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Synthesis of 2:3-benzo-4-hydroxy-1, 1-dimethyl-1-silacyclohex-2-ene Russell, William Ward 1969

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SYNTHESIS OF 213-BENZO-J+-HYDROXI-1,1-D IMETHTL-l-SILACYGLGHEX-2-ENE by WILLIAM WARD RUSSELL; B.S.P., University of Br i t i s h Columbia, 1962 A THESIS' SUBMITTED IN PARTIAL FULFILMENT: OF THE REQUIREMENTS FOR THE DEGREE; OF MASTER OF SCIENCE IN PHARMACX in the Department: of Pharmaceutical Chemistry of the Faculty of Pharmacy We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA. Apr i l , 1969 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and Study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thes,is for financial gain shall not be allowed without my written permission. The University of British Vancouver 8, Canada Department of Date i ABSTRACT Following the successful synthesis of 2:3-Benzo-l,l-dimethyl-l-silacyelohex-2-ene and i t s ^ -bromo deriva t i v e , attempts were made to prepare further d e r i v a t i v e s . The syn-theses of 2:3-Benzo-^-cyano-l,l-dimethyl-l-silacyclohex-2-ene and 2:3-Benzo-^-hydroxy-l,l-dimethyl-l-silacyclohex-2-ene were attempted v i a substitution reactions under various conditions. Attempts to prepare the ^ -cyano compound were in vain, while the ^ -hydroxy compound was re a d i l y prepared, on the strength of inf r a r e d analyses. The ^-hydroxy compound, however, presented a problem i n characterization, as attempts to produce several derivatives of the compound were unsuccess-f u l . Attempts were also made to improve the methods of syn-thesis and the yields of various intermediate compounds. Signature of Examiners ACKNOWLEDGEMENT The author expresses his sincere gratitude to Dr. T. H. Brown f o r the assistance and encouragement given to him during the course of t h i s project. Thanks are also due to Dr. F. S. Abbott, and the entir e roster of graduate students i n the department of Medicinal Chemistry, whose opinions, ad-vic e , and kind words were much appreciated. i i TABLE OF CONTENTS Part Page Abstract i L i s t of Figures v L i s t of Tables v i i I. INTRODUCTION 1 A. S i l i c o n : I t s Biochemical Role 1 B. B i o i s o s t e r i c Properties of S i l i c o n and Carbon Compounds . 3 C. General Characteristics of Local Anesthetics 7 Chemistry and Structure-Activity Relationships . . . . . . . . . . . . . 7 Action 12 Metabolism . . . . . . . . . 16 Overlapping Properties of Local Anesthetics 17 I I . STATEMENT OF PROBLEM 19 I I I . CHEMISTRY OF CYCLIC ORGANOSILICON COMPOUNDS . . . 20 A. Chemical Behaviour of S i l i c o n . 20 B. Ring Size and R e a c t i v i t y 23 C. Synthesis of Cy c l i c Organosilicon Compounds. 27 Grignard Synthesis 27 i i i Part Page Wurtz-Fittig Synthesis 30 Lithium Synthesis 31 IV. DISCUSSION 33 V. EXPERIMENTAL kk o-Bromotoluene (90) hh o-Bromobenzyl Bromide **5 S-(o-Bromobenzyl)-isothiourea picrate 3-(o-Bromophenyl)-propan-l-ol . . 6^ 3T(o-Bromophenyl)-propyl-°<-naphthylcarbamide . *+8 3-(o-Bromophenyl)-propyl Bromide *+8 S-(3-(o-Bromophenyl)-propyl)-isothiourea picrate M-9 Synthesis of 2 i 3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene 50 Synthesis of 2:3-Benzo- 1+-bromo-l,l-dimethyl-l-silacyclohex-2-ene 51 Synthesis of 2:3-Benzo-^-cyano-l,l-dimethyl-l-silacyclohex-2-ene (attempted) ,. . 52 Synthesis of 2:3-Benzo- l+-hydroxy-l,l-dimethyl-l-silacyclohex-2-ene 5^  Synthesis of 2 : 3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene-l+-phenylurethan (attempted) (101). . 55 Synthesis of 2 : 3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene-1*- oc-naphthylurethan (attempted) (101) 56 iv Part Page Synthesis of 2 :3-Benzo-l,l-dimethyl-l-silacyclo-hex-^-ene-M-benzoate (attempted) (101). . . . 56 Synthesis of 2 :3-Benzo-l,l-dimethyl-l-silacyclo-hex~2-ene-U-(3,5-dinitrobenzoate) (attempted) (101, 103, 10*0 57 Synthesis of 2 j3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene-LK (2,^-dinitrophenylhydra zone) (attempted) (105) 59 Gas Chromatography of 2::3-Benzo-J+-hydroxy-l,l-dimethyl-l-silacyclohex-2-ene 60 VI. INFRARED SPECTRA 61 VII. SUMMARY 66 VIII. BIBLIOGRAPHY 68 V LIST OF FIGURES Figure Page 1. Model of binding of l o c a l anesthetic molecule to the receptor 10 2. Resonance forms of a l o c a l anesthetic mole-cule 11 3. Displacement of hydride ion by a flank nucleo-p h i l i c attack on s i l i c o n 21 . h. Infrared spectrum of o-Bromotoluene: 61 5. Infrared spectrum of o-Bromobenzyl Bromide . . 61 6. Infrared spectrum of 3-(o-Bromophenyl)-propan-l-ol . . . . . . . . 61 7. Infrared spectrum of 3-(o-Bromophenyl)-propyl bromide 62 8. Infrared spectrum of 2 :3-Benzo-l,l-dimethyl-l-silacyclohex-2-ene 62 9. Infrared spectrum of 2:3-Benzo-Wbromo-l,l-dimethyl-l-silacyclohex-2-ene . 62 10. Infrared spectrum of l i q u i d f r a c t i o n from the reaction of 2:3-Benzo- 1+-brorao-l,l-dimethyl-l-silacyclohex-2-ene and potassium cyanide i n THF at 0 C. f o r 20 hours 63 11. Infrared spectrum of s o l i d formed i n attempt to prepare 2 : 3-Benzo-l,l-dimethyl-l-sila-cyclohex-2-ene-l+- -naphthylurethan . . . . 63 v i Figure Page 12. Infrared spectrum of s o l i d formed i n attempt to prepare 2 :3—Benzo-l,l-dimethyl-l-sila-cyclohex-2-ene-^-phenylurethan 63 13. Infrared spectrum of s o l i d formed i n attempt to prepare 2 : 3-Benzo-l,l-dimethyl-l-sila-cyclohex-2-ene-1+-(3»5-<iinitrobenzoate) . . . 6*f ih. Infrared spectrum of f r a c t i o n No. 1 from gas chromatography of 2:3-Benzo-l+-hydroxy-.l,l-dimethyl-l-silacyclohex-2-ene . . . . . . . 6*f 15. Infrared spectrum of f r a c t i o n No. 2 from gas chromatography of 2:3-Benzo-l+-hydroxy-l,l-dimethyl-l-silacyclohex-2-ene . 6k 16. Infrared spectrum of 2:3-Benzo- 1f-hydroxy-l,l-dimetlryl-l-silacyclohex-2-ene 65 v l i LIST OF TABLES Table Page I. S t r u c t u r a l formulae o f l o c a l anesthetics of t e r t i a r y or secondary amino type 8 I I . Reaction conditions used i n attempts to pre-pare h—cyano compound 53 1 PART I  INTRODUCTION Interest has been shown by many workers i n the medicin-a l properties of compounds containing s i l i c o n . Compounds have been tested for therapeutic a c t i v i t y i n areas such as hypnotics, muscle relaxants, a t a r a c t i c s , and sympathomimet-ics;, (1, 2, 3> »^ 5> 6, 7, 8, 9)> as well as action as insect-i c i d e s , b a ctericides, and fungicides. No work, however, seems to have been successful i n deriving l o c a l anesthetic a c t i v i t y from organosilicon compounds. The goal of the re-search at hand was to prepare compounds which might serve as Intermediates i n the synthesis of ester and amide d e r i -vatives with possible l o c a l anesthetic a c t i v i t y . A general summary of the biochemical and medicinal aspects of organosilicon compounds and also a general pre-sentation of current l o c a l anesthetic pharmacology follow i n t h i s introduction. A. SILICON: ITS BIOCHEMICAL ROLE S i l i c a i s so abundant as to be found as a contaminant i n a l l l i v i n g matter, and i t can cause serious disease; i t i s involved i n the metabolism of a few species of plants and animals as w e l l . In animal evolution, calcium seems to have superseded s i l i c o n i n metabolic pathways. No higher 2 animals u t i l i z e s i l i c o n . S i l i c o n and calcium both are "acc-umulated," however, by some plants even at high l e v e l s of evolutionary development. Organosilicon compounds, however, are not found i n nature, except for the rare mineral moissanite, composed of s i l i c o n carbide. They can be synthesised, however, and behave chemically and b i o l o g i c a l l y as organic compounds. S i l i c o n i n the form of soluble s i l i c a or s i l i c a t e s i s an e s s e n t i a l nutrient for many types of b i o l o g i c a l systems. S i l i c a i s found i n c e r t a i n lov/er plant and animal s k e l e t a l structures, and i n general, s i l i c a t e s are absorbed from the nutrient medium and deposited by the organism i n the form of amorphous s i l i c a . An example i s the diatom, a microscop-i c plant with a s i l i c e o u s skeleton which depends on s i l i c a t e s f o r growth and reproduction. Studies have been made on the mode of uptake of s i l i c a t e solutions (10, 11, 12, 13). S i l i c a t e bacteria capable of breaking down insoluble potassium aluminosilicates i n the s o i l have been studied, also^ and i t was found that these bacteria could be cultured i n a granite bowl or i n a medium of powdered glass (1*+). Some higher plants such as r i c e , wheat, and beets de-pend on soluble s i l i c a t e s for growth, reproduction, and d i s -ease resistance; metabolic processes are involved i n the s i l i c o n uptake (15). In the higher animals, traces of s i l i c a are found i n a l l tissues, but no b i o l o g i c a l need i s indicated. The am-3 ounts of s i l i c o n found i n d i f f e r e n t tissues varies i n d i f f -erent; organs and i n d i f f e r e n t i n d i v i d u a l s . Examples of the amount found include: adult human blood, 1.0 mg. of s i l i c a per 100 ml.; the lung, ^0-2,000 mg./lOO mg. of dry t i s s u e . S i l i c o n content of lungs and the lymphatic system increases with age and exposure to s i l i c e o u s dust. Small amounts of s i l i c o n are harmless, but large amounts are quite toxic, causing lung, l i v e r , and kidney disorders. The most frequent of these are s i l i c o n pneumoconioses, conditions of the res-p i r a t o r y t r a c t r e s u l t i n g from prolonged inha l a t i o n of s i l i c a or s i l i c a t e s (16). B.. BIOISOSTERIC PROPERTIES OF SILICON AND CARBON COMPOUNDS Isosteres, or compounds having the same number and a r r -angement of electrons i n t h e i r molecules, are also termed , ,bioisosteres, , , a term introduced by Freidman (17), i f t h e i r b i o l o g i c a l a c t i v i t i e s are also s i m i l a r . S i l i c o n i s d i r e c t -l y below carbon i n the periodic table and the two elements are similar enough that they can be interchanged i n various structures to give isosteres. As with carbon, s i l i c o n has tetrahedral geometry with respect to attached atoms in many compounds, eg., SIH^., (CH^i+Si, ( C H - ^ S i C ^ , and r e l a t i v e energies of the 3s, 3p, and 3d o r b i t a l s of s i l i c o n and c a r -bon also indicate t h e i r similar preference for sp^<?