridge moieties 24 l i n k e r g u e s t conditions h a l f l i f e (t, 2) 46 2 0 m i n b 6 0 ° C , i n CDCI3 3 0 m i n O C F , a 1 0 h / 11 h 49 C H 3 C N C H 3 6 3 8 m i n 1 0 0 ° C , i n CDCI2CDCI2 2 0 9 m i n CH3CH2O2CCH3 4 0 9 m i n 41 C H 3 C H 3 6 4 5 ° C , i n CDCI2CDCI2 2 8 m i n 18 ° C , i n CDCI2CDCI2 2 .5 m i n 25 41 cont... 18 °C, in C D C 1 2 C D C 1 2 1.6 min 16.5 h 45 °C, in CDCI2CDCI2 4.2 h Table 1. Shows the effect of varying the linker and how it determines the guest and the rate at which a guest enters the cavity of the host. Fairly large polycyclic guests such as norbornene, exo-2,3,-epoxynorbornane, 2-adamantanone, and quadricyclane, have been successfully encapsulated in the pentamethylene 44,53 hexamethylene 45 5 3 and diethylene glycol-bridged 46 5 5 hemicarcerands. The flexibility of these bridges though, renders a vast majority of these complexes with poor kinetic stability. In an attempt to prevent this, Cram and co-workers investigated the synthesis of a series of hosts with substantially larger cavities but with more rigid inter-bowl bridges, resulting in the ability to create more kinetically stable complexes. There is a high sensitivity of the decomplexation rate to the solvent structure which implies that, in the transition-state for complexation-decomplexation, guest-solvent contacts are energetically important. Thus, the transition-state possesses a structure in which the guest is just starting to exchange host-guest interactions for solvent guest interactions. C H 3 C H 3 C H 2 0 2 C C H 3 26 1.8. Giant Carceplex entrapping three Organic Molecules W e have already introduced the concept of carceplexes as hosts capable of encapsulating guests within their internal cavity, yet with such a vast array of carceplexes, there are only a few that can accommodate multiple guests. A current trend i n supramolecular chemistry is the creation o f large hosts that can accommodate several guests or one large guest. Particularly exciting is the possibility of encapsulating several molecules within molecular vessels and thus facilitating the study of a "microsolvent". To date, carceplexes which permanently entrap molecules within their conf ines 5 9 have been shown to entrap predominantly single small guest molecules. Sherman et al. reported on the synthesis of a carceplex with a cavity roughly triple the size of any previously reported. 6 0 In designing a large carceplex, certain criteria must be met, including structural rigidity and an effectively closed surface. Sherman et al. recently reported on the synthesis of a cyclic trimer of bowls 5 0 , 6 0 which is a rigid barrel-shaped molecule with an enforced cavity. Trimer 50 seems ideally suited as a precursor for a large carceplex, and hence was combined with cap 51 in D M F with K2CO3 as the base i n the presence of K I at room temperature for 24 hr. The product was identified as carceplex complex 52 • 3 D M F (36% yield). N o D M F was lost from 52 • 3 D M F on heating to 160 °C for 6 h in nitrobenzene. Thus the vessel is effectively sealed. The * H N M R spectrum of trimer carceplex 52 • 3 D M F shows the A8 values (free 3Q D M F versus encapsulated D M F ) are somewhat smaller than those o f 34 • DMF, and 27 this implies a more spacious interior for 52. Indeed, a C P K model of 52 • 3 D M F reveals that D M F has ample room to move around inside. The N M R data shows only one set of signals for the D M F ; this suggests that all three move rapidly within the carceplex on the ' H N M R timescale. 50 51 52*3 DMF Scheme 1.5. Formation of trimer carceplex 52«3 D M F . 28 1.9. Disulfide Bonds as linker units. In the following chapter the first carceplex with a disulfide linker bridging the two hemispheres will be reported, therefore it would be constructive to introduce the reader to disulfide bonds. Disulfide bonds can be formed by oxidative coupling via a thiol disulfide exchange, or by a substitution reaction between a thiol and a protected thiol as well as a radical reaction. Disulfide bonds occur as covalent linkages between amino acids in proteins and peptides and are found between two cysteine residues. Disulfide bonds between pairs of cysteine residues can cross-link different chains of a protein which gives rise to covalent chain assemblies. NH I 0 = C NH I c = o C H C H 2 S — S C H 2 C H NH NH disulphide bond Figure 1.11. Disulfide bond between cysteine residues in a peptide chain. 29 Disulfide bonds have been utilized as linkages in the assembly o f de novo protein, where the S-S bonds allow for attachment of peptide chains to a template macrocycle resulting i n the formation of template assembled proteins (TASP) . To date, the only system that exhibits this specific connectivity can be found in the design of caviteins, reported by Causton et a l . , 6 1 wherein a rigid concave template, cyclotribenzylene having three thiol groups on the upper rim allowing for the attachment of peptides via a disulfide link between the cysteine residue in the peptide chain and the thiol of the macrocycle template was facilitated. The resulting cavitein system was found to consist of three peptide chains attached to the scaffold creating a three-helix bundle T A S P 53 . 6 1 53 Figure 1.12 Cavitein 53, a cavitand templated, disulfide linked three helical bundle. 30 1.10. Project outline and Thesis Goals This chapter has provided insight into the formation of rigid cavities, and the ability to connect the two hemispherical cavities to create a spherical shaped complex. The emphasis has been placed on the size of the internal cavity, and the variations that are available to increase the internal volume, allowing a larger or multiple guests to be encapsulated within the interior. This thesis concerns the synthesis of a carceplex 65 that has a large internal cavity, C$ symmetry and disulfide linkers coupling the two cavitand hemispheres. The formation of host structure 65 from these hemispherical moieties requires the functionality upon the upper rim of the cavi[5]tand 58 to be altered appropriately. The selective conversion of cavi[5]tand 58 methyl substituent, to the cavi[5]tand 68, and the subsequent cavi[5]tand 61 shall be discussed in the following chapter. The size and shape of the guest is an important factor to consider, as the non-covalent interactions that occur between the guest and the internal functionality of the host cavity determine whether a guest is a suitable template. The dimensions of carceplex 65 are different from more familiar carceplex interiors (that are created by the combination of two cavi[4]tand hemispheres), which may allow an opportunity to explore a multiple guest encapsulation within the host. 31 1.11. References 1. Whitesides, G . M . ; Mathias, J.P.; Secto, C . T . Science, 1991, 254, 1312. 2. Whitesides, G . M . ; Mathias, J.P.; Secto, C . T . Acc. Chem. Res. 1995, 28, 37. 3. Fan, E . ; Yang, J.; Geib, S.J.; Vincent, C ; Garcia-Tellado, F.; Tecilla, P.; Hamilton, A . D . Macromol Sym. 1994, 77, 209. . 4. Vreekamp, R . H . ; van Duynhoven, J .P .M. ; Hubert, M . ; Verboom, W. ; Reindhoudt, D . N . Angew. Chem. Int. Ed. Engl. 1996, 35, 1215 5. Pedersen, C . J. J. Am. Chem. Soc. 1967, 89, 2495. 