-bonding i n the majority of compounds. The degree to which bioisosterism i s produced has been shown to be quite v a r i a b l e . No bioisosterism r e s u l t s i f the substitution of s i l i c o n changes grossly the chemical prop-e r t i e s of the compound. Thus t r i c h l o r o s i l a n e (Cl^SiH) has none of the anesthetic properties of chloroform (CT^CH), nor does s i l i c o n t etrachloride (SICl^) possess the anthel-minthic properties of carbon tetrachloride (CCl^). In many compounds, however, only subtle chemical and physical changes resul t from s i l i c o n s u b s t i t u t i o n for a carbon atom. Although data are scarce, there also seems to be subtle b i o l o g i c a l changes. Bioisosterism was shown by Fregert. and Rorsman (9) using 2,2-Bis(p-hydroxyphenyl)propane, also known as bis-phenol-A ( I ) . This compound causes a l l e r g i c response i n some i n d i v i -duals who may become sensit i z e d to i t s presence. Bis-(p-hydroxyphenyl)dimethylsilane (II) was shown to cause the same a l l e r g i c response as bis-phenol-A i n individ u a l s previous-l y sensitized to bis-phenol-A. (p-HOC 6H l f) 2C(CH 3) 2 (p-HGC 6H l f) 2Si(CR 3) 2 (I) ( I D Fessenden and Coon (3) studied the adrenergic drug 2-methyl-2-phenyl-3-aminobutane hydrochloride (III) and i t s s i l i c o n isostere (IV). The s i l i c o n compound was more a c i d -i c by 0 A 3 pKa units, l e s s soluble i n water as a free base, but similar i n gross b i o l o g i c a l a c t i v i t y and t o x i c i t y l e v e l s , (LD^ G: 110 mg./Kg., intraperitoneal i n j e c t i o n , mice). More recent work has shown the carbon compound to be more potent 5 at sublethal l e v e l s , although conclusive reports are not as yet a v a i l a b l e . CH, CH, CHn CBo I 3 I 3 I 3 I 3 C 6H 5-C — CH-NH3C1 C 6 H ^ - S i — CHNH 3C1 CH 3 CH3 ( I I I ) (IV) Sili c o n - s u b s t i t u t e d carbamates related to meprobamate (V) have also been studied by Fessenden and Coon (2). CH, I 3 H 2NC00CH 2-C-CH 20C0NH 2 CH 3 (V) CH, CH, I 3 I 3 H 2NC00CH 2-Z-CH 20C0NH 2 R-Z-CB^OCONHg R CH 3 CH, CH, , 3 | 3 H 2NC0GCH 2-Z-(CH 2 ) nGC0WH 2 CH 3-Z-(CH 2) n 0C0KH 2 CH 3 "^^ 3 Zi G, S i ; Rr CH 3, C ^ , C^H^, C ^ ; nr 2, 3, h. T o x i c i t i e s were generally s i m i l a r (intra-peritoneal i n j e c t i o n , mice). Meprobamate was four times longer acting, and silameprobamate showed no o r a l a c t i v i t y although i t was 6 absorbed and eliminated by the urinary system.. Detoxication occurs via d i f f e r e n t chemical changes i n each of the two compounds. One pa i r of carbamates (VI & VII) which bear a s t r i k i n g resemblance to the cholinergic drug carbachol (VIII) d i f f e r e d grossly i n b i o l o g i c a l responses. The carbon compound was ten times more toxic and the s i l i c o n compound appeared to be a short-acting muscle relaxant. The carbon compound gave no muscle relaxation but a f t e r an induction period 1 (20-kO min.) gave r i s e to a convulsive response. Both compounds gave a cholinergic response of long duration when microim-planted into the l a t e r a l hypothalamic region of the brain Crat) (18). (GH3)3CCH2CH20G0NH2 (CH 3) 3SiCH 2CH 20C0NH 2 (VI) (VII) (CH 3) 3NCH 2CH 20C0NH 2 (VIII) Metcalf and Fukoto (19) showed silicon-carbamate. insec-t i c i d e s to have properties s i m i l a r to carbon isosteres. Fessenden, Larsen, Goon, and Fessenden (1) studied s i l i -con-substituted: spirobarbiturates and found the s i l i c o n an-alogs to have a lower therapeutic r a t i o (N D ^Q / L D ^Q). They attributed t h i s to s t e r i c f a c t o r s and ring d i s t o r t i o n due to the s i l i c o n atom. 7 Belsky, Gartner, and Z i l k h a (6) reported weak sedative a c t i v i t y and an t i c o n v u l s a n t a c t i v i t y lower than that of phenobarbital or mesantoin i n s i l i c o n - c o n t a i n i n g b a r b i t u r -a t e s . These same workers (7, 8) a l s o studied the CNS depres-sant a c t i v i t i e s of s i l i c o n - s u b s t i t u t e d amides of aromatic c a r b o x y l i c a c i d s and the a n t i c h o l i n e r g i c p r o p e r t i e s of DL-@ -N,N-dialkylaminoethyl e s t e r s of s u b s t i t u t e d < * - t r i m e t h y l -s i l y l p h e n y l - $ -hydroxypropionic a c i d s . These l a t t e r compounds showed some p r o t e c t i o n against organophosphate poisoning. C. GENERAL CHARACTERISTICS OF LOCAL ANESTHETICS Chemistry and S t r u c t u r e - A c t i v i t y R e l a t i o n s h i p s Of the many compounds capable of causing l o c a l anesthe-s i a , many are of no use due t o systemic t o x i c i t y , l o c a l t i s -sue i r r i t a t i o n , or low potency. With few exceptions, u s e f u l a n e s t h e t i c s are composed of three c o n s t i t u e n t s : (a.) a c a r b o x y l i c or h e t e r o c y c l i c r i n g of aromatic type ( l i p o p h i l i c p o r t i o n ) , (b) an intermed-i a t e chain, and'(c) an amino group ( h y d r o p h i l i c p o r t i o n ) (20). Many s t r u c t u r a l m o d i f i c a t i o n s w i t h i n t h i s general pat-t e r n s t i l l give r i s e t o block of conduction i n nerve f i b e r s . The l i p o p h i l i c group may be an a l k y l or a r a l k y l group. The h y d r o p h i l i c p o r t i o n i s g e n e r a l l y a secondary or t e r t i a r y amino group. The l i n k between the intermediate group; and the aromatic l i p o p h i l i c group i s u s u a l l y an e s t e r f u n c t i o n . T h i s f u n c t i o n i s hydrolyzed during metabolic degradation 8 T a b l e I . S t r u c t u r a l Formulae of L o c a l A n e s t h e t i c s of T e r t i a r y or Secondary Amino Type. AROMATIC RESIDUE INTERMEDI-ATE CHAIN AMINO GROUP AROMATIC RESIDUE INTERMEDI-ATE CHAIN AMINO GROUP I P r o c a i n e C^Hf f : o Cocaine l COx-OCHCHj. C/y-Jw \ CHj, CHx-\ CH CHfCOo C/f,J-\ 1 I [ I r it Butethamine I c***"*"^ 1 1 V 1 ; wft^C 0\ OCHzC Mu l v / ^ * ^ '6' • C h l o r o p r o c a i n e Hr COY— NHCH^ Cr/,.—j A/N C*H< OC+Hf I I Dibucaine! >co Benoxinate Naepaine wry Phenacaine H7C30 Proparacaine P OCH^CH± \ Ct*r H \ I C(c/f3) \*/' OCHt CHV Cyclomethycaine 9 Table I . (Continued) AROMATIC INTERMEDI- AMINO AROMATIC ^INTERMEDI- AMINO RESIDUE ATE CHAIN GROUP RESIDUE ATE CHAIN GROUP i Hexylcaine tH3 | CH. 3 I Lidocadne i N H — CO &H3 I Mepivacaine <^J^  C O ] — OCHxCZ/^C^Y-/V. i Piperocairie / \ CH, O //9c¥o | /C"> I CH, Dimethisoquin \ / \ I T e t r a c a i n e i 10 i n the body (22, 23). In r e l a t i n g chemical structure and l o c a l anesthetic ac-t i v i t y , Buchi and P e r l i a (21) suggested that the drug i s bound to the receptor by three types of forces, namely van der Waals forces, dipole-dipole interactions, and electro-s t a t i c binding. Pig. 1 Model of binding of l o c a l anesthetic molecule to the receptor byr V, van der Waals forces; D, dipole-dipole i n t e r a c t i o n ; E, e l e c t r o s t a t i c forces. Lofgren (20) found that a l l e f f e c t i v e l o c a l anesthetic compounds i n the carboxylic acid ester and amide series are 11 characterized by a highly reactive carbonyl group, in which the electron cloud at the oxygen atom is dense enough to act as an electron donor capable of forming hydrogen bonds. Buchi and Perlia support this theory. For example, the e l -ectron-donating groupa -NH2, -NHE, -OH, or -OR in the para position of diethylaminoethyl benzoate result in a partial shift of electrons along the conjugated carbon series, con-centrating electrons at the carbonyl oxygen (Fig. 2), and increasing local anesthetic potency. P - NH—^ y- C - 0 — CHZ CHT —N(CZHS) ,0 C-0—CH*CHT— N(CZ \ Fig. 2 Resonance forms of a local anesthetic molecule. The arrows indicate the electron shifts. Thus in procaine (p-NH2 group), tetracaine (p-C^H^-NH group), and pramoxine (p-C^H^O group) the electron-donating groups results in intensification of the weak effects of the parent compounds. Substitution of electron-withdrawing groups such as N0 2 have the opposite effect, as shown by diethyl-amino ethyl paranitrobenzoate;, which has negligible local 12 a n e s t h e t i c a c t i o n . M o d i f i c a t i o n o f the i n t e r m e d i a t e c h a i n o f the l o c a l a n e s t h e t i c molecule and the e f f e c t s on i t s potency can a l s o be e x p l a i n e d i n terms of e f f e c t s of the e l e c t r o n d i s t r i b u t i o n around the ca r b o n y l oxygen. For example, a d d i t i o n o f e i t h e r one or two methyl groups to the «<-carbon of the c h a i n pro-duces a s h i f t of e l e c t r o n s from the orT-carbon towards the c a r b o n y l group, makes the e l e c t r o n c l o u d of the c a r b o n y l oxygen more dense, and r e s u l t s i n i n t e n s i f i e d a c t i v i t y . S e v e r a l f u n c t i o n s have been a s s i g n e d to the aromatic moiety of the potent l o c a l a n e s t h e t i c molecule; i t p r o v i d e s adequate l i p i d s o l u b i l i t y of the l o c a l a n e s t h e t i c ; i t all o w s s u f f i c i e n t c a p a c i t y f o r r e c e p t o r b i n d i n g by van der Waals f o r c e s ; and i t p a r t i c i p a t e s i n the establishment o f a strong a n i o n i c r e a c t i o n s i t e i n the c a r b o n y l group of the i n t e r -mediate c h a i n (21, 2 h ) . While i n t r a m o l e c u l a r charge d i s t r i b u t i o n has been im-p o r t a n t i n determining potency of l o c a l a n e s t h e t i c s , other s t r u c t u r a l aspects may a l s o have some degree of b e a r i n g on i n t r i n s i c potency and c l i n i c a l e f f i c a c y . For example, s t e r i c h indrance by the methyl groups i n the ortho p o s i t i o n of the benzene r i n g of l i d o c a i n e prevents r a p i d h y d r o l y s i s o f the amide group, l e a d i n g t o enhanced l o c a l a n e s t h e t i c p r o p e r t i e s (20). A c t i o n L o c a l a n e s t h e t i c s i n c r e a s e the t h r e s h o l d f o r e l e c t r i -13 c a l e x c i t a t i o n i n nerve, slow p r o p a g a t i o n of the impulse, reduce the r a t e of r i s e of the a c t i o n p o t e n t i a l , and even-t u a l l y b l ock c o n d u c t i o n ( 2 5 ) . They do t h i s by i n t e r f e r i n g w i t h the process fundamental to the ge n e r a t i o n o f the nerve a c t i o n p o t e n t i a l , namely the l a r g e t r a n s i e n t r i s e i n the p e r m e a b i l i t y of the membrane to sodium Ions t h a t i s produced by a s l i g h t d e p o l a r i z a t i o n of the membrane. There i s a r e d u c t i o n i n the c a r r y i n g c a p a c i t y o f the system which a l l o w s sodium i o n s to be t r a n s p o r t e d a c r o s s the membrane i n response to c o n c e n t r a t i o n and e l e c t r i c a l p o t e n t i a l g r a d i e n t s . (26, 2 5 , 2 7 ) . Regarding the c o n c e n t r a t i o n , the b l o c k caused by cocaine can be a l l e v i a t e d simply by r a i s i n g the e x t e r n a l sodium c o n c e n t r a t i o n . ( 2 8 , 29, 3 0 ) . There i s a l s o a r e d u c t i o n i n i n c r e a s e i n potassium conductance t h a t occurs i n response to a d e p o l a r i z i n g step i n v o l t a g e , but the e f f e c t i s much smaller than t h a t on sodium conductance ( 2 5 , 2 6 ) . T h i s r e -d u c t i o n of potassium