6. Pedersen, C . J. Am. Chem. Soc. 1967,15, 153. 7. Pedersen, C . J. (Nobel Lecture) Angew. Chem. 1988,100, 1053; Angew. Chem., Int. Ed. Engl. 1988, 2 7, 1021. 8. Lehn, J . - M . (Nobel Lecture) Angew. Chem. 1988,100, 91; Angew. Chem., Int. Ed. Engl. 1988, 27, 89. 9. Cram, D . J. (Nobel Lecture) Angew. Chem. 1988,100, 1041; Angew. Chem., Int. Ed. Engl. 1988,27, 1009. 10. Lehn, J . - M . Pure Appl. Chem. 1978, 50, 871. 11 a).Dietrich, B. Inclusion Compounds. V o l 2 (Atwood, J.L.; Davies, J .E. and MacNicol , D.D.Eds), Academic Press, London 1986, p.337. (b). Hosseini, M . W. ; Blacker, A . J.; Lehn, J . - M . J. Chem. Soc , Chem. Commun.,19$8, 596. (c). Lehn, J . - M . et al., Helv. Chim. Acta, 1988, 71 685. 12. Lehn, J . - M . Pure Appl. Chem. 1917, 49, 857. 13. Cram, D.J. and Cram, J . M . , Science, 1974,183, 803. 14. a) Cram, D . J Nature, 1992, 356, 29. b) Cram, D . J.; Tanner, M . E . ; Thomas, R. Angew. Chem. Int. Ed. Engl. 1991, 30, 1024. 15. Cram, D.J . ; Helgeson, R . C . ; Sousa, L.R. ; Timko, J . M . ; Newcombe, M . ; Moreau, P.; de Jong, F. ; Gokel, G . W . ; Hoffman, D . H . ; Domeier, L . A . ; Peacock, S .C. ; Madan, K . and Kaplan, L . Pure Appl. Chem., 1975, 43, 327. 16. Kyba, E.P.; Helgeson, R . C . ; Madan, K . ; Gokel, G . W . ; Tarnowski, T . L . ; Moore, 32 S.S. and Cram, D.J. J. Am. Chem. Soc, 1977, 99, 2564. 17. Freudenberg, K . ; Cramer, F. Z. Naturforsch., Teil B, 1948, 3, 464. 18. Hyatt, J. A . J. Org. Chem. 1978, 43, 1808. 19. Gutsche, C . D . ; Muthukrishnan, R. J. Org. Chem. 1978, 43, 4905. 20. Gutsche, C D . ; Iqbal, M . Org. Synth, 1989, 68, 234. 21. Munch, J .H. ; Gutsche, C . D . Org. Synth. 1989, 68, 243. 22. Gutsche, C . D . ; Dhawan, B. ; Leonis, M . ; Stewart, D . Org. Synth. 1989, 68, 238 23. Stewart, D . ; Gutsche, C . D . Org. Prep. Proced. Int. 1993, 25, 137. 24. Nakamoto, Y . ; Ishida, S. Makromol. Chem Rapid. Commun. 1982, 3, 705 25. Iwamoto, K . ; Shinkai, S. J. Org. Chem. 1992, 57, 7066 26. a). Baeyer, A . Ber. Dtsch. Chem. Ges.1812, 5, 25. b). Baeyer, A . ibid.1872, 5, 280. 27. a).Michael, A . J. Am. Chem. 1883, 5, 338. b).Niederl, J.B.; Vogel, H.J . J. Am. Chem. Soc. 1940, 62, 2512. 28. a).Erdtman, H . ; Hogberg, S.; Abrahamsson, S.; Nilsson, B. Tetrahedron Lett. 1968, 1679. b).Nilsson, B . Acta Chem. Scand. 1968, 22, 732. 29. Konishi, H . ; Iwasaki, Y . ; Morikawa, O. ; Okano, T . ; Ki j i , J. Chem. Express 1990, 5, 869. 30. Cometti, G . ; Dalcanale, E . ; D u Vosel, A . ; Levelut, A . - M . ; Liquid Crystals 1992, 77,93. 31. a) Hogberg, A . G . S . J. Am. Chem. Soc. 1980,102, 6045-6050 b). Hogberg, A . G . S . J. Org. Chem. 1980, 45,4498. For a review see Timmerman, P.;Verboom, W . ; Reinhoudt, D . N . Tetrahehron, 1996, 52, 2663. 32. Konishi, H . ; Iwasaki, O. J.Chem. Soc Chem. Commun., 1993, 33 33. Konishi, H . ; . Ohata, K . ; Morikawa, O . ; Kobayashi, K . J. Chem. Soc,Chem. Commun., 1995, 309. 34. Konishi, H . ; Nakamura, T . ; Ohata, K . ; Kobayashi, K . ; Morikawa, O . Tetrahedron Lett, 1996, 37, 7383. 35. a) Moran, J.R.; Karbach, S.; Cram, D.J. J. Am. Chem. Soc. 1982, 104, 5826 b).Cram, D.J . ; Karbach, S.; K i m , H - E . ; Knobler, C . B . ; Maverick, E .F . ; Ericson, J.L.; Helgeson, R . C . Am. Chem. Soc. 1988,110, 2229. c). Cram, D.J . ; Stewart, 33 K . D . ; Goldberg, I.; Trueblood, K . N . J. Am. Chem. Soc. 1985, 107, 2574.d). Tunstad, L . M . ; Tucker, J .A. ; Dalcanale, E . ; Weiser, J.; Bryant, J .A. ; Sherman, J .C. ; Helgeson, R . C . ; Knobler, C . B . ; Cram, D.J. J. Org. Chem. 1989, 54, 1305. (e). Tucker, J .A. ; Knobler, C . B . ; Trueblood, K . N . ; Cram, D.J . J. Am. Chem. Soc. 1989, 111, 3688. 36. Timmerman, P.; Verboom, W. ; van Veggel, F. C . J. M . ; van Hoorn, W . P.;Reinhoudt, D . N . Angew. Chem. Int. Ed. Engl. 1994, 33, 1292. 37. Desjardins, R. L . ; Sheridan, R. P.; Seibel, G . L . ; Dixon, J. C ; Kuntz, I. D . J.Med. Chem. 1988, 31, 722. 38. Corrine, L . D . ; Gibb, E . D . ; Bruce, B. C . Chem Commun., 2000, 363. 39. X i , H . ; Gibb, G . L . D . ; Gibb, B. C . Chem. Commun. 1998, 1743. 40. Cram, D . J.; Karbach, S.; K i m , Y . H . ; Baczynkyj, L . ; Kalleymeyn, G . W . J. Am. Chem. Soc. 1985,107, 2575. 41. Maverick, E . ; Cram, D.J . ; Chapter 12. Carcerands and Hemicarcerands: Hosts that Imprison Molecular Guests; Vogtle, F. V o l . E d . ; in the series Comprehensive Supramolecular Chemistry; Lehn, J - M . ; Atwood, J .L. ; Davies, J .E .D. ; MacNicol , D . D . ; Vogtle, F. E d . ; Pergamon: New York, 1996, V o l 2, pp 367-418 42. Chapman, R. G . ; Sherman, J. C . J. Org. Chem. 1998, 63, 4103. 43. Sherman, J. C ; Knobler, C . B. ; Cram, D . J. J. Am. Chem. Soc. 1991,113, 2194. 44. Chapman, R. G . ; Chopra, N . ; Cochien, E . D . Sherman, J. C . J. Am. Chem. Soc. 1994,116, 369. 45. Chapman, R. G . ; Sherman, J. C . J. Org. Chem. 2000, 65, 513. 46. a) Helgeson, R. C ; Paek, K . ; Knobler, C . B. ; Maverick, E . F.; Cram, D . J. J. Am Chem. Soc. 1996,118, 5590. b) Jasat, A . ; Sherman, J. C . Chem. Review, 1999, 99, 932. 47. Helgeson, R. C ; Knobler, C . B . ; Cram, D . J. / . Am. Chem. Soc. 1997,119, 3229. 48. Park, B. S.; Knobler, C . B . ; Eid, C . N . , Jr.; Warmuth, R.; Cram, D . J. Chem. Commun. 1998, 55. 49. Yoon, Y . ; Cram, D . J. Chem. Commun. 1997, 497. 50. Eid, C . N . , Jr.; Knobler, C . B. ; Gronbeck, D . A . ; Cram, D . J. J. Am. Chem. Soc. 1994,116, 8506. 34 51. Robbins, T . A . ; Knobler, C . B. ; Bellew, D . R.; Cram, D . J. J. Am. Chem. Soc. 1994,7/5,111. 52. Byun, Y . -S . ; Robbins, T . A . ; Knobler, C . B. ; Cram, D . J. Chem. Commun. 1995, 1947. 53. Makieff, D . ; Pope, D . J.; Sherman, J. C . J. Am. Chem. Soc. 2000, 722, 1337. 54. Byun, Y . -S . ; Vadhat, O . ; Blanda, M . T . ; Knobler, C . B . ; Cram, D . J. Chem. Commun. 1995, 1825. 55. Farran, A . ; Deshayes, K . ; Matthews, C ; Balanescu, I. J. Am Chem. Soc. 1995, 777,9614. 56. Quan, M . L . C ; Knobler, C . B . ; Cram, D . J. Chem. Commun. 1991, 660. 57. Judice, J. K . ; Cram, D . J. J. Am. Chem. Soc. 1991, 775, 2790. 58. Chopra, N . ; Sherman, J. C . Angew. Chem. Int. Ed. 1999, 38, 1955. 59. a) Cram, D . J.; Cram, J. M . Container Molecules and Their Guests from the series Monographs in Supramolecular Chemistry (Ed.; Stoddar), Royal Society of Chemistry, Cambridge b) Sherman, J. C . Tetrahedron, 1995, 51, 3392. 60. Chopra, N . ; Sherman, J. C . Angew. Chem. Int. Ed. Engl. 1997, 36, Mil. 61. Causton, A . S.; Sherman, J. C . Bioorg. Med. Chem. 1999, 7, 23. 35 Chapter 2. Formation of Cavitands and Carceplexes with C 5 Symmetry. 2.1. Introduction. A s summarized in chapter 1, several carceplexes and many hemicarceplexes have been prepared that contain C 4 symmetry. These carceplexes all manifest small cavities that permanently entrap one small guest molecule. Our group has also prepared a large carceplex (trimer carceplex 52), which entraps 3 molecules of D M F . Our interest is in creating other large carceplexes that manifest any of the following properties: (1) they contain larger cavities than trimer carceplex 52, (2) they are synthetically easier to prepare and/or (3) they present potential new properties, specifically, different guest affinity due to the different host shape. The latter two points are most relevant to this thesis. This chapter presents the synthesis of carceplex 65«guest(s) , which is more readily prepared than is trimer carceplex 52, and as carceplex 65»2 D M F contains a novel C 5 axis of symmetry and may offer new binding properties (to be discussed later in the chapter). The original goal of this thesis work was the formation of sulfide linked carceplex 64«guest(s) , as follows: Resorcin[5]arene 55 was converted to [5]cavitand 58 (Scheme 2.1 pg. 38) , which was brominated to give Br-[5]cavitand 60, which was then converted to SH-[5]cavitand 61 (Scheme 2.2 pg. 43) . Attempted linkage of Br-[5]cavitand 60 and SH-[5]cavitand 61 led to a product which was at first thought to be carceplex 64«2 D M F (Scheme 2.3 pg. 50) , but turned out to be carceplex 65*2 D M F . This chapter describes the 3 6 "accidental," then intended synthesis of carceplex 65«2 D M F (Scheme 2.4 pg. 60). A successful synthesis o f carceplex 64»2 D M F has now been prepared in our laboratory (by Christoph Naumann) and w i l l be discussed only briefly. 2.2. Results and Discussion 2.2.L The synthesis [5]cavitand 58 W e prepared resorcin[5]arene 55 under similar conditions to those used by Konishi et al . , who obtained a mixture of resorcin[n]arenes (where n = 4, 5 and 6).1 A s we were interested i n optimizing the yield of resorcin[5]arene 55, we used a milder set of conditions: we ran the reaction at 60 °C for 30 min (Scheme 2;1). W e subjected the crude resorcin[n]arene mixture directly to bridging conditions to generate a mixture of cavitands (Scheme 2.1). Thus, conditions for optimization of resorcin[5]arene 55 were developed by monitoring subsequent formation of [5]cavitand 58. C H 3 H O ^ A w O H HCI/EtOH (1:4 v:v) (EtO) 2 CH 2 60°C, 30min DMA, K 2 C 0 3 > CH 2BrCI 60°C, 24 hr Crude mixture containing 54 n = 4 55 n = 5 56 n = 6 57 n = 4 (2.4%) 58 n = 5 (3.4%) 59 n = 6 (7.5%) Scheme 2.1. The formation of resorcin[5]arene 55 developed by Konish i 1 and subsequent formation of [5]cavitand 58. The % yields o f [njcavitands are calculated from 2-methyl resorcinol (starting material) 37 The [njcavitand (where n = 4, 5 and 6) were separated as follows: [5]cavitand 58 and [6]cavitand 59 were separated from [4]cavitand by their low solubility in ethylacetate. [6]Cavitand 59 is relatively insoluble i n chloroform and thus could be separated from [5]cavitand 58 by precipitation. The remaining filtrate contained [5]cavitand 58 in a 3.4 % yield (starting from 2-methyl resorcinol). [5]Cavitand 58 crystals were grown in our laboratory by Christoph Naumann and the structure was determined by Brian Patrick (Chemistry, U B C ) . It is clear that from the structure there is an enforced cavity and Csv symmetry (Figure 2.1). The ' H N M R spectrum of [5]cavitand 58 (Figure 2.2) was assigned by Christoph Naumann, and complements the crystal structure data. 58 Figure 2.1 X-ray crystal structure of [5]cavitand 58 38 The 2-methyl substituent is a useful feature of the [5] cavitand 58 structure as it potentially lends itself to conversion into a variety of functional groups. We were interested in selective bromination at the methyl substituent and then converting to S H & O H derivatives. These functionalized [5] cavitands may be utilized in the formation of carceplex 64«guest(s) or other desired products. 39 The selectivity of the radical reaction towards the 2-methyl group is worth mentioning, since radical stability is in the order: (most stable) A l l y l i c * > R 3 0 > R 2 H O > R H 2 0 > H 3 0 > Vinylic* (least stable) Thus, it would be expected that the reaction occurs at the A r C F b A r methylene position rather than the 2-methyl positions. This was not the case and shall be discussed in further detail later in this chapter. Unlike the previously published [4]cavitand derivatives, [5]cavitand 58 structure lacks "feet", possessing only a methylene bridge on the lower rim of the [5]cavitand structure. Feet appendages normally consist of aromatic or aliphatic substituents which often enhance the solubility of the cavitand. We found that the [5]cavitands were soluble in chloroform, allowing facile separations and then analysis by M A L D I M S and ' H N M R . The dimensions of [5]cavitand 58 and [4]cavitand 57 were calculated from the crystallographic data.3 The diameter of the lower rim of 57 was calculated by measuring from the carbon at the base of the aromatic ring to the carbon at the base of aromatic ring across from it (Figure 2.3). Upper rim diameter was calculated by measuring the distance between the carbon in one methyl and the carbon in the methyl group directly across (Figure 2.3). For [5]cavitand 58, simple trigonometry was used to calculate the width of the upper and lower rims. We know the distance b and c (Figure 2.3) from the crystallographic data and applying equation 1: a 2 + b 2 = c 2 (Equation 1) 40 we can calculate distance "a". This measurement is somewhat conservative, but, gives an idea of the width of [5]cavitand 58. leight of cavity 57 A „ 58 = Carbon Figure 2.3. Schematic representation of the method of measuring the distance of the upper and lower rims and the height of cavitands 57 and 58. a The top rim of the structure of [4]Cavitand 57 has a diameter of approximately 7.75 A and [5]cavitand 58 9.25 A , and the bottom rim of [4]cavitand 57 has a diameter of 3.35 A and [5]cavitand 58 4.75 A . Both [4]cavitand 57 and [5]cavitand 58 have an o approximate height of 3.7 A . Thus, it is obvious from these dimensions that [5]cavitand 58 contains a larger cavity than [4]cavitand 57 (207 A 3 and 122 A 3 respectively). Half the upper rim distance for the radius distance and calculating the volume of a hemisphere using the equation [4/3(7uR3)]/2 ). [5]Cavitand 58 could therefore possess different binding properties, opening the door to many new studies. 2.2.H. Selective Functionalization of [5]Cavitand 58 2.2.ila) Radical Bromination of 2-methyl substituent The 2-methyl position of [5]cavitand 58 (Scheme 2.2) was brominated via treatment with N-bromosuccinimide (NBS) and A I B N in CCI4. It is not clear from the *H 41 N M R spectra of Br-[5]cavitand 60 that complete bromination occurred, as there appear to be unbrominated methyl groups ( 2.05 ppm, Figure 2.4). These signals may be trace amounts of partially brominated products that could not be separated from Br-[5]cavitand 60. Also, the signals of the new CH^Br protons could not be resolved, resulting in the uncertainty of the resulting brominated product. M A L D I M S did not assist in the characterization of Br-[5]cavitand 60, as the spectrum resulted in a broad signal (Figure 2.5), it did however indicate the absence of the [5]cavitand 58 which, i f present, has a strong peak at m/z 740. Scheme 2.2. The selective functionalization of [5]cavitand 58 to Br-[5]cavitand 60 and SH-[5]cavitand 61. Conversion of [5]cavitand 60 and 61 to the acetylated derivatives 62 and 63 respectively. 4 2 nbout n bin 60 K, CDCI, unbrominated CH. b out I I I I | I I I I | i I i i | i i i i | 7.0 6.0 i I i i i i I i i i i | i i i i | i i i i [ i i i i | i i i i | i i i i | i i i i | i i i i | i ' 5.0 4.0 3.0 2.0 1.0 ppm Figure 2.4. * H N M R spectrum of Br-[5]cavitand 60 (CDC13, 400 M H z , 300K). 