conductance would tend t o lower the t h r e s h o l d and.thus p a r t l y counteract the b l o c k i n g a c t i o n o f l o c a l a n e s t h e t i c s . There i s a l s o a reduced p e r m e a b i l i t y of r e s t i n g nerve ( 2 5 ) and of muscle membrane (31 , 32) to sodium and potassium ions caused by l o c a l a n e s t h e t i c s . Some workers (33) have hypothesized the com p e t i t i o n of l o c a l a n e s t h e t i c s w i t h a c e t y l c h o l i n e a t some membrane s i t e i n v o l v e d i n nerve c o n d u c t i o n as the mode of a c t i o n of l o c a l a n e s t h e t i c s . T h i s i s based p r i m a r i l y i n the s i m i l a r -i t y i n s t r u c t u r e of p r o c a i n e and a c e t y l c h o l i n e , and t h i s b a s i s 11+ seems u n l i k e l y on examination of other l o c a l a n e s t h e t i c s t r u c -t u r e s . Furthermore, no c o r r e l a t i o n e x i s t s between potencies or pH values of l o c a l a n e s t h e t i c s r e q u i r e d to block a c e t y l -c h o l i n e s t e r a s e and to block nerve impulses (3*+, 3 5 ) . Involvement of ATP and the a c t i o n of l o c a l a n e s t h e t i c s i s s t i l l under study. The e x i s t i n g s i t u a t i o n i s q u i t e complex, f o r , w h i l e ATP and procaine are each capable of s t a b i l i z i n g c a l c i u m - d e f i c i e n t nerve, ATP (36) antagonizes the block brought about by procaine. (Calcium i s not necessary f o r the s t a b i l i z i n g e f f e c t of procaine, but i s necessary f o r maximum s t a b i l i z i n g e f f e c t of the n u c l e o t i d e s ( 3 7 ) . Both calcium ions and l o c a l a n e s t h e t i c s " s t a b i l i z e " e x c i t a b l e membranes, i . e . , the e l e c t r i c a l t h r e s h o l d i s r a i s e d , spontaneous discharges may be a b o l i s h e d , and conduction of impulses may be blocked w i t h almost no change i n r e s t i n g p o t e n t i a l . Thus the hypothesis t h a t removal of calcium ions from s i t e s or c a r r i e r s i n the nerve membrane by d e p o l a r i z a t i o n leads to t r a n s i e n t increase i n sodium p e r m e a b i l i t y during the a c t i o n p o t e n t i a l . I t has been suggested that both calcium ions and l o c a l a n e s t h e t i c s act on the system r e s p o n s i b l e f o r c a r r y i n g sodium ions through the nerve membrane ( 3 8 ) . A l a t e r suggestion regarding calcium ions stated t h a t the primary a c t i o n of a l o c a l a n e s t h e t i c i s to i n h i b i t calcium r e l e a s e from s i t e s to which i t i s bound i n the membranes. As a r e s u l t , the changes i n sodium and potassium p e r m e a b i l i t y which normally f o l l o w calcium r e l e a s e are prevented, and 15 impulse generation.,is prevented (39,^0). In summarizing, R i t c h i e and Greengard (kl) s t a t e d t h a t the a g o n i s t i c and ant-a g o n i s t i c e f f e c t s of c a l c i u m and procaine c o u l d both he accounted f o r on the assumption that p r o c a i n e competes w i t h c a l c i u m f o r the same r e c e p t o r s i t e s t h a t c o n t r o l the sodium and potassium conductances, but that p r o c a i n e i s l e s s e f f e c -t i v e because of d i f f e r e n c e s i n the k i n e t i c s of the r e a c t i o n s . of the two substances w i t h the r e c e p t o r . Reports of i n t e r a c t i o n of thiamine w i t h l o c a l a n e s t h e t i c s have been c o n f l i c t i n g . For i n s t a n c e , one r e p o r t s t a t e d t h a t thiamine antagonized the a c t i o n of p r o c a i n e i n t o p i c a l , i n f i l t r a t i o n , and nerve b l o c k a n e s t h e s i a , w h i l e i t a l s o pro-longed the d u r a t i o n of pro c a i n e - i n d u c e d s p i n a l a n e s t h e s i a . Much work has been done t o determine the form of l o c a l a n e s t h e t i c s which r e a c t s w i t h r e c e p t o r s i n nerve membrane to produce a n e s t h e s i a . Most u s e f u l a n e s t h e t i c s are secondary or t e r t i a r y amines and can e x i s t as charged (BH) or uncharged (B) molecules, r e l a t i v e p r o p o r t i o n s of these two s p e c i e s depending on the pH of the s o l u t i o n and pKa of the a n e s t h e t i c . S t u d i e s w i t h a c i d i c , b a s i c , and n e u t r a l media i n d i c a t e d t h a t l o c a l a n e s t h e t i c s blocked conduction most e f f e c t i v e l y i n an a l k a l i n e medium. T h i s has l e d some workers to b e l i e v e 16 the uncharged molecule i s the a c t i v e form (^2), but o t h e r s have questioned the handling of the experimental data l e a d i n g to such a c o n c l u s i o n (20, 1+3). The argument a g a i n s t stated t h a t the presence of a constant amount of uncharged base i n the medium would not be p r o o f that the uncharged molecule was a c t i v e , s i n c e a c t i v i t y might j u s t r e s u l t from the anes-t h e t i c a c t i n g on the other s i d e of a b a r r i e r permeable on l y to the uncharged form. Arguments f o r the c a t i o n of the l o c a l a n e s t h e t i c as the a c t i v e form are many (^3, *+h, ^6), but two phases are i n v o l v e d both f o r and a g a i n s t , namely the p e n e t r a t i o n from the s i t e o f a p p l i c a t i o n to the s i t e o f a c t i o n , and the a c t u a l a n e s t h e t i c a c t i o n at the r e c e p t o r s i t e . R i t c h i e and Greengard (*+l) showed the c a t i o n to be the a c t i v e form, u s i n g unsheathed nerve p r e p a r a t i o n s , and suggested t h a t the l o c a l a n e s t h e t i c p e n e t r a t e d i n the uncharged form and was then a c t i v e i n the c a t i o n i c form. They a l s o i m p l i e d that the l o c a l a n e s t h e t i c molecule i s bound to the membrane by i t s l i p o p h i l i c , aromatic p o r t i o n , and t h a t i t s h y d r o p h i l i c , amino group, a c t i n g i n the c a t i o n i c form, i s r e s p o n s i b l e f o r the a n e s t h e t i c a c t i o n . The p e n e t r a t i o n as an uncharged molecule and a c t i o n as a charged molecule hypothesis e f f e c -t i v e l y e x p l a i n s the experimental f i n d i n g of most recent s t u d i e s . Metabolism The r a t e of a b s o r p t i o n and r a t e of e l i m i n a t i o n of l o c a l a n e s t h e t i c s governs t h e i r degree of t o x i c i t y . Too r a p i d a b s o r p t i o n , too slow e l i m i n a t i o n , or d e g r a d a t i o n to 17 other t o x i c substances, are a l l f a c t o r s i n v o l v e d i n the s a f e use of a l o c a l a n e s t h e t i c . Non-ester type l o c a l a n e s t h e t i c s are g e n e r a l l y d e s t r o y e d by l i v e r enzymes, while the e s t e r - t y p e s a re u s u a l l y meta-b o l i z e d by h y d r o l y s i s i n the l i v e r and plasma by e s t e r a s e s . M e t a b o l i c d e g r a d a t i o n by human plasma i s from *+-10 times f a s t e r than by the plasma of any other animal (*+7), and plasma seems to be the major s i t e of h y d r o l y s i s o f l o c a l anesthe-t i c s i n man, as shown by p r o c a i n e which i s not hydrolyzed to any extent i n the l i v e r (*+8). For a g i v e n s p e c i e s d i f f e r e n t l o c a l a n e s t h e t i c s may be metabolized i n d i f f e r e n t ways. In man, f o r example, pro c a i n e i s destroyed mainly i n plasma, w h i l e cocaine i s de-graded i n the l i v e r . In d i f f e r e n t s p e c i e s , manner of meta-bol i s m v a r i e s a l s o ; c o c a i n e i s hydrolyzed r a p i d l y by r a b b i t serum, but not by horse serum or human plasma ( ^ 9 ) . Those a n e s t h e t i c s t h a t are s l o w l y destroyed i n the l i v e r are i n small p a r t e l i m i n a t e d i n the u r i n e . Overlapping P r o p e r t i e s of L o c a l A n e s t h e t i c s S e v e r a l p h a r m a c o l o g i c a l a c t i o n s i n a d d i t i o n to blockage of nerve impulses are ev i d e n t f o r many l o c a l a n e s t h e t i c s . These i n c l u d e the systemic a n a l g e s i c a c t i o n of pro c a i n e ( a l -though t h i s i s of l i t t l e v a l u e due to the hig h i n c i d e n c e o f nausea, e t c . ) , and a l s o p r o c a i n e ' s a p p l i c a t i o n as an a n t i -histamine i n t r e a t i n g d e l a y e d serum s i c k n e s s and u r t i c a r i a . 18 L i d o c a i n e has been used i n t r a v e n o u s l y w i t h success i n management of v e n t r i c u l a r a r r y t h m i a s , as an a n t i t u s s i v e which suppresses coughing caused by end o t r a c h e a l tubes, and as an a n t i c o n v u l s a n t i n doses of 2 to h mg./Kg., As an a n t i -convulsant i t has the s e i z u r e - p r o t e c t i v e e f f e c t of 10 mg./ICg. of p e n t o b a r b i t a l , and i n s m a l l doses l i d o c a i n e a c t s syner-g i s t i c a l l y w i t h b a r b i t u r a t e s to minimize s e d a t i o n d u r i n g s e i z u r e p r o p h y l a x i s . Mepivacaine and l i d o c a i n e have a c t i o n s s i m i l a r to d i p h e n y l h y d a n t o i n i n standard screening t e s t s on mice. 19 P A R T ; I I  S T A T E M E N T ' O F P R O B L E M The aim of t h i s investigation was to attempt to pre-pare functional derivatives of 2:3-Benzo-Wbromo-l,l-di-methyl-l-silacyelohex-2-ene by means of substitution reac-t i o n s . These derivatives were to include the *f-cyano and h-hydroxy compounds which, i t was anticipated, would be use-f u l i n the synthesis of various types of ester and amide derivatives with possible l o c a l anesthetic a c t i v i t i e s . As indicated by Lo (50), the s t r u c t u r a l s i m i l a r i t y of t e t r a l i n derivatives possessing l o c a l anesthetic properties (5D and the compound 2:3-Benzo-l,l-dimethyl-l-silacyclohex-2-ene, tends to support the hypothesis that bioisosterism should e x i s t between t e t r a l i n d e r i v a t i v e s and derivatives of the organosilicon. compound.. Thus the l o c a l anesthetic properties shown by the t e t r a l i n derivatives should also b@ demonstrated by the organosilicon analogs. 