4 3 B r - [ 5 J c a v i t a n d tn i/y K> <J~> *-) o » o — BOO 1OOO 1 ?00 MOO 1600 1 BOO /p.port/M-*/oatft/«*l/ifst/n 0 v??5io?6/lSftft/DOMa/1 tO( Fr , Nov ?8 16 30 38 1960 Figure 2.5. M A L D I M S spectrum of Br-[5]cavitand 60 (positive mode, />nitroaniline as the matrix). The masses shown correspond to Br-[5]cavitand 60 (1133.6 m/z), four methyl groups brominated (1055.3 m/z) and three methyl groups brominated (975.1 m/z). Early in this chapter we asserted that bromination would be expected to occur at the A r C F b A r methylene position rather than the 2-methyl positions. However, since radical intermediates prefer a planar (or slightly pyramidal) structure, unobtainable by the rigid ArCH2Ar bridge yet adoptable by the 2-methyl position, the reverse has been proven. Attempts to isolate Br-[5]cavitand 60 by various chromatographic techniques were not successful. To gain further confidence that we in fact had a reasonable, albeit crude, sample of Br-[5]cavitand 60, we acetylated the crude product with sodium acetate in D M F and separated the ensuing acetylated equivalents by column chromatography 44 (Scheme 2.2). OAc-[5]Cavitand 62 was characterized by ' H N M R (Figure 2.6) and M A L D I M S . The conversion of Br-[5]cavitand 60 to the acetylated derivative 62 (28.8 % starting from [5]cavitand 58) gave an indirect method for determining the structure of Br-[5]cavitand 60 (calculated to be at least 26.1 % yield starting from [5]cavitand 58). The ! H N M R spectrum of 62 (Figure 2.6) confirming the symmetry of OAc[5]cavitand 62 as being the same as [5]cavitand 58, C5V. 4 5 Figure 2.6. NMR spectrum of 0Ac-[5]cavitand 62 (CDCI3,400 MHz, 300 K). 46 2.2.iub. Conversion of Br-[5] cavitand 60 to SH-[5] cavitand 61. The SH-[5]cavitand 61 was synthesized as a potential nucleophile to link with the electrophilic Br-[5]cavitand 60 and create the sulfide linked carceplex 64»guest . The condition for the synthesis of SH-[5]cavitand 61 was as follows: Br-[5]cavitand 60 was dissolved in D M F and thiourea, followed by a hydrolysis and an acidic work up (Scheme 2 .2) . Separation by column chromatography yielded 17.7 % SH-[5]cavitand 61 (starting from [5]cavitand 58). The ! H N M R data accounts for all the protons ( H e is masked by the CDCI3 peak) and thus supports the proposed structure of SH-[5]cavitand 61 (Figure 2 .7 . ) . However, the M A L D I M S is somewhat ambiguous, as the mass of 61 is consistently reported as 9 5 0 (negative mode, /7-nitroaniline as the matrix), despite an expected mass of 9 0 0 . Further mass spectroscopic techniques could not verify the expected mass of S H -[5]cavitand 61. To clarify the structure of 61, the product was acetylated to give 63 (Scheme 2 .2 . ) . The acetylated derivative 63 was characterized by *H N M R and M A L D I M S , the results clearly indicated the expected structure for 63 and thus it could be concluded that SH-[5]cavitand 61 had been synthesized. 47 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm Figure 2.7. ! H NMR spectrum of SH-[5]cavitand 61 (CDCI3, 400 MHz, 300 K). 4 8 2.2.iii. Synthesis of Carceplex 65»guest(s). The original objective of this thesis was to link Br-[5]cavitand 60 with S H -[5]cavitand 61 under suitable reaction conditions and form the sulfide linked carceplex 64«guest(s) (Scheme 2.3). However, the resulting experimental data proved that carceplex 64«guest(s) was not the product of the reaction. In fact, a disulfide linked carceplex 65«guest(s) was synthesized, a result of two SH-[5]cavitand 61 linking (Scheme 2.4 pg. 60). The results and the discussion of the experimental data are reported chronologically, giving the reader an insight into how we resolved the carceplex 65«guest(s) from that of carceplex 64»guest(s). 60 61 Scheme 2.3. Carceplex 64«guest formation via linking of Br-[5]cavitand 60 with S H -[5]cavitand 61. 4 9 2.2-iii.a) Attempted synthesis of Carceplex 64 «guest(s) The initial reaction conditions for the synthesis of carceplex 64»guest(s) were as follows: SH-[5]cavitand 61 was dissolved in N F P (1-Formylpiperidine) and CS2CO3, Br-[5]cavitand 60 was then added to the reaction mixture (Scheme 2.3). Analysis of the resulting products showed no evidence for the synthesis of carceplex 64»guest(s). Thus, it was thought that N F P was an inappropriate guest/template for this system. Alternate guests were required to pursue the synthesis of carceplex 64»guest(s). The choice of guest were larger analogues of those found successful in the synthesis of the [4]cavitand derived carceplexes.4 They were larger in size in order to compensate for the aforementioned host's smaller interior. These guests were ineffective templates for the synthesis of carceplex 64«guest (Figure 2.8). 0 0 o n A X H3cr0-cr0-cH3 H 3 U O 01-I3 Q H 2 Figure 2.8. Unsuccessful templates for the formation of sulfide linked carceplex 64»guest(s). A s the reaction conditions chosen so far were unsuccessful in the synthesis of carceplex 64«guest, we endeavored to change the conditions. Two reaction conditions 5 0 1 were prepared. In the first: SH-[5]cavitand 61 was dissolved in D M F and CS2CO3 with the addition of benzene as a guest molecule, Br-[5]cavitand 60 was then added to the reaction mixture after 1 hour. In the second set of conditions: SH-cavitand 61 was dissolved in D M A and CS2CO3 with the addition of ferrocene acetate as a guest molecule, Br-[5]cavitand 60 was then added to the reaction mixture after 1 hour. C P K modeling prior to these reactions show that ferrocene acetate and multiple benzene molecules could be accommodated within the cavity of 64. The M A L D I M S indicated that the mass was between 260 - 400 m/z greater than that of the unoccupied carceplex (carcerand) 64 (which would have a mass of 1630) for both the DMF/benzene and the DMA/ferrocene acetate reactions. However we were uncertain as to whether the reaction had gone to completion and formed the carceplex 64»guest. We interpreted the M A L D I M S from the reaction involving D M F and benzene (Figure 2.9) where peaks at 1891, 1906, 1967 and 1981 m/z were observed. The experimental masses were similar to the theoretical values for carceplex 64*3 benzenes + N a + (theoretical mass 1887), 64«3 benzenes + K + (theoretical mass 1903), 64«4 benzenes + N a + (theoretical mass 1965) and 64»4 benzenes + K + (theoretical mass 1981). 51 0 ©080 • 0 0076 • 0 0070 -0 0065 -j 0 O O M • U ) f»» — o» o u> no oo ffi o <r U O ( 0 0 I0OC HOC 1600 I M C WOO ??O0 t « C IftOO M O O < F - ^ Figure 2.9. M A L D I M S of the resulting product from DMF/Benzene carceplex reaction. Further experimental analysis was required to validate that benzene was the encapsulated guest. The reaction was repeated with the same conditions, with the omission of benzene; surprisingly, the M A L D I M S gave identical masses to those previously reported. These findings ruled out the possibility of benzene as an encapsulated guest in carceplex 64. A s D M F was present during the reaction as the solvent, it was possible that D M F could act as a potential guest and be encapsulated within the interior of the host. This proposal was speculative and additional experimental data used to determine the product. 5 2 2.2.iiLb) 'HNMR data Analysis by *H N M R spectra enabled us to assign the Ar -CHb -Ar , Ar-0-CH2-0-A r and A r - H protons (Figure 2.10) for the host 64. It was also obvious that the C$ symmetry present in the cavitands had been retained in the structure of the host 64. The ' H N M R spectra did not resolve the signals for the A r C H i S C F b A r protons (linking unit between two cavitand hemispheres) at ambient temperature. However, they were resolved by low temperature ] H N M R (to be discussed later in this chapter). The upfield region of the ] H N M R spectra showed two singlet peaks at 0.28 and 0.20 ppm, possibly representing the N - M e of D M F . Further analysis via 2D N O E S Y showed that these signals were correlated to a signal downfield ( 5 . 3 6 ppm) which was believed to be the formyl proton of D M F . These signals also had nOe signals correlating to the protons of the host structure, thus providing further evidence that D M F was entrapped within the interior of the carceplex. Integration of the ' H N M R spectra calculated that the signals at 0.28 and 0.20 ppm each represented 6 protons, suggesting that 2 D M F molecules had been entrapped within the host. Analysis performed on the product of the D M A carceplex reaction by ! H N M R (performed by Christoph Naumann) resolved 2 D M A molecules entrapped within the cavity of 64. The evidence from the *H N M R spectra suggests that we had separately synthesized carceplex 6 4 » 2 D M F and carceplex 6 4 » 2 D M A , however, initial M A L D I M S data reported masses for these products that were greater than the theoretical values. 53 Further M A L D I M S experiments were performed and shall be discussed in the next section. I | I I I I | I I I I | I I I II I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | I I I I | M II | I II I [ I I I I | I I I I | I I I I | I I I |-[ I I I I | 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm Figure 2.10. *H N M R spectrum of disulfide carceplex 65*2 D M F (500 M H z at 300 K in C D C b ) . Due to the structural similarities between 65 and 64 it was thought that spectrum was of carceplex 64»2 D M F 5 4 2.2.iiuc) Verifying Parent Peaks in MS data The theoretical mass for carceplex 6 4 » 2 D M F and carceplex 64*2 D M A are 1776 for the former and 1808 for the latter, however, the M A L D I M S data reports that the mass for both of these systems are higher than the theoretical value. We were doubtful that we had synthesized carceplex 64*2 D M F and had actually synthesized a different host-guest system, carceplex 65*2 D M F , further experimental analysis would elucidate the structure Counter ions ( H + , N a + , K + etc.) can be present during the conditions of the M A L D I M S experiments. It is difficult to know which counter ions are responsible for which signal. For us to resolve the actual mass of the parent peak we purposely spiked both carceplex 6 5 » 2 D M F and carceplex 6 5 » 2 D M A samples with a known counter ion A g + . The resulting M A L D I M S signal would be a combination of the parent mass and the mass of the A g + counter ion (Figure 2.11). The results are reported in Table 2. 5 5 DMF i n Ag + / C H C 1 3 DMA i n Ag + / C H C 1 3 3 1 Figure 2.11. The M A L D I M S of 65*2 D M F and 65*2 D M A spiked with C F 3 S 0 3 A g ( A g + source) to verify parent mass. 65«2 D M F (m/z) 65»2 D M A (m/z) mass of sample spiked with A g + 2048.7 .2077.5 subtract A g + (mass 107) 1941.7 1970.5 subtract mass of 2 guests 1795.4 1795.9 expected mass of 64 (unoccupied) 1630 1630 actual mass - expected mass 165.4 165.9 Table 2. M A L D I data performed with />nitroanaline as a matrix. Carceplex 65»2 D M F and 65«2 D M A spiked with A g + affording a calculation of the parent peak. 5 6 Extrapolation of the data from M A L D I M S gave us a mass of 1941 for carceplex 65«2 D M F and 1970 for carceplex 65*2 D M A . We were also able to confirm that the additional mass is 165, and was not due to the presence of a counter ion. Two plausible explanations for the additional mass occurring in both systems are 1) that an additional guest had been encapsulated, or 2) the structure of the host is not that of the expected sulfide linked carceplex 64. 2.2.iiLd) I.R. Spectroscopic data. Carceplex 65»2 D M F was analyzed by I.R. spectroscopy (Figure 2.12). The majority of the signals could be attributed to the structural feature of carceplex 65*2 D M F , in particular, the two encapsulated D M F molecules provided characteristic carbonyl stretching at 1681 cm - 1 . The I.R spectrum also showed a strong absorbance peak between 1005-979 cm which could not be attributed to the structural features of the proposed carceplex 65»2 D M F . A search of reference I.R. spectra, found that a strong signal at this frequency maybe characteristic for disulfide bonds. A plausible explanation for the presence of disulfide bonds in the carceplex structure is that the cavitand hemispheres are linked by disulfide bonds, rather than sulfur bonds as was expected. Such a structural alteration would account for 5 additional sulfur atoms with a combined mass 5 7 of 160, approximately the same mass that we could not account for in the M A L D I M S data shown in Table 3. 59.5 3000 2000 1500 500.0 crn-1 • 7 • Figure 2.12.1.R. spectrum of carceplex 65«2 D M F . To prove this hypothesis, the carceplex reaction was repeated: SH-[5] cavitand 61 was dissolved in D M F and CS2CO3 (Scheme 2.4). The product (13.9 % yield) has a mass of 1937 ( M A L D I MS) , with a theoretical mass of disulfide carceplex 65«2 D M F being 1936. This evidence along with the M A L D I M S , I.R. and ' H N M R data convinced us that we had synthesized the disulfide carceplex 65»2 D M F . 5 8 65- 2 DMF Scheme 2.4. Formation of the disulphide carceplex 65*2 DMF A closer look at the reaction conditions that were used for the attempted synthesis of carceplex 64»2 DMF shows that SH-[5]cavitand 61 was dissolved in DMF and CS2CO3 for an hour prior to the addition of Br-[5]cavitand 60. Thus the disulfide carceplex 65*2 D M F was synthesized before Br-[5]cavitand 60 could link with SH-[5]cavitand 61. Further research into the synthesis of carceplex 64«2 DMF has been successful (performed by Christoph Naumann). From the aforementioned reaction we know that introducing the SH-[5]cavitand 61 to the reaction medium prior to the Br-[5]cavitand 60 results in the synthesis of disulfide carceplex 65»2 DMF. In order to inhibit this, the Br-[5]cavitand 60 was dissolved in DMF and CS2CO3 (N2 atmosphere), then SH-[5]cavitand 61 was added. The resulting product was confirmed as carcplex 64»2 DMF. There is a close similarity between the structures of host 64 and 65 and theoretically, they are indistinguishable by ' H NMR alone. With the knowledge that the 5 9 structure of the host is indeed the disulfide carceplex 65*2 D M F , the initial ! H N M R data which was believed to be for carceplex 64>2 D M F , was actually that of the disulfide carceplex 65»2 D M F . The N M R data did not resolve the A r C H 2 S methylene protons, H c , which gave broad signals at 300 K (Fig.2.10). At 250 K , the ! H N M R spectrum resolves the A r C H 2 S - S C H 2 A r protons, which give doublets at 4.38 ppm and 3.99 ppm (Figure 2.12, low temperature lH N M R experiments performed by Christoph Naumann) and were assigned as H c o u t and H c ; n respectively. The geminally coupled H c o u t and H c m protons are non-equivalent, which is thought to be due to the different shielding they experience. We are speculating that at 250 K the H c o u t protons are further (in distance) from the disulfide bond than the H c j n protons, resulting in the latter experiencing a lower electric field (higher ppm) and the former a higher electric field (lower ppm). The structural conformation of the disulfide bond and the H c protons has been investigated using computer simulations and will be discussed later in this chapter. 