20 PART. I l l CHEMISTRY OF CYCLIC ORGANOSILICON COMPOUNDS A. CHEMICAL BEHAVIOUR OF SILICON Positioned below carbon i n the periodic table, s i l i c o n should fofm tetracovalent compounds with tetracovalent bond angles. T h i s : i s generally the case, with tetrahedral con-f i g u r a t i o n confirmed by X-ray, electron d i f f r a c t i o n , i n f r a -red, and micro-wave studies. (53). The tetrahedral angle of s i l i c o n i s believed to be more e a s i l y deformable than that of carbon (52). Unlike carbon, however, s i l i c o n has *d' orbitals; (Cr. I s 2 , 2 s 2 , 2 p 2 ; S i : I s 2 , 2 s 2 , 2 p 6 , 3 s 2 , 3 p 2 ) i n i t s valence s h e l l , and sp3d 2 hybridization leads to compounds i n which s i l i c o n has a coordination number of six (5*0. A c l a s s i c a l example of t h i s i s the he x a f l u o r o s i l i c a t e ion, S i F ^ , which has bonds directed to the corners of an octahedron: 21 Five d - o r b i t a l s are av a i l a b l e for bonding, but possibly-due to s t e r i c l i m i t a t i o n s , and i n common with other elements i n the second short period, s i l i c o n probably never uses more than two of them, re s u l t i n g i n the maximum coordination num-ber of s i x . Analogous, ions (eg., S i C l ^ = ) are not found, l i k e l y due to s t e r i c limitations.. Amines, however, do com-plex, with s i l i c o n tetrachloride and some rela t e d halides. This complexing i s not exhibited by organosilicon compounds C53?) • Tetracovalent s i l i c o n compounds are more Vulnerable to nucleophilic attack than carbon compounds because empty 'd' o r b i t a l s are available for receiving an unshared pair of electrons. ( F i g . 3)« H \ H -> H — —H OH + HA0 H-H 1 H • Hji +• O H ® F i g . 3: Displacement of hydride ion by a flank nucleo-p h i l i c attack on s i l i c o n (5*+). Other differences between properties of s i l i c o n and carbon compounds also a r i s e due to valence electrons being farther from the nucleus i n the larger s i l i c o n atom than 22 i n carbon. Thus, (1) valence electrons are held less strong-l y by the nucleus and hence s i l i c o n i s less electronegative than carbon ( S i , 1.8;; G, 2.5 ) ( 53, 5^); (2) there i s more room for atoms or groups to bond to s i l i c o n ; (3) over-lap of 'p:' o r b i t a l s with fp* o r b i t a l s of other elements i s l e s s , with the re s u l t that ordinary double bonds do not form. Due to s i l i c o n ' s lower electronegativity, Si-G bonds break i n the d i r e c t i o n S i C under e l e c t r o p h i l i c attack at carbon Or nucleophilic attack at s i l i c o n . The low e l e c t r o -negativity of s i l i c o n compared to carbon r e s u l t s i n approx-imately 12$ i o n i c character i n the silicon-carbon bond. The el e c t r o n e g a t i v i t y difference between s i l i c o n and carbon leads to a greater inductive e f f e c t of the Me^Si group) than the corresponding Me^C group (53)» Apart: from Sl-H and Sl-C bonds, bonds to s i l i c o n are stronger than the corresponding bonds to carbon. It i s l i k e l y that the d - o r b i t a l s of s i l i c o n are used i n reaction with a nucleophilic reagent, the use of these o r b i t a l s r e s u l t i n g i n formation of a pentacovalent s i l i c o n intermediate. The existence of such an intermediate should be detectable i n p r i n c i p l e , although there i s no dir e c t e v i -dence that such an intermediate i s ever involved i n a d i s -placement, reaction at s i l i c o n i n an organosilicon compound. (Some evidence exists for inorganic s i l i c o n compounds). The d - o r b i t a l s would f a c i l l i t a t e nucleophilic attack by low-ering the energy of the t r a n s i t i o n state. The approach of a nucleophile Y: to R-SIX may take place either to the back 23 of the s i l i c o n , to give a YSiX: angle of 180° i n the t r a n s i t i o n state, or at the flank to give a YSiX. angle of less than o 90 i n the t r a n s i t i o n state. S t e r i c hindrance from large R: groups w i l l be more serious In the second case, but i n both cases w i l l be greater than i n a simple S 2-type s u b s t i -t u t i o n process (5*+). B> RING SIZE AMD REACTIVITY Attempts to prepare a silacyclopropane compound by S k e l l and Goldstein (55) were unsuccessful ( 5 6 ) , leading only to v l n y l s i l a n e s . Strong evidence suggested that s i l a c y c l o p r o -pane was formed, but i t s thermal i n s t a b i l i t y caused i t to undergo rearrangement. The thermal i n s t a b i l i t y (E .= 36 kcal./mole as compared to cyclopropane, Eae^.= 60 kcal./mole) was attributed to ring s t r a i n enhanced by the large size of the s i l i c o n atom, making the C-S'i-C angle hQ° . The s i l a c y c l o -propane could not be trapped before rearrangement occurred. Four-membered rings containing a s i l i c o n atom have been prepared (57, 58, 59, 6 0 ) , but are e a s i l y opened by polar reagents, due perhaps to the s t r a i n introduced by the s i l i -con atom (57, 5 8 ) . If the r i n g i s assumed planar with the C-C-C angle tetrahedral ( I ) , the C-Si-C angle would be SM-0^' and the C-C-Si angles 8h°52* ( 5 7 ) . While the tetrahedral angles of s i l i c o n can be more e a s i l y deformed than those of carbon ( 5 8 ) , the s t r a i n i s nevertheless considerable. 2h ft) Compound ( I ) , as an example, reacts vigorously with aqueous-alcoholic a l k a l i , and v i o l e n t l y with concentrated s u l f u r i c acid at room temperature ( 5 7 ) . The acid reaction can be controlled at lower temperature. Other reagents caus-ing ring opening are ethanolic s i l v e r n i t r a t e ( 5 9 ) , bromine ( 5 9 ) , and hydrogen halides ( 6 0 ) . S'ommer et a l . (61) used the reaction of hydroxide and methyl-cyclobutane to study rates of reactio n . S'ommer found the geometry of the addition compound (II) would approximate one of two i d e a l structures: (1) a: H, b: OH; (2) a: OH, b:: H. c c w S t r u c t u r e - a c t i v i t y relationships were explained i n terms of: (1) ease of formation of the complex r e s u l t i n g from groups on s i l i c o n being "pulled back" away from the path of reagent attack; (2) I - s t r a i n ( i n t e r n a l strain) i n the 25 complex r e l a t i v e to I - s t r a i n i n the parent compound; (3) s t e r i c s t r a i n i n the complex r e l a t i v e to the parent compound due to increased "crowding" of groups i n the complex. Gilman and A t w e l l (60) agreed w i t h West (58) who s t a t e d that ease of r i n g opening i n s i l a c y c l o b u t a n e s could not he a t t r i b u t e d to added s t r a i n introduced by the s i l i c o n atom, but must be p a r t i a l l y due to some mechanism a v a i l a b l e to the s i l a c y c l o b u t a n e s but not the cyclobutanes. Gilman and A t w e l l (60) stated that the d i f f e r e n c e i n r e a c t i v i t i e s i s a s s o c i a t e d w i t h the p a r t i c i p a t i o n of the d - o r b i t a l s of s i l i c o n during the s u b s t i t u t i o n r e a c t i o n , r e s u l t i n g i n the formation of a pentacovalent a d d i t i o n complex such as that of Sommers ( 6 1 ) . Gilman and A t w e l l compared the r e a c t i v i t i e s of a s i l a -cyclobutane ( I I I ) and a s i l a c y c l o p e n t a n e (IV) w i t h respect to r i n g opening. P o l a r reagents r e a d i l y cleaved ( I I I ) , but not ( I V ) . The d i f f e r e n c e i n r e a c t i v i t i e s was a t t r i b u t e d t o : (1) r i n g s u b s t i t u e n t s on ( I I I ) are " p u l l e d back" r e l a t i v e to those of ( I V ) , g i v i n g e a s i e r access to the a t t a c k i n g reagent; (2) the C-Si-C angle i n the a d d i t i o n complex formed i n the r e a c t i o n would be expected to be about 90° , and as t h i s approx-26 imates; the r i n g angle of ( I I I ) , less I - s t r a i n should be in-^ troduced during formation of (IV), i e . , (IV) i s less reac-t i v e ; (3;) increased crowding of ring substituents i n the complex r e l a t i v e to (III) should produce an increased s t e r i c s t r a i n during complex formation. These assumptions closely-approximate and add strength to those of Sommer (61) i n i n -dicating that the formation of a complex l i k e (V) would be more ene r g e t i c a l l y favourable from (III) than from (IV). The e f f e c t of ring size on the r e a c t i v i t y of some c y c l i c organosilicon hydrides towards aqueous-alcoholic a l k a l i shows the order of r e a c t i v i t y as: The r e l a t i v e r e a c t i v i t i e s of the 5 - , 6 - , and 7-membered ri n g compounds, and of the open-chain compound i n the series l i s t e d above can be interpreted as the ^ -membered compound; namely i n terms of the changes i n in t e r n a l s t r a i n i n proceeding 2 7 to t r a n s i t i o n states analogous to (V). The s t a b i l i t y of the s i x and seven-membered heterocycles i s l i k e l y a r e f l e c t i o n of reduced i n t e r n a l s t r a i n due to the more e a s i l y deformed tetrahedral bond angles of the s i l i c o n atom. Assuming a l l bond angles to be tetrahedral, geometric calculations can be made for silacyclohexane with the C.-C distance taken as 1.9+ A and the C- S i distance as 1 . 9 3 A ( 6 2 ) . C. SYNTHESIS OF CYCLIC ORGANOSILICON COMPOUNDS The l i t e r a t u r e studied indicated the following methods as the major means of c y c l i c organosilicon compound synthesis. Grignard Synthesis This method i s most widely used due to the large num-ber of substitutions which can be made with varied organic groups. Chlorosilanes are r e a d i l y available and most often chosen as starting material. D i e t h y l ether i s normally the solvent i n c l a s s i c a l Grignard syntheses, but i t s self-inflammatory nature on evaporation has led to use of the safer tetrahydro-furan (THF). This solvent has been demonstrated to be quite v e r s a t i l e , used even with normally unreactive halides ( 6 3 ) . The polar solvent THF may increase r e a c t i v i t y of the Grig-28 nard reagents or the s i l i c o n halides i n reactions. Several examples of c y c l i c compounds made using Grignard reagents prepared from organic dihalides follow* V (6¥j CH, 2. &r(C«i)3 S i (CHS^CJ Jh > E t l 0 [S7) MS Highest y i e l d s are obtained i n the case of six-membered rings and lowest i n case of seven-membered r i n g s . West (6U-) found that a higher number of chlorine atoms on s i l i c o n f a -voured ri n g closure by causing a strong dipole. D i l u t i o n of reaction mixture also favoured ring closure. B i c y c l i c and t r i c y c l i c silanes can also be prepared: 2 9 6. scNA.CH,C 1$ 7. CH-L.CI CH, Cf 5<J m ft Attempts to repeat; t h i s work were unsuccessful (71) While the mechanism of the Grignard synthesis i s not absolutely established, several suggestions have been put forward. K i n e t i c r e s u l t s (72) and observed s t e r i c e f f e c t s indicate that the reaction proceeds by an i n i t i a l n ucleophilic attack at the s i l i c o n atom by the negative organic moiety of the complex, under simultaneous coordination of magnesium with halogen or the alkoxy group, t h i s r e s u l t i n g i n a c y c l i c synchronous process with a t r a n s i t i o n state of the type (VI) where 'X' i s either halogen or the •OR1 group (53, 7 3 ) . —Si R /&X (3ZTJ Some authors have suggested a r a d i c a l mechanism f o r the Grignard synthesis (7*0. When the reaction i s carried out as a