6 0 I j I I II j I I M I I I I I I I I I I j I 1 I I I I I II I i I I I [ I I II I I I I I I I I I I I I M I I 1 11 I [ I I I I I I I I l I I I l l I M 7^0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 p p m Figure 2.12. *H N M R spectrum of carceplex 65»2 D M F (500 M H z at 250 K in CDC1 3 ) . 61 2.2.iiue) Variable High Temperature 1HNMR Variable temperature ' H N M R has been used to probe the mobility of guests entrapped in carceplexes.5'6 For example, the energy barrier to rotation about amide bonds is sensitive to phase and to the polarity of the solution. The barrier generally decreases on moving from a polar solvent to a non-polar solvent to the gas phase.7 High temperature *H N M R experiments were performed on carceplex 65«2 D M F in order to investigate the nature of the carceplex interior (Figure 2.13). The A G * for amide bond rotation is calculated using Equation 2. A G 1 = R T c [23 + In (T c / Av)] (Equation 2.) T c is the temperature at which the N-methyl signals coalesce and Av is the frequency separation between the N-methyl signals at low temperature (250 K) . The variable high temperature (300-400 K) ! H N M R spectra of carceplex 65»2 D M F shows the N-methyl signals coalescing at an estimated temperature of 400 K and Av = 40, which corresponds to a A G * value of 20.6 kcal mol" 1 . This energy barrier is similar to that of free D M F in nitrobenzene (20.2 kcal mol" 1) 5 and higher than that of the D M F molecule in 32»DMF (18.9 kcal mol" 1) 5 and the three D M F in trimer carceplex 53»3 D M F (19.3 - 19.5 kcal mol" 1 ) , 1 0 suggesting that the D M F molecules in carceplex 65 exhibit a more liquid-like phase. This data is supported by the I.R. data that resolves the carbonyl stretching at 1681 cm which, interestingly, is similar to the carbonyl absorbance when in a liquid-like phase. 62 300 K ppm ppm 1 1 1 i | i i i i | i i i i | i i i i | i i i i | i i i i i i i i i | i i i i i i i i i | i i i i i i i i i i i i 7.0 6.0 5.0 4.0 3.0 2.0 1 0 0.0 ppm Figure 2.14. High Temperature Variable *H NMR of carceplex 65*2 DMF (500 MHz nitrobenzene)a a V T ' H N M R experiments performed by Christoph Naumann, Sherman Laboratory 63 2.2.UL f) Guest Orientation within the Carceplex Interior A s previously cited in chapter 1, the ' H N M R signals for the guest molecule encapsulated within the carceplex are shifted upfield due to the shielding effect of the T C -electron rich cavities. The degree of shielding varies significantly, with guests residing deep in the cavity being highly shie lded . 5 ' 6 ' 8 ' 9 As the guest becomes further removed from the bowls the shielding effect diminishes, 1 0 thus providing a "magnetic map" of how the guest may be oriented. Comparing the ' H N M R data of carceplexes 3 2 « D M F 5 and 52*3 D M F 9 with that of 6 5 « 2 D M F gave us a notion of how the two D M F molecules were oriented in the interior of host 65. Table 3 summarizes the observed chemical shift for D M F in carceplex 3 2 « D M F , the trimer carceplex 52*3 D M F and carceplex 6 5 « 2 D M F 3 2 . D M F R -CH 2 CH,Ph 5 2 . 3 D M F 6 5 * 2 D M F Figure 2.15. Structural comparison between carceplex 3 2 « D M F , carceplex 52* 3 D M F and carceplex 65*2 D M F . 64 H e H f H g He H f Hg 5/ppm. 8/ppm 8/ppm - A 8 a -AS -A8 free D M F 8.05 2.98 2.96 — carceplex 32»DMF b 4.28 -0.04 -1.02 3.77 4.00 2.90 trimer carceplex 5.97 1.04 -0.11 2.08 1.94 2.97 52* 3 D M F C carceplex 65*2 5.36 0.28 0.20 2.73 2.60 2.72 D M F Table 3. Comparison of chemical shift values for free and encapsulated D M F in CDCI3 for various sized carceplexes a -AS = 5(free D M F ) - 8(complexed D M F ) b reference 5 . c reference 10. The AS values observed for carceplex 65»2 D M F lie somewhere between those of 32 and 52 suggesting that the D M F molecules do not lie in very close proximity to the cavitands and yet are not extremely close to the equator of the structure but somewhere between the two locations. The difference between A5 values for the N-methyls of D M F i n 65 is 0.08 ppm compared to 0.98 for carceplex 32«DMF and 1.15 ppm for trimer carceplex 52*3 D M F . 6 5 Large differences as exhibited by carceplex 32 and trimer carceplex 53 are characteristic of one N - M e lying deeply within the arene-lined cavity and the other N - M e position being close to the equator. Thus, they are experiencing very different electric fields within the confines of the host which are represented by the corresponding chemical shifts in the ' H N M R spectra. The small difference between the N - M e signals of both D M F entrapped in carceplex 65 suggests that they lie in very similar environments, possibly parallel to one another. In the next section we shall see how the simulated computer dynamic experiments performed upon carceplex 65*2 D M F orients the D M F molecules within the host interior. 2.2.iiug) Computer Simulation of Guest Orientation. The computer generated simulations of 65*2 D M F can give us some indication of how the D M F molecules are oriented and positioned within the interior of 65. The modeling shall also provide a theoretical representation of the most stable conformation of host carcerand 65 . 1 1 6 6 Figure 2.16. Computational representation of 65»2 D M F . The theoretical simulation for 65»2 D M F shows the most stable orientation of the C H 2 S - S C H 2 linkers and accounts for the non-equivalence of the H c protons. The C H 2 S protons ( H c i n and H c o u t shown in the enhanced picture on the right hand-side of Figure 2.16) are diastereomeric since H c o u t are close in proximity to both sulfur atoms in the disulfide bond, H c i n are close to only one sulfur atoms. Therefore, due to their proximity to the sulfur atoms H c o u t should experience a greater magnetic field than H c i „ . These observations from the computer simulation correlate to ' H N M R data (Figure 2.13), where, H c o u t signals are further downfield (larger ppm) and H c i n signals are further upfield (smaller ppm). 