Kharasch reaction, i e . , under c a t a l y s i s of chlor-30 ides of Co, Fe, Ni, Mn, Cu, Cr, etc., the r a d i c a l mechanism cannot be excluded ( 7 5 ) . Wurtz-Fittlg Synthesis The method of reacting an organic halide with a s i l y l halide i n the presence of sodium i s an analogy of the Wurtz-F i t t i g r e a c t i o n . The reaction may be c a r r i e d out i n ether, i n i t i a t e d by ethyl acetate, or more recently, i n higher-boil-ing solvents such as xylene, decalin, or toluene, with the advantage that sodium i s more reactive i n the fused state. The method i s most suitable for preparation of tetraorgano-substituted compounds, e s p e c i a l l y i n the aromatic s e r i e s . The halides may be, for example, bromobenzene ( 7 6 ) , chloro-benzene ( 7 7 ) , or bromodiphenyl ( 7 8 ) . Intramolecular a l k y l a t i o n proceeds i n good y i e l d to give c y c l i c organosilicon compounds. Examples include: CHt. i . r I I Y* —> r I I j w ^ ^ TkfF (60) CM/ SCH, 31 3 . C/z t C/±-C-CH-C^ > CH3 CH (SO) The mechanism of the Wurtz-Flttig reaction has not been uniquevoeally explained, but i t i s l i k e l y that there i s a transient formation of an organic sodium compound and a l k y l -ation by an ionic mechanism or by a r a d i c a l mechanism ( 8 1 ) . Lithium Synthesis The main cred i t for t h i s a p p l i c a t i o n i s due to H. Gilman, who has developed i t over the l a s t 18 years. Organolithium compounds are more reactive than organomagnesium compounds, leading to increased use of the former i n syntheses of t e t r a -organo substituted derivatives, e s p e c i a l l y i n cases involving bulky groups. Examples of syntheses of s i l i c o n r i n g compounds are shown as follows: 1. (C6"*)M * ^<^z>^ s (82) \ y \ (8S) 32 As w i t h the Grignard method, s t e r i c e f f e c t s are i n f l u -e n t i a l , a lthough t o a. l e s s e r e x t e n t . 3 3 PART IV  DISCUSSION In i n i t i a l stages of the work, o-bromotoluene was p r e -pared as the s t a r t i n g m a t e r i a l i n the r e a c t i o n sequence, using the Gatterman r e a c t i o n (90).. The low y i e l d o b t ained by t h i s method (S5-k7%) l e d to use of reagent o-bromotoluene (Fluka) made a v a i l a b l e i n the l a t t e r stages of the program. A d i s c u s s i o n of the Gatterman r e a c t i o n f o l l o w s . Reagent o - t o l u i d i n e was d i a z o t i z e d a t i c e - b a t h temper-atur e i n h0% hydrobromic a c i d w i t h sodium n i t r i t e , and the diazonium s a l t group was then r e p l a c e d by bromine w i t h e f -f e c t i v e c a t a l y s i s by copper t u r n i n g s . The equations a r e : B r W (ZE) w The HBr used was k-0% i n s t e a d o f k-8% reagent grade t o ensure c o n t r o l o f the v i g o r o u s d i a z o t i z a t i o n . Ice was em-ployed a f t e r a d d i t i o n o f the copper t u r n i n g s to l i k e w i s e c o n t r o l the vigorous e v o l u t i o n of n i t r o g e n . U 3^ An alternate reaction c a l l e d the Sandmeyer reaction i s e s s e n t i a l l y the same with the exception of the bromine replacement of the diazonium s a l t group which i s effected using one molecular equivalent of the cuprous s a l t compon-ent instead of copper turnings. This i s apparently due to formation of an intermediate molecular complex. A f r e e - r a d i -c a l mechanism i s suspected (91). The reaction follows the equations: +. Na.Br CH, C u t Cl% > CnClz - c o w / ' / e * + The Gatterman process was used as copper turnings were more r e a d i l y a v a i l a b l e . The second step i n the sequence of reactions involved preparation of o-bromobenzyl bromide by bromination of o-bromotoluene. Holliman and Mann's (92) modification of Kenner and Wilson's method (93) was employed.. This entailed using a temperature range of 1^ 0-15© C. and adding 85$ of the c a l -culated quantity of bromine without vigorous a g i t a t i o n of the reaction mixture.. In an alternate procedure described by Gorsich (9*+) N-bromosuccinimide (NBS) was substituted for bromine and the reaction was i n i t i a t e d by u l t r a v i o l e t NH, + Z ftJBh t A / A A / 0 * 35 l i g h t . The y i e l d from t h i s modified method was lower than the Kenner and Wilson method, and thus i t was not employed. The mechanism suggested f o r these procedures involves a- f r e e - r a d i c a l reaction. The inductive e f f e c t of the phenyl rin g and elect r o n e g a t i v i t y of the o-bromo substituent i n the molecule enhance the extraction of a proton i n the a l k y l side chain. This favors the free: Br» r a d i c a l attack. A chain reaction i n i t i a t e d by the free bromine atom proceeds slowly and terminates l i k e l y a f t e r most molecules have become brominated. As k i n e t i c chains are short i n these brominations, many: acts of i n i t i a t i o n are required, and these are accom-plished by supplying constant heat to the reaction mixture. Steps are shown as:: 1. I n i t i a t i o n : : S r : Sir A > -t- Gr « 2. Propagation:: H H Br* + Br*. 36 3. Termination:: The halogenation by f r e e - r a d i c a l may also be accomplished using N-bromosuccinimide (NBE) as the ' h a l o - c a r r i e r 1 . The N-Br bond i s e a s i l y broken i n the i n i t i a t i n g step by u l t r a -v i o l e t light, (95) i n the Gorsich method (9*0. The i n i t i a l attack on o-bromotoluene i s l i k e l y by the; succinimido>radical, the r e s u l t i n g carbon r a d i c a l then at-tacking a second NBS molecule. As; the bromine and s u c c i n i — mido r a d i c a l s can recombine, continued i r r a d i a t i o n i s required to provide an adequate supply of i n i t i a t i n g r a d i c a l s . The chain reaction mechanism i s shown as:-37 The t h i r d step i n the reaction sequence was the prepa-r a t i o n of 3~(o-Bromophenyl)-propan—l-ol. The o-bromobenzyl bromide was treated with one atomic proportion of magnesium to give o-bromobenzyl magnesium bromide, and t h i s Grignard reagent then reacted with ethylene oxide to give the alco-hol. Reactions are shown as: The reaction of the Grignard reagent with the oxide i s a nucleophilic addition which i s i n i t i a t e d by attack of the p o s i t i v e l y polarized carbon i n the oxide by a poten t i a l carbanion i n the Grignard reagent ( 9 6 ) . H & H H H An atmosphere of dry nitrogen was necessary during the Grignard formation to f o r e s t a l l oxidation and subsequent formation of o-bromobenzyl al c o h o l . Some side reactions 3 8 did occur, notably formation of low-boiling ethylene brom-hydrin (identified by infrared spectrum, boiling point, and refractive index), and possibly 2:2'-dibromobenzyl (93), colourless crystals with m.p. 6%-8k.5*C. The two major side reactions are shown as: The fourth step of the synthesis involved treating the prepared propanol with phosphorous tribromide to give the corresponding 3-(o-Bromophenyl)-propyl bromide. The reaction is similar to.Gilman and Marrs' (68) preparation of 2-(o-chlorophenyD-ethyl bromide, and was successful with 75-80$ yield . The ring closure product, 2:3 l-benzo-l,l-dImethyl-l-sila~ cyclohex—2-ene, was prepared in a di-Grignard reaction (97) involving the 3-(o-bromophenyl)-propyl bromide reacting with magnesium in tetrahydrofuran and the simultaneous addition of dichlorodimethylsilane. The product was identified by elemental analysis and by infrared spectrum absorptions at 1080 cm."1, 1125 cm."1, and 114-0 cm.-1, characteristic for 39 the silacycloalkene nucleus (68). The di-Grignard reagent said to be involved may be shown as either? If dichlorodimethylsilane i s added to the pre-formed •di-Grignard reagent', three d i f f e r e n t l i q u i d f r a c t i o n s re-s u l t instead of the expected ring product. Thus a modifi-cation i s neccessary. Successful synthesis of the r i n g struc-ture was accomplished by simultaneous addition of the silane and the bromide to the magnesium, with THF as the solvent. The completion of the reaction was determined using Michler's Ketone and Color Test I (98). The reaction l i k e l y proceeds i n two stages? formation of 3-(o-bromophenyl)-propyldimethyl-chlorosilane (XO, and with excess magnesium, the s i l a c y c l i c product (XI). ho Preparation of the ^ -bromo deriv a t i v e of 2 : 3-benzo-l,l-dimethyl-l-silacyclohex - 2-ene was accomplished by treating the parent; compound with N-bromosuccinimide ( N B S ) . The struc-ture of the product 2 : 3 rbenzo-Wbromo-l,l-dimethyl-l-sila-cyclohex-2-ene was based on elemental analysis, infrared spectrum, and i t s reactions. Absorption bands on the i n f r a -red spectrum at 1082 cm."1, 1135 cm."1, and .1150 cm. - 1 were present and apparently indicate the c h a r a c t e r i s t i c benzosila?-cycloalkene nucleus ( 6 8 ) . A c h a r a c t e r i s t i c test f o r benzylic halide, namely r e a c t i v i t y with s i l v e r n i t r a t e , was pos i t i v e , excluding possible broraination of (XI) at the 5— or 6 - posi-t i o n s . Attempts to react the *+-bromo compound with 2-dimethyl-aminoethanol by Lo (50) proved unsuccessful, and d i r e c t syn-t h e s i s of a compound with a possible l o c a l anesthetic side chain was abandoned. Attempts were made to synthesize the ^ - - n i t r i l e compound using potassium cyanide i n various solvents under several dif f e r e n t ; sets of conditions. The product ••was to be used to prepare an acid which might be used to synthesize ester and amide derivatives which might possess the desired l o c a l anesthetic a c t i v i t y . The r e s u l t was f a i l u r e , however, with elimination occurring instead of the n i t r i l e s u b s t i t u t i o n . The only product i s o l a t e d was suspected to be an o l e f i n , (XIII), according to the reactions: hi The r a t i o of o l e f i n to substitution product involves a competition between the elimination and Sn reactions. The E/Sn r a t i o may be raised or lowered depending on the base used (99). A weak base such as CN" which i s strongly nucleophilic toward carbon should be very e f f e c t i v e i n bring-ing about bimolecular substitution (where attack on carbon i s required) and f a r l e s s e f f e c t i v e i n bringing about b i -molecular elimination (where extraction of a proton i s required). The f a i l u r e of the cyano group to replace the bromo group indicated that the varied b a s i c i t y had no e f f e c t on the re-a c t i o n . Thus the assumption was made that the reactions proceeded v i a an E l or unimolecular elimination mechanism, shown as: k2 Attempts to enhance substitution by using highly polar solvents such as THF, DMSO, and DMF, and by using lower tem-peratures f a i l e d to prevent elimination from occurring. The synthesis of 2:3-benzo-Whydroxy-l,l-dimethyl-l-silacyclohex-2-ene was p r o v i s i o n a l l y successful when the Wbromo compound was refluxed i n a basic hydro-alcoholic solution for h8 hours. CH3 OH Under the conditions used i t was d i f f i c u l t to determine whether the mechanism of the reaction was unimolecular (S^l) or bimolecular (S'JJ2) s u b s t i t u t i o n . The low concentration of nucleophile and the polar solvent should favour S ^ L mech-anism with formation of a carbanion i n the t r a n s i t i o n state. The strong nucleophilic nature of the sodium hydroxide base, however, would indicate: an S^2 mechanism. The hydroxy compound was i d e n t i f i e d from infrared spec-t r a which showed 0-H group; stretching absorbance peaks at 3350 cm."1. Peaks c h a r a c t e r i s t i c of benzosilacycloalkene and a l k y l s i l i c o n groups remained. An attempt to prepare the phenylurethan deri v a t i v e of the hydroxy compound f a i l e d when the presence of water led to formation of diphenylurea.. The equations are shown as: ^3 o The same resu l t occurred when a naphthylurethan deriv-ative was attempted. The compound formed i n t h i s case was possibly di-(c< -naphthyl)-urea. The benzoate derivative could not be produced, and at-tempts to make the 3 :5-dinitrobenzoate deri v a t i v e resulted i n formation of an o i l y substance and a non-melting chalky substance. Neither of these were i d e n t i f i e d . In another attempt some 3 :5-dinitrobenzoic. acid was produced. Ring cleavage was indicated from infrared studies. Samples of the ^ -hydroxy compound injected into the gas chromatogram were broken down to what appeared to be an olefin., At any rate, the hydroxy function was l o s t i n the treatment. P u r i f i c a t i o n by t h i s means was thus f r u i t l e s s . 44 PART V  EXPERIMENTAL A l l m e l t i n g p o i n t s and b o i l i n g p o i n t s are u n c o r r e c t e d . A l l e l e m e n t a l microanalyses were performed by Dr. A l f r e d Bernhardt, Hohenweg, West Germany. I n f r a r e d s p e c t r a were recorded on a Unicam SP 200 I n f r a r e d Spectrophotometer or a Beckman IR-10 I n f r a r e d Spectrophotometer. Gas chromato-graphy a n a l y s e s were done using a M i c r o t e k MT 220 gas chromato-graph, and a Beckman GC-2 gas chromatograph. o-Bromotoluene (90) A s o l u t i o n of O - t o l u i d i n e (162 gm., 1.5 mol.) i n 880 ml. (6 mol.) of k-0% hydrobromic a c i d i n a three l i t e r f l a s k was c o o l e d to 5°C. and d i a z o t i z e d w i t h 116 gm. (1.7 mol.) of powdered sodium n i t r i t e added about 10 gm. at a time. A f t e r each a d d i t i o n the f l a s k was stoppered and s t i r r e d v i g -o r o u s l y u n t i l the red fumes were absorbed, w i t h the temper-atu r e kept below 10 GC. When the d i a z o t i z a t i o n was complete, about 5 gm. of copper t u r n i n g s were added, and the f l a s k was a t t a c h e d to a condenser and heated v e r y c a u t i o u s l y . As soon as the f i r s t s i g n o f r e a c t i o n was observed, the f l a s k was c o o l e d w i t h i c e . N i t r o g e n was evolved v i g o r o u s l y . When the r e a c t i o n subsided, the f l a s k was heated on a steam bath f o r o n e - h a l f hour. One l i t e r of water was added and the mixture was d i s t i l l e d h5 w i t h steam u n t i l about 1.5 l i t e r s passed over. The d i s t i l l a t e was made a l k a l i n e w i t h 10% sodium hydroxide and the o r g a n i c l a y e r s e p a r a t e d . The crude o-broraotoluene was washed twice w i t h c o n c e n t r a t e d s u l f u r i c a c i d , and then t h r e e times w i t h water. The washings removed most of the c o l o u r . The o r g a n i c l a y e r was d r i e d over sodium s u l f a t e o v e r n i g h t , f i l t e r e d , and d i s t i l l e d a t atmospheric p r e s s u r e . The pure product, ll»t-li*2 gm. y i e l d ) b o i l s at 1 7 8 - l 8 l°C. ( l i t . b.p. 1 7 9 - 1 8 1°C). (90) The i n f r a r e d spectrum showed the c h a r a c t e r i s t i c o-sub-s t i t u t i o n a b s o r p t i o n band at 760 cm." 1, and the a b s o r p t i o n band at 138O cm." 1 was a s s i g n e d to the methyl bending mode. The band a t 2990 cm." 1 was assigned t o the c h a r a c t e r i s t i c methyl C-H a b s o r p t i o n . The low y i e l d obtained and the l e n g t h y procedure i n v o l v e d prompted the use of reagent o-bromotoluene (Fluka) i n the l a t e r stages of t h i s work. o-Bromobenzvl Bromide A o n e - l i t e r three-necked f l a s k was equipped w i t h a mechan-i c a l s t i r r e r , condenser, and dropping f u n n e l . o-Bromotoluene (171 gm., 1 mol.) was heated i n the f l a s k ( t o approximately lM)°C.) and s t i r r e d a t a v e r y slow r a t e . Bromine (128 gm., 0.8 mol.) was added dropwise w i t h the temperature kept be-tween 1^0-15000. The a d d i t i o n of bromine was f i n i s h e d i n t h r e e hours, and s t i r r i n g continued f o r an a d d i t i o n a l hour; d u r i n g t h a t time, most of the HBr formed escaped through the condenser, and was channeled through the fume hood by means 4-6 of a rubber hose l e n g t h . The s o l u t i o n was cooled and d i s -t i l l e d under reduced pressure. The pure product, a strong lachrymator which s o l i d i f i e s on r e f r i g e r a t i o n , d i s t i l l e d at 93-96°C/l mm. Hg i n 75% y i e l d (160 gm.), ( l i t . b.p. (93) 129°C/19 mm. Hg; (94-) 66-69°C/0.3 mm. Hg). The y i e l d was not bettered by using double q u a n t i t i e s of reagents. An equal q u a n t i t y of unreacted o-bromotoluene was c o l l e c t e d on each occasion. The i n f r a r e d spectrum showed absence of methyl-bending a b s o r p t i o n . The bands at 2990 cm.""1 and 3°60 cm."1 were assigned t o s t r e t c h i n g modes of methylene group and aromatic C-H r e s p e c t i v e l y . S-(o-bromobenzyl)-isothiourea p i c r a t e F i n e l y powdered t h i o u r e a (1 gm.), o-bromobenzyl bromide (1 gm.), and e t h y l a l c o h o l (10 ml.) were r e f l u x e d f o r a period of 5 minutes. P i c r i c a c i d (1 gm.) was then added, and the mix-ture was heated u n t i l a c l e a r s o l u t i o n was obtained and cooled. The c r y s t a l s were removed by f i l t r a t i o n and r e c r y s t a l l i z e d from ethanol to give y e l l o w needles which melted at 227-228°C. An a l . Calcd. f o r C ^ H ^ O ^ B r S : C, 35.4-5; H, 2 . 5 1 ; N, 14-.76; S, 6 . 7 6 . Found: C, 3 5 . 7 7 ; H, 2.54-; N. 15 .51; S, 6 . 9 6 . 3 -(o-Bromophenyl)-propan-l-ol This r e a c t i o n was run throughout i n an atmosphere of dry n i t r o g e n . o-Bromobenzyl bromide (160 gm., 0.64- mol.) i n ether (500 ml.) was added dropwise to a s t i r r e d mixture >+7 of magnesium (16 gm., 0.66 gm.-atom) and ether (50 ml..). The reaction was i n i t i a t e d by the addition of an iodine crys-t a l , or by crushing the magnesium against the bottom of the vessel with a glass s t i r r i n g rod. Gentle heat was also ap-p l i e d . When the formation of the Grignard reagent had been accomplished a f t e r three hours' s t i r r i n g , the mixture was cooled In an ice bath, and a solution of ethylene oxide con-densed by cooling i n a bath of dry ice and acetone, (63 ml., 1.25 mol.) i n ether (100 ml.) was slowly added. A sticky white semisolid slowly separated. The mixture, after standing overnight, was hydrolyzed with d i l u t e s u l f u r i c acid. The ethereal layer was dried over anhydrous magnesium su l f a t e and d i s t i l l e d under reduced pressure to give the following f r a c t i o n s : a. 39 ^ l C/3 nmn Hg-, b. 120-123dC./2 mm. Hg: c. 123-11+5"c./2 mm. Hg. Fract i o n 20 (b) was the c o l o r l e s s propanol (68 gm., k-9% y i e l d ) , n D 1.5699. Fraction (a) was i d e n t i f i e d from infrared spectra to be e t h y l -ene brorahydrin, while f r a c t i o n (c) could not be p o s s i t i v e l y i d e n t i f i e d . The infrared spectrum showed the c h a r a c t e r i s t i c 0-H absorption band at 3300 cm."1. The strong absorption bands at 1^ 70 era." 1, 2850 cm. - 1, and 2900 cm."1 were assigned to methylene stretching. The o-substitution absorption band was shown at: 760 cm."1. Reactions using multiple quantities gave the highest y i e l d s of the alcohol. An attempt was made to increase the y i e l d by adding the formed Grignard reagent to the l i q u i d ethylene oxide, 1*8 but the r e s u l t i n g y i e l d was lower, w i t h an i n c r e a s e d amount of ethylene bromhydrin ( f r a c t i o n (a)) being formed. 3- (o-Bromophenyl)-•propyl'*' -naohthylcarbamide Anhydrous 3-(o-Bromophenyl)-propan-l-ol ( 0 . 5 gm.) was pla c e d i n a t e s t tube, and 0 . 5 gm. of the ^ - n a p h t h y l i s o c y a n a t e was added. The mixture was heated g e n t l y f o r 2 minutes and was then cooled i n a beaker of i c e . The s i d e of the t e s t tube was scratched to induce c r y s t a l l i z a t i o n . When the c r y s t a l s had been formed, 5 ml. of petroleum ether (b.p. 66-75°C.) was added, and the mixture was warmed and f i l t e r e d . The f i l t r a t e was cooled i n a beaker of i c e , and the urethan c r y s t a l s s l o w l y p r e c i p i t a t e d . The c r y s t a l s were r e c r y s t a l l i z e d from p e t r o -leum e t h e r , and melted a t 112-113°C. A n a l . C a l c d . f o r C 2 0 H l 8 0 2 B r : , C, 6 2 . 5 1 ; H, ^ . 7 2 ; N, 3.56 Found: C, 6 2 . 6 5 ; H, ^ . 6 6 ; N, k.26. 3-(o-Bromophenyl)-propyl Bromide A 500-ml. three-necked f l a s k was equipped w i t h a mechan-i c a l s t i r r e r , a condenser, and dropping f u n n e l . 3-(o-Bromo-p h e n y l ) - p r o p a n - l - o l (100 Gm., 0.^6 mol.) was p l a c e d i n the f l a s k and cooled to i c e bath temperature; then phosphorus t r i -bromide (63 gm., 0.23 mol.) was slowly added w i t h s t i r r i n g . When a d d i t i o n was completed, the mixture was warmed to room temperature and s t i r r e d f o r 2 . 5 hours; f o l l o w e d by heating on a steam bath f o r 1.5 hours. On c o o l i n g and h y d r o l y s i s w i t h water, ether was added and the organic l a y e r was sep-k9 arated. The organic layer was dried over anhydrous magnesium sul f a t e and the solvent was d i s t i l l e d . The pure product was a colourless l i q u i d , b.p. l l 4 ~ l l 5 ° C . / 2 mm. Hg., n^°: .1.5830. The y i e l d from the reaction was 9 7 . 5 grams (75%). An improved y i e l d of 116 grams (90$) was obtained using double or t r i p l e quantities of the reactants. On an infrared spectrum of the product, bands at 1465 cm."1, 2830 cm."1, and 2910 cm. - 1 were assigned to methy-lene stretching. Methylene absorption was shown at 14-38 cm."1. Aromatic C-H absorption and o-substitution were shown at 3010 cm. - 1 and 750 cm.~l respectively. S-(3-(o-Bromophenyl)-propyl)-isothiourea pic r a t e F i n e l y powdered thiourea ( 0 . 5 gm.), 3-(o-brompphenyl)-propyl bromide ( 0 . 