67 Figure 2.17. Theoretical simulation, showing the 2 D M F molecules orientation within the cavity of 65. The theoretical representation of 65»2 D M F (Figure 2.17), with the D M F molecules are represented by the dark atoms, shows that the two D M F molecules are oriented anti-parallel to one another and perpendicular to the Cs symmetry axis. They are also not set deeply inside the cavity of their respective hemispheres nor do they lie in very close proximity to the equator. Thus there is a positive correlation between these computational results and the results predicted by the N M R data The height of host 65 is approximately 8.5 A and the width is approximately 8.5 A , therefore the internal volume would be approximately 320 A , assuming the structure is spherical and the diameter is approximately 8.5 A . The holes at the top and the bottom of 65 are reasonably large, having a diameter of 5.2 A (calculated using the same method for the lower rim dimensions of [5]cavitand 58), and may allow for the escape of some guests molecules, thus creating a hemicarceplex, which, by definition does not require the 6 8 breakage of bonds to enable the guest to escape. A s yet the guest movement in and out of the host has not been investigated. i _ I = C a r b o n O = Sulfur 65 65 Figure 2.18. Schematic diagram that shows the calculation of the height and width of carceplex 65»2 D M F . 2.2.iii.h) Possible Mechanism for the Formation of Disulfide Carceplex 65*2 DMF. A possible formation of the disulfide bond could be due to oxidative coupling of the SH-[5]cavitand resulting in the synthesis of the disulfide linked carceplex 65*2 D M F . In our condition the presence of atmospheric oxygen in the reaction vessel (or dissolved in D M F ) is believed to be sufficient for this process to occur (Figure 2.19). The weakness of the S-H bonds makes a good hydrogen donor for free radicals, however, as mechanistic studies have not been performed, these mechanism (Figure 2.19), while a plausible suggestion for the disulfide bond formation are merely speculative. 69 61 Figure 2.19. Proposed oxidative coupling mechanistic representation of the formation of disulfide carceplex 65*2 D M F 70 2.3. Conclusions In Chapter 2 we have reported the synthesis of carceplex 6 5 « 2 D M F . [5]cavitand 58 was synthesized and the 2-methyl groups then underwent selective free radical bromination to give Br-[5]cavitand 60 (characterized indirectly by the formation of O A c -[5]cavitand 62), which was converted to SH-[5]cavitand 61 (characterized indirectly by the formation of SAc-[5]cavitand 63). The coupling of two molecules of SH-[5]cavitand 61 proved to be successful and led to the formation of carceplex 6 5 » 2 D M F which has a unique C$ symmetry as well as hemispheres that are linked by disulfide bonds. ' H N M R data showed Carceplex 65 to have encapsulated 2 D M F molecules. I.R. spectroscopy indicated the presence of the disulfide bond stretching and M A L D I M S experiments confirm the correct mass of disulfide carceplex 6 5 » 2 D M F . Computational studies have given an insight into the conformation of the host 65, as well as the possible orientation of the two D M F molecules within the interior of 65. These results agree with the data obtained from ! H N M R spectroscopy, suggesting that the D M F molecules are neither deeply set in the cavities, nor in close proximity to the equator. It has also been shown that the solubility of [5] cavitand 58 (and functionalized derivatives 60 and 61) and carceplex 6 5 » 2 D M F are relatively high in organic solvents, thereby allowing for separation, purification and analysis of these compounds. 71 2.4. Future developments and Applications The synthesis of self-assembling structures that contain a cavity capable of encapsulating multiple guest lend themselves to possible future applications, possibly drug delivery devices and miniature reaction chambers.11 Cram has continued to develop other molecular host systems that encompass his idea of preorganization. 1 1 - 1 3 Although we have shown that carceplex synthesis from [5]cavitand moieties are possible, the potential of this larger host system has yet to be fully examined. A s mentioned in chapter 1, ongoing research into the design of de novo proteins has been performed by the Sherman research group, where the [4] cavitand acts as a template to attach peptides and form a cavitein. A s the symmetry and shape of the [5]cavitand is somewhat similar, the [5]cavitand may be utilized as a template for the de novo design of proteins appears feasible. Figure 2.20. Proposed structure 66 of a [5]cavitand with 5 helical bundles attached via disulfide bonds. 72 The formation of a carceplex from the coupling of two cavi[5]tand-OH 68 hemispheres (Scheme2.6) is also of current interest for our research purposes, although similar to carceplex 65, carceplex 67*guest will possess different functionalities within the internal cavity which should allow for different guest encapsulation to that of carceplex 65. 67 Scheme 2.5. The formation of carceplex 67 via the coupling of cavi[5]tand-OH 68 While the formation of disulfide carceplex 65«guest(s) is still in its infancy, continued studies of this compound will provide a further indication to the boundaries of its capabilities. The potential of these compounds, as a vessel, for delivering drugs to different parts of the body is a realistic application. However, for this to be applicable they must be soluble within the aqueous medium of the human body. Carceplex 65»guest(s) is currently soluble in only organic solvents, the development of a water soluble derivative of 65 would be a great achievement. 7 3 2.5. Experimental. General experimental NBS was recrystallized in water. The solid was then dried in vacuo over P2O5 and the purified NBS was stored away from direct contact with light. CCI4 was dried with Na2SC>4, filtered and distilled and stored away from direct contact with light. A l l other commercially available reagents were purchased without further purification unless otherwise stated. Matrix assisted laser desorption ionization (MALDI) mass spectra were recorded on a V G Tofspec in reflectron mode. N M R spectra were recorded on a Bruker W H -400 spectrometer in CDCI3 at ambient temperature using the residual ' H as a reference (7.24 ppm) unless otherwise noted. The column chromatography was performed using silicycle 230-400 mesh silica gel. 2.5.L Synthesis of [5] cavitand 58 A mixture of 2-methylresorcinol (20 g, 0.161 mol) and diethoxymethane (20 mL, 0.161 mol) were dissolved in ethanol (360 mL) in a reaction vessel and then heated in an oil bath at 60 °C. The mixture was allowed to equilibrate to the temperature for 30 min. upon addition of concentrated hydrochloric acid (90 mL). The mixture stirred for 30 min. under a nitrogen atmosphere. After 30 minutes, the mixture was poured into water/diethyl acetate (500 mL / 500 mL). The organic phase was separated and kept, while the aqueous 74 phase was extracted with 3 x 100 mL aliquots of diethyl acetate, procuring additional organic phases which were combined with that of the initial organic separation. The combined organic phase was washed with water until the aqueous extract had a neutral pH. The organic phase was then dried with MgSCU and the solvent was removed in vacuo at 50 °C to yield 25 g of a brown solid mixture. The crude product (25 g) from the resorcinarene formation was added to bromochloromethane (25 mL) and