5 gm.), and ethyl alcohol (5 ml.) were refluxed for a period of 15 minutes. P i c r i c acid ( 0 . 5 gm.) was added and the mixture was heated for an additional f i v e minutes. A clear solution was obtained and cooled; the picrate c r y s t a l s were slowly p r e c i p i t a t e d by adding a few drops of water. The c r y s t a l s were removed by f i l t r a t i o n and recrys-t a l l i z e d from ethanol to give yellow prisms, with melting point of 1 8 2 - 1 8 2 . 5°C Anal. Calcd. for C^Hi^OyN^BrS: C, 3 8 . 5 7 ; H, 2.4-3; N, 14-. 10; S, 6 .44 Found: C, 3 8 . ^ 5 ; H, 2 .27; N. 14.80; S, 6.74-. 50 Synthesis of 2 :VBenzo-l.l-dimethyl-l-silacyclohex - 2 - ene 3-(o-bromophenyl)-propyl bromide (27.8 gm., 0 .1 mol.) di l u t e d to 100 ml. with tetrahydrofuran was slowly added to 5 .0 gm. (0 .22 Gm.-atoms) of magnesium i n 20 ml. of the same solvent. When the formation of the di-Grignard reagent was i n i t i a t e d , the simultaneous addition of 13 .0 gm. (0 .1 mol.) of dichlorodimethylsilane was begun. The reaction mixture was refluxed during the addition of the chlorosilane (2 hours) and then for an ad d i t i o n a l four hours. At thi s time the mixture gave a negative test for organomagnesium compound using Michler's ketone (Color test I) ( 9 8 ) . The mixture was cooled and f i l t e r e d through glass wool and was hydrolyzed with d i l u t e ammonium chloride solution u n t i l heat and effervescence were no longer produced. The organic layer was dried over magnesium sulfate and was con-centrated by using a f l a s h evaporator. The concentrated o i l was then taken up by petroleum ether (b.p. 66-75°C.) and passed through a column of alumina. The petroleum ether eluate was d i s t i l l e d to give 6 .7 gm. (38$) of product, b.p. 57-59°C./l mm. Hg. The infrared spectrum of the compound showed bands at 1082 cm.""1, 1125 cm."1, and 114-1 cm."1, which constitute the c h a r a c t e r i s t i c s of a benzosilacycloalkene nucleus. Methyl-ene bending absorption was shown at 14-38 cm."1 and the bands at 2830 cm."1 and 2950 cm."1 were assigned to methylene stretch-ing, whereas the band at 2880 cm."1 was assigned to stretching 4 51 of the methyl group*. The a l k y l - s i l i c o n absorption was shown at 1250 cm. - 1, 850 cm."1, and 800 cm."1. Anal. Calcd. for C^H^Sis- C, 7^ .9^ 5 H, 9.15; S i , 15.92 Found: C, 7^.93; H, 8.92; S i , 1^.55. It should be noted that found values reported f o r s i l i c o n were always about 1% low due to the method of analysis used. Synthesis of 2:3-Benzo-1+-bromo-l«l-dimethyl-l-silacyclo-hex-2-ene A mixture of N-Bromosuccinimide (*+.8 gm., 0.027 mol.), 2:3-Benzo-l,l-dimethyl-l-silacyclo-hex-2-ene (k,Q gm., 0.027 mol.), and benzoyl peroxide (0.05 gm.) i n 100 ml. of carbon tetrachloride was heated at r e f l u x temperature for 3»5 hours. The suspension was cooled i n an i c e bath; f i l t r a t i o n of o the cold suspension gave 3.5 gm. of succinimide, m.p. 125-126 C. The f i l t r a t e was concentrated on a f l a s h evaporator and the re s u l t i n g o i l d i s t i l l e d under reduced pressure to give k.2 gm. (57$ y i e l d ) of the product, with b.p. 115-119°C/3 mm. Hg;. Yields were increased to h.7 gm. (6k-% y i e l d ) by using multiple quantities of reagents. Solid succinimide was depos-i t e d i n the condenser during the d i s t i l l a t i o n and caused some inconvenience. The product had to be stored i n a t i g h t l y stoppered container away from l i g h t , as i t turned dark and emitted fumes on exposure to l i g h t and a i r . It was prepared i n small quantities p r i o r to use i n further work. The infrared spectrum showed the c h a r a c t e r i s t i c benzo-silacycloalkene nucleus absorptions at 1082 cm. 1 , 1135 cm. 1 , 52 and 1150 cm." (1G0). The a l k y l - s i l i c o n absorption was shown at 1250 cm."1, 858 cm."1, and 798 cm."1. Anal. Calcd. for:.; C j j H ^ S i B r : C, 51.73; H, 5.88; Br, 31.38;: S i , 10.98 Found: C, 51.73*, H, 6.02; Br, 31.21. Synthesis of 2:l-Benzo-^-cyano-l. 1-dimethyl-l-silacyclo-hex-2-ene (attempted). The procedure reported by Lo (50) involved r e f l u x i n g 2:3-Benzo-1+-bromor-l, l-dimethyl-l-silacyclohex-2-ene and potassium cyanide i n equimolar quantities i n a 50$ a l c o h o l -water or a 50$ absolute methanol-water mixture. Following d i s t i l l a t i o n to remove the alcohol, ether extraction, and drying overnight; over anhydrous magnesium sulfate, the r e -sul t i n g mixture was d i s t i l l e d under reduced pressure to give a clear l i q u i d , b.p. 65-69°C./l mm. Hg. The l i q u i d decolour-ized bromine i n carbon tetr a c h l o r i d e and f a i l e d to react with ethanolic s i l v e r n i t r a t e . No n i t r i l e peak was evident i n an i n f r a r e d spectrum. An elemental analysis suggested pos-s i b l e o l e f i n formation i n the s i l i c o n r i n g . In t h i s research, attempts were made to accomplish 4-cyano substitution by changing solvents and adjusting r e f l u x times and temperatures i n order to prevent or minimize the elimination problem. 53 Table JL Reaction conditions used i n attempts to pre-pare ^—eyano compound. RUN SOLVENT TIME (Hrs.) TEMP. (°C.) 1. 50$ Et0H-H20 1 Reflux 2. 50$ EtOH-H20 5 10 3 . 50$ EtOH-H20 5 0 h. 50$ EtOH-H20 5 -10 5. Me OH l Reflux 6 . DMSO l Reflux 7. DMS-0 12 10 8. DMSO 12 0 9 . DMSO 12 -10 10. DMF 12 10 11. DMF 12 0 12. DMF 12 -10 13 . THF 20 0 In each case, the l i q u i d recovered using the above tech-nique decolourized bromine i n carbon tetr a c h l o r i d e , did not react with ethanolic s i l v e r n i t r a t e , and showed no n i t r i l e peak on the inf r a r e d spectrum. Sodium fusion procedures showed no elemental nitrogen to be present. Elimination was suspected, mainly from in f r a r e d spectra, which had i n general, peaks at 3020 cm."1 and 3060 cm."1, indi c a t i n g that an unsaturated =CH- (aromatic) group was present. The ab-sorbance peaks previously noted to be c h a r a c t e r i s t i c of the silacycloalkene and a l k y l s i l i c o n groups were, however, s t i l l present on the infrared spectra studied. 5h S y n t h e s i s of 2:3-Benzo-4--hydroxy-l.l-dimethyl-l-sila-eyclohex-2-ene RUN 1. A 2 gm. sample of 2r3-Benzo-4--bromo-l,l-diniethyl-l-sila-cyclohex-2-ene was p l a c e d i n about 100 ml. of d i s t i l l e d water i n a 250 ml., f l a s k and the mixture was r e f l u x e d f o r 4-8 hours, a f t e r s u f f i c i e n t e t h a n o l was added t o e f f e c t m i s c i b i l i t y . A f t e r removing the e t h a n o l by f l a s h e v a p o r a t i o n and e x t r a c t i n g the remaining l i q u i d w i t h anhydrous e t h e r , the mixture was d r i e d over anhydrous magnesium s u l f a t e i n the r e f r i g e r a t o r . , Then the ether was f l a s h e d o f f and the remaining l i q u i d was d i s t i l l e d under reduced p r e s s u r e . Two f r a c t i o n s were c o l l e c -t e d ; the f i r s t a t 75-77°C/0.5 mm. Hg, and the second at 131+.-137°C./0.5 mm. Hg. Ne i t h e r f r a c t i o n showed a n t i c i p a t e d 0-H s t r e t c h i n g absorbances at 34-00-3600 cm."1, i n d i c a t i n g absence o f the d e s i r e d , a l c o h o l . Again, the b e n z o s i l a c y c l o -alkene and a l k y l s i l i c o n peaks remained, at. 1082., 1135, 1150 cm." 1, and 1250, 858, 798 cm." 1 r e s p e c t i v e l y . A p o s i t i v e e t h a n o l i n s i l v e r n i t r a t e t e s t i n d i c a t e d that the f i r s t f r a c -t i o n was l i k e l y unreacted 4-bromo compound. RUN 2.. A 2 gm. sample of the 4—bromo compound was t r e a t e d as i n Run 1, but. w i t h % NaOH added t o the s o l v e n t . D i s t i l l a t i o n under reduced p r e s s u r e y i e l d e d a c l e a r l i q u i d , b.p:. 115-118 °C. A peak c h a r a c t e r i s t i c of 0-H s t r e t c h i n g at 3350 cm." 1 was p r e s e n t on the i n f r a r e d spectrum prepared, and the ben-z o s i l a c y c l o a l k e n e and a l k y l s i l i c o n peaks a l s o remained. 55 Based on t h i s evidence, s u b s t i t u t i o n of a hydroxy group at posi t i o n four was assumed. RUN 3. The reaction solvent was changed to 50$ ethanol-water to f a c i l l i t a t e m i s c i b i l i t y of the bromo compound i n the basic solution used i n Run 2. The r e s u l t i n g l i q u i d was d i s -o t i l l e d under reduced pressure at 117-118 C./5 mm. Hg. An infrared spectrum showed the same c h a r a c t e r i s t i c peaks as i n Run 2. Synthesis of 2;:3-Benzo-l.l-dimethyl^l-silacyclohex-2-ene-^f-phenylurethan (attempted) (101) About 1 gm. of the compound (alcohol) was placed i n a test tube and about 0.5 ml. of phenyl isocyanate was added. Reaction was catalyzed by addition of a few drops of anhy-drous pyridine followed by heating on a steam bath for 5 minutes. The r e s u l t i n g needles were r e c r y s t a l l i z e d from eth-anol and melted at 2*f 0-2^ 1° C. Elemental analysis showed that diphenylurea had been produced instead of the desired phenylurethan, due to the presence of water. This was v e r i -f i e d by comparing the infrared spectrum of the prepared com-pound to a spectrum of f r e s h l y prepared diphenylurea, which has m.p. 238-239°C. (102). Anal.. Calcd. for:- C; l 8H 2 1Nr C, 69.^1; H, 6.80; N, ^ .50 Found: C, 72.98% H, 5.57* N, 1^.78. 56 Synthesis of 2:3-Benzo-l.l-dimethyl-l-silacyclohex-2- ene-4-t* -naphthylurethan (attempted) (101) The same procedure was followed as with the phenylure-than attempt above. A white amorphous s o l i d resulted which melted at 77-79°C. after r e c r y s t a l l i z a t i o n from ethanol. Elemental analysis indicated possible formation of d i ( * -naphthyl);-urea, again due to the presence of moisture. The peaks associated with the benzosilacycloalkene nucleus ap-peared to be absent; i . e . , at 1082 em."1, 1135 cm."1, and 1150 cm."1. They could have been shifted due to the presence of the amide function, however, but the absence of these peaks seemed more l i k e l y to indicate r i n g cleavage had occurred. Anal. Calcd. f o r : C22H23N: C, 73.09; H, 6.4-1; N, 3.88 Found: C, 71.4-9; H, 5.84-; N, 7.07. The presence of s i l i c o n i n the compounds was not indicated i n the submission of the samples for an a l y s i s . It was thought l a t e r that the presence of s i l i c o n might necessitate employ-ing d i f f e r e n t assay procedures with more accurate r e s u l t s . Nevertheless, the res u l t s indicated f a i l u r e to produce the desired d e r i v a t i v e s . Synthesis of 2:3-Benzo^l.l-dimethyl-l-silacyclohex-2-ene-4—-benzoate (attempted) (101) One ml. of the alcohol compound was dissolved i n 3 ml. of anhydrous pyridine, and 0.5 gm. of benzoyl chloride was added. The expected i n i t i a l reaction did not occur. The mixture was warmed over a low flame for a minute and poured with vigorous s t i r r i n g into 10 ml. of water. No pr e c i p i t a t e formed. 