the resulting mixture was dissolved in D M A (360 mL), to which potassium carbonate (37.5 g) was added. The mixture was left to stir at 60 °C for 48 hrs. The reaction mixture was cooled to room temperature before filtering through Celite, removing excess potassium carbonate. The solvent was then removed in vacuo to yield 27.5 g of an orange-brown solid. The components were partially separated via column chromatography with chloroform as the mobile phase, yielding 3.0 g [njcavitand (where n = 4, 5, 6) as a white solid. This solid was then dissolved in chloroform and refrigerated overnight, resulting in the precipitation of cavi[6]tand (1.8 g, 7.5 % yield from 2 steps). The solvent was removed from the filtrate and then partially dissolved in diethyl ether, the insoluble product (0.8 g, 3.35 % yield starting from 2-methyl resorcinol) was found to be [5]cavitand 58. ! H NMR (CDC13, 400 MHz); 6 7.14 (s, 5H, H c ) , 5.97 (d, J= 6.8 Hz, 5H, H a o u t), 4.35-4.33 (m, 5H, H b o u t , 5H, H a i n ) , 3.37 (d, J = 12.4 Hz, 5H, Hb i„), 2.04 (s, 15H, H d) MALDI MS m/z: 740 (M + ) Calcd for C45H40O10 = 740 7 5 2.5.ii. Functionalization of [5]cavitand 58. 2.5.iua) Synthesis of Br-[5)1 cavitand 60 [5]cavitand (232 mg, 0.313 mmol) was added to NBS (285 mg, 1.601 mrnol), A I B N (catalytic amount) and dissolved in carbon tetrachloride (160 mL. The reaction was performed in a nitrogen atmosphere and exposed to a 100 W lamp positioned 30 cm from the reaction vessel. The mixture was left to stir for 18 hrs., the solvent was then removed in vacuo resulting in a white solid. The removal of the succinimide was possible by quenching the reaction mixture with water and extracting the brominated species with chloroform. The resulting yield was approximately 26 % starting from cavitand 58 and characterizated of Br-[5]cavitand 60 by converting to OAc-[5]cavitand 62. 2.5.iLb) Synthesis of SH-[5]cavitand 61 To the crude Br-[5]cavitand 60 mixture (285 mg), thiourea (500 mg, excess) was added and dissolved in D M F (35 mL, degassed). The reaction mixture was stirred for 2 hrs under vacuum (0.01 torr). The reaction mixture was then poured onto 2 M aqueous sodium hydroxide (35 mL, degassed) and stirred for 1 hr under vacuum (0.001 torr). The mixture was added to 5% acetic acid (35 mL) and the resulting solid was filtered, washed with water, dissolved in chloroform and then dried with sodium sulfate. The crude product (90 mg) was cream in color. The crude product was subjected to column 76 chromatography, with chloroform:methanol (19:1) as the eluent, resulting in S H -[5]cavitand 61 (50 mg, 17.7 % starting from 58) as the product. *H NMR (CDC1 3 , 400 MHz): 5 7.25 (s, 5H, H c ) , 6.06 (d, J= 7.2 Hz, 5H, H a 0 u t ) , 4.57 (d, J= 7.2 Hz, 5H, H a i n ) , 4.38 (d, J= 13.0 Hz, 5H, H b o u t ) , 3.77 (d, J= 7.1 Hz, 10H, H e ) , 3.38 (d,J= 13.8 Hz , 5H, H b i n ) , 1.54 (t, J= 7.2 Hz, 5H, H d + H 2 0 . MALDI MS m/z: 950 ( M " , in negative mode) Calcd for C45H40O10S5 = 900. 2.5.ilc) Synthesis of OAc-[5]cavitand 62 T o the crude Br-[5]cavitand 60 (285 mg) sodium acetate (250 mg, dried, in excess) was added, and then dissolved in D M F (70 mL, distilled). The reaction mixture was stirred for 12 hrs under a nitrogen atmosphere. The mixture was poured onto water, and the product extracted with chloroform. The organic phase was dried with sodium sulfate and removed in vacuo. The crude product (160 mg) was purified by column chromatography, with chloroform as the eluent. To give 120 mg (28.8 % starting from 58) of OAc[5]cavitand 62 as a white solid. lB. NMR (CDCI3, 400 MHz): 5 7.31 (s, 5H, H c ) , 5.98 (d, J= 8.8 Hz , 5H, H a o u t), 5.18 (s,10H, H e ) , 4.45 (d, J = 8.8 Hz, 5H, H a i n ) , 4.38 (d, J= 13.6 Hz, 5H, H b o u t ) , 3.39 (d, J = 13.6 Hz, 5H, H b i n ) , 1.83 (s, 15H, H f ) . MALDI MS m/z: 1054 ( M + Na + ) ; Calcd for C55H45O20 + N a + = 1053. 77 2.5.iud) Synthesis of SAc-[5]cavitand 63. To the SH-[5]cavitand 61 (30 mg, mmol) pyridine (12 mL) and acetic anhydride (5 mL) were added. The reaction was left to stir in an open vessel for 12 hr. The crude product was purified by column chromatography, the resulting product (8 mg, 21.6 % yield) was a white solid. *H NMR (CDCI3, 500 MHz) 8 7.21 (s, 5H, H c ) , 5.97 (d, J= 7.5 Hz, 5H, H a o u t ) , 4.38 (d, / = 7.5 Hz, 5 H , H a ;„), 4.33 (d, J= 13.2 Hz, 5H, H b o u t ) , 4.15 (s, 15H, SCH 3 ) , 3.34 (d, J = 13.1 Hz, 5H, H b i n ) MALDI MS m/z: 1134 (M + Na +); Calcd for C55H50O15S5 + N a + = 1133 2.5.iii. Synthesis of Carceplex 65»2 D M F SH-[5]cavitand 61 (20 mg, 0.022 mmol) and cesium carbonate (0.5g in excess) were dissolved in D M F (15 mL). The reaction was performed under a nitrogen atmosphere and stirred for 6 hrs. The work up involved removal of D M F in vacuo, the crude product was then dissolved in acidified water and the product was extracted with chloroform. The crude product was purified by column chromatography with CHCI3 as the eluent. The resulting solid (6 mg, 13.9 % yield) was a pale yellow solid. ! H NMR (500 MHz, CDCI3 at 300 K) 8 7.14 (s, 10H, H d ) , 5.94 (d, J= 7.55 Hz, 10 H , H a o u t), 5.32 (s, 2H, H e ) , 4.56 (d, J= 7.75 Hz, 10H, H a i n ) , 4.38 (b, 10H, H c o u t ) , 4.27(d, J= 78 12.9 Hz, 10H, H b o u t), 3.99(b, 10H, H c i n), 3.29 (d,J = 12.9, 10H, H b i n), 0.28 (s, 6H, H f ) , 0.20 (s, 6H, H g ) . M A L D I M S m/z: 1937 (MH+»2 DMF) and 1960 (M«2 D M F + Na + ) Calcd for C9oH7o02oSio«C6H1402N2= 1936 7 9 2.6. References 1. Konishi, H . ; Nakamura, T.; Ohata, K. ; Kobayashi, K. ; Morikawa, O. Tetrahedron Lett, 1996, 37, 7383. 2. Naumann, C ; J. C. Sherman, unpublished work. 3. The computer software package, Platon, measured the dimensions for [4] cavitand 57 and [5]cavitand 58 from the crystal structure data. The lower rim dimension of 57 were calculated from carbon at the base of the aromatic ring to the carbon at the base of aromatic ring directly across the width of the cavitand. Upper rim dimension were calculated by measuring the distance between the carbon in one of the methyl substituent and the carbon in the methyl group directly across the width of the cavitand. For [5]cavitand 58, simple trigonometry was used to calculate the distance 4. Jasat, A . ; Sherman, J. C. unpublished work. 5. Sherman, J. C ; Knobler, C. B.; Cram, D. J.; J. Am. Chem. Soc. 1991,113, 2194. 6. Fraser, J. R.; Borecka, B.; Trotter, J.; Sherman, J. C. J. Org. Chem. 1995, 60, 1207. 7. Drahenberg, T.; Dahlquist, K. I.; Forsen, S. J. Phys. Chem. 1972, 72, 2178. 8. Cram, D. J.; Tanner, M . E.; Knobler, C. B. J. Am. Chem. Soc. 1991,113, 7717. 9. Chapman, R. G. ; J. C. Sherman. J. Org. Chem. 2000, 65, 513. 10. Chopra, N . ; Sherman, J. C. Angew. Chem. Int. Ed. Engl, 1999, 38, 1955. 11. The most stable conformation for carceplex 65«2 D M F were determined through M M 2 energy minimization (Chem 3-D software) of the computer generated model of carceplex 65»2 D M F . 12. Cram, D.J. Science, 1983, 219, 1177. 13. Cram, D.J.; Cram, J .M. Container Compounds and Their Guests; The Royal Society of Chemistry: Cambridge, 1994, Vol . No.4. 14. Cram, D.J. Angew. Chem. Int. Ed. Engl. 1985, 25, 1039. 80 

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