57 Synthesis of 2:3-Benzo-l.l-dimethyl-l-silacyclohex-2- ene-*+- (3«5-dinitrobenzoate) (at tempted)  RUN 1. (101) About 0.5 gm. of 3,5-dinitrobenzoyl chloride was mixed with 2 ml. of the alcohol compound i n a test tube and the mixture was boiled gently for 5 minutes. Then 10 ml. of d i s -t i l l e d water was added and the solution was cooled i n an i c e bath. The mixture separated from the water as a t a r r y mass, although some cry s t a l s formed. Washing with 2% Na 2C0 3 dissolved the c r y s t a l s , which could not be recovered by r e -a c i d i f i c a t i o n . A second attempt u t i l i z i n g - t h e above proce-dure, i n which no washing with NagCO^ was done yielded only an o i l . RUN 2. (103) • Small pieces of metallic sodium were added to about 1 ml. of the alcohol at room temperature. Some effervescence occurred, but reaction was so s l i g h t that eventually gentle flaming was employed. Excess sodium was avoided, and removed i f necessary. A thick dark l i q u i d with c h a r a c t e r i s t i c odour resulted. Then about 0.5 gm. of 3,5-dinitrobenzoyl chloride was added and mixed w e l l . A small amount of heat was generated, and the colour changed from a dark purple to a tan-brown. After heating gently and s t i r r i n g to ensure complete reaction, 10 ml. of d i s t i l l e d water was added and the mixture was a g i -tated vigorously. The re s u l t i n g s o l i d o i l y mass was c o l l e c -ted and washed with 10 ml. of 2% NagCO^. R e c r y s t a l l i z a t i o n attempts with acetone were unsuccessful; the s o l i d could 58 not be recovered once dissolved, but yielded only an o i l . It was concluded that the ester was l i k e l y a l i q u i d or a very low-melting s o l i d which turned e a s i l y to an o i l . While f i r s t attempts at r e c r y s t a l l i z a t i o n using a mixture of ethanol and d i s t i l l e d water resulted i n o i l formation, more de t a i l e d work produced some 3,5-diriitr©benzoic acid plus a water-sol— uble chalky substance which would not melt at temperatures attainable i n the laboratory ( i . e . , up to 320 C ) . The acid formation was v e r i f i e d by infrared analysis and mixed melting points, and the non-melting s o l i d was shown, from i t s i n f r a -red spectrum, to have no organic c h a r a c t e r i s t i c s . Tests with aqueous solutions of the l a t t e r s o l i d with 2$ AgNO^ i n ethanol yielded a brown p r e c i p i t a t e , indicating a chloride s a l t . A l l i n f rared spectra showed absence of benzosilacyclo— alkene nucleus, in d i c a t i n g ring cleavage had occurred. An infrared spectrum of reagent 3 , 5-dinitrobenzoyl chlor-ide did not ressemble any of the formed so l i d s mentioned above. RUN 3. (10*0 About 0 . 5 gm. of 3 , 5-dinitrobenzoyl chloride was mixed with 2 ml., of the alcohol i n a test tube and the mixture was heated for 30 minutes on a steam bath. Then 10 ml. of d i s t i l l e d water were added and the solution was cooled i n an i c e bath. The s o l i d which formed when the water was added was neutralized with 10 ml. of % NaHCO^ sol u t i o n . Following t h i s , the compound was subjected to acetone i n an attempt to r e c r y s t a l l i z e ; i t . No c r y s t a l s reformed. Infrared spec-59 t r a of more of the crude compound were compared unsuccessfully; to a spectrum of 3,5-dinitrobenzoyl chloride, r u l i n g out the theory that the s o l i d might have been excess reagent. Synthesis of 2:3-Benzo-l.l-dimethyl-l-silacyclohex-2- ene:-^-(2.Winitrophenylhydrazone) (attempted) (105} A solution of 1 or 2 drops of the compound under study i n 2 ml. of 95$ ethanol was added to 3 ml. of the 2, lf-dinitro-phenylhydrazine reagent., Vigorous shaking resulted i n a s l i g h t p r e c i p i t a t e . Thus a deriva£ive>-scale procedure was c a r r i e d out. (106). A solution of 2, l+-dinitrophenylhydrazine was prepared and added to a mixture of 5 ml. of the test compound i n 20 ml. of 95$ ethanol. Crystals formed i n f i v e to ten minutes at room temperature. R e c r y s t a l l i z a t i o n was effected by s i d -solving the collected c r y s t a l s i n 30 ml. of 95$ ethanol and about 10 ml. of ethyl acetate* The red c r y s t a l s reformed overnight at room temperature and melted at 263~265°C A second attempt to prepare t h i s derivative met with f a i l u r e , and the conclusion was reached that some impurity i n the o r i -g i n a l alcohol compound had led to success i n the f i r s t i n -stance. Nothing could be derived from a comparison of i n f r a -red spectra of 2, i+-dinitrophenylhydrazine and the compound formed here. The spectra were not i d e n t i c a l , but differences were too minor to suggest the nature of any reaction. The benzosilacycloalkene and a l k y l s i l i c o n nuclei were absent from the infrared spectra, indicating r i n g cleavage had l i k e l y 60 occurred. I n s u f f i c i e n t material was produced to f a c i l l i t a t e an elemental a n a l y s i s . Gas Chromatography of 2 :3-Benzo-Whydroxy-l.l-dimethyl- l-silacyclohex - 2-ene. A f r e s h sample of the synthesized hydroxy compound was injected into the Microtek MT-220 chromatogram. Seven f r a c -tions were indicated, and i t was decided to t r y to c o l l e c t samples on a preparative scale f o r further study. Thus a larger sample was injected into the Beckman GC-2 gas chrom-atogram with the following s p e c i f i c a t i o n s : C a r r i e r gas, He; pressure, 30 p s i g ; operating temperature, 160°C; maximum temperature, 1 9 0*C; column, 30$ carbowax 20,000 on U l t r a -port 60/70; exhaust temperature, 200*C.; chart speed, per min. Only f i v e peaks showed on the Beckman chromatogram, present as two major peaks and three shoulders. An attempt was made to c o l l e c t the 2 major f r a c t i o n s , the f i r s t with four inherent sub-fractions, and the second as a pure l i q u i d . An examination of infrared spectra of the co l l e c t e d f r a c t i o n s showed loss of the'c h a r a c t e r i s t i c OH-peak at about 3500 cm.*"1, and the presence of peaks at 164-0 cm."*1 and 3,000 cm."1 i n -dicated possible o l e f i n formation. This was attributed to either the operating temperature and/or a basic I n s t a b i l i t y problem, or perhaps a reaction with the column adsorbent. Lack of time prevented pursuit of further chromatography studies, which on f i r s t inspection, did not seem promising. PART. V I  INFRARED SPECTRA 61 F i g u r e k. I n f r a r e d Spectrum of o-Bromotoluene. L i q u i d f i l m between sodium c h l o r i d e p l a t e s . F i g u r e 5* I n f r a r e d Spectrum of o-Bromobenzyl Bromide. L i q u i d f i l m between sodium c h l o r i d e p l a t e s . CHi.Br S r F i g u r e 6. I n f r a r e d Spectrum of 3-(o-Bromophenyl)-p r o p a n - l - o l . L i q u i d f i l m between sodium c h l o r i d e p l a t e s . Br-V. 6 2 F i g u r e 7. I n f r a r e d Spectrum of 3-(o-Bromophenyl)-P r o p y l Bromide. L i q u i d f i l m between sodium c h l o r i d e p l a t e s . F i g u r e 8 . I n f r a r e d Spectrum of 2 * 3 - B e n z o - l , l - d i m e t h y l -l - s i l a c y c l o h e x - 2 - e n e . L i q u i d f i l m between sodium c h l o r i d e p l a t e s . CM9' ^H3 F i g u r e 9« I n f r a r e d Spectrum o f 2 : 3-Benzo- Li—bromo - 1 , 1 -d i m e t h y l - l - s i l a c y c l o h e x - 2 - e n e . L i q u i d f i l m between sodium c h l o r i d e p l a t e s . 8K 63 F i g u r e 10. I n f r a r e d Spectrum of, l i q u i d f r a c t i o n from r e a c t i o n of 2::3-Benzo-4--bromo-l,l-dimethyl-l - s i l a c y c l o h e x - 2 - e n e and Potassium Cyanide i n THF a t 0°C. f o r 20 hours. L i q u i d f i l m between sodium c h l o r i d e p l a t e s . F i g u r e 11. I n f r a r e d Spectrum of s o l i d formed i n attempt to prepare 2 : 3 - B e n z o - l , l - d i m e t h y l - l - s i l a -cyclohex-2-ene-4—ocnaphthylurethan. S o l i d i n potassium bromide d i s k . F i g u r e 12. I n f r a r e d Spectrum of s o l i d formed i n attempt to prepare 2 r 3 - B e n z o - l , l - d i m e t h y l - l - s i l a c y c l o -hex-2-ene-4—phenylurethan. S o l i d i n potassium bromide d i s k . 6k F i g u r e 13 . I n f r a r e d Spectrum of s o l i d formed i n attempt to prepare 2 s 3 - B e n z o - l , l - d i m e t h y l - l - s i l a c y c l o -hex-2-ene-k— ( 3 , 5 - d i n i t r o b e n z o a t e ) . S o l i d i n potassium bromide d i s k . F i g u r e 1*+. I n f r a r e d Spectrum of f r a c t i o n No. 1 from gas chromatography of 2 : 3 - B e n z o - L i ~ h y d r o x y - l , l -d i m e t h y l - l - s i l a c y c l o h e x - 2 - e n e . L i q u i d between sodium c h l o r i d e p l a t e s . F i g u r e 15. I n f r a r e d Spectrum of f r a c t i o n No. 2 from gas chromatography of 2 : 3-Benzo- lf-hydroxy-l,l-d i m e t h y l - l - s i l a c y c l o h e x - 2 - e n e . L i q u i d between sodium c h l o r i d e p l a t e s . WAVELENGTH IN MICRONS 7 7.5 • 9 10 65 Figure 16. Infrared Spectrum of 2:3-Benzo-4~hydroxy-1,1-d ime t hyl— 1 -s i l a cy c lohex-2^-ene. Liquid f i l m between sodium c h l o r i d e plates. WHfN REOtClING SPtOlt CHAM NO. 104*1 66 PART VII  SUMMARY The synthesis of 2:3-benzo-4--hydroxy-l,l-dimethyl-l-silacyclohex-2-ene has been reported. Characterization was accomplished by means of infrared spectra, but attempts to prepare derivatives were not successful. The reaction sequence used was as follows:: o-bromo-toluene was brominated with free bromine to give o-bromo-benzyl bromide. This compound was then treated with mag-nesium turnings to form a Grignard reagent which gave 3-(o-bromophenyl)-propan-l-ol when ethylene oxide was added to i t . This propanol was then brominated with phosphorous tribromide to give 3-(o-bromophenyl)-propyl bromide. After preparing a Grignard from t h i s compound, simultaneous addition of dichlorodimethylsilane yielded,2:3 b e n z o-l,l-dimethyl-l-silacyclohex-2-ene. Treatment with N-bromosuccinimide gave the 4—bromo de r i v a t i v e . Attempts were made to prepare the 4--cyano derivative by reacting the 4—bromo compound with potassium cyanide under various conditions. Elimination was the only r e s u l t . The h-hydroxy compound was successfully prepared by means of a substitution reaction of ^ -bromo compound with sodium hydroxide i n hydro-alcoholic solution. Infrared studies indicated a successful hydroxide substitution, but attempts 67 to confirm the structure of the hydroxy compound by forming solid derivatives met no success. Gas chromatography was of no use in resolving the characterization problem. 68 PART V I I I  REFERENCES 1. R. J . Fessenden, J . G. Larsen, M. E. Coon, and J . 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