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Winter 1968
SOME REACTIONS OF ARYLLITHIUMS WITH DIARYL SULFOXIDES
SANDRA YEAGER BAST
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BAST, Sandra Yeager, 1939- SOME REACTIONS OF ARYLLITHIUMS WITH DIARYL SULFOXIDES.
University of New Hampshire, Ph. D ., 1968 Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. SOME REACTIONS OF ARYLLITHIUMS WITH
DIARYL SULFOXIDES
by
SANDRA YEAGER BAST
B. A. Thiel College, 1960
M. S. University of New Hampshire, 1963
A THESIS
Submitted to the University of New Hampshire
In Partial Fulfillment of
The Requirements for the Degree of
DOCTOR OF PHILOSOPHY
Graduate School
Department of Chemistry
February 1968
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis has been examined and approved.
Thesis director, Kenneth K. Andersen Associate Professor of Chemistry
» V O l JJ Alexander R. Amell, Prof. of Chemistry
Q h j a L G L . ______Paul R. Jones, #rof. of Chemistry
Robert E. Lyle, Prof. of Chemistry
David H. Chittenden, Assistant Prof. of Electrical Engineering
h ic u c A . I 11^ t______Date
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS
The author wishes to express her sincere appreciation
to Dr. Kenneth K. Andersen for his encouragement and help in
the direction of this research. The author also wishes to
thank Dr. J. J. Uebel for his assistance with the gas 'ij ‘ chromatographic analyses and interpretation of the nuclear
magnetic resonance spectra which was of immeasurable help
during the absence of Dr. Andersen.
Thanks are expressed to Miss Anne Kohl and to
Dr. Charles M. Wheeler, whose friendship and understanding
were a constant source of encouragement throughout the
author’s stay at the University of New Hampshire. Thanks
are also due to Miss Kohl for the typing of this manuscript.
Financial assistance for this work from the National
Institutes of Health is gratefully acknowledged.
The author is' most indebted to her husband, John,
whose advice greatly furthered the completion of this work.
111• • •
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS
Page
LIST OF TABLES...... vi
S LIST OF FIGURES...... vii
ABSTRACT...... viii
I. INTRODUCTION...... 1
II. RESULTS AND DISCUSSION...... 12
A. Preparation of Symmetrical Diaryl Sulfoxides .. .12
B. The Reaction of jo-Tolyllithium with jo-Tolyl Sulfoxide...... 14
C. The Reaction of Mesityllithium with Mesityl Sulfoxide...... 22
III. EXPERIMENTAL...... 30
A. Preparation of Symmetrical Diaryl Sulfoxides and Derivatives...... 30
1. The Reaction of Grignard Reagents with N,N*-Thionyl di-imidazole...... 30
2. Oxidation of Sulfoxides to Sulfones...... 34
3. Reduction of Sulfoxides to Sulfides...... 35
B. Preparation of m,p’ -Bitolyl...... 35
1. Attempted Preparation by a Diazotization Reaction...... 35
2. The Reaction of £-Tolylmagnesium Bromide with 3-Methylcyclohexanone...... 36
iv
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLES OF CONTENTS (continued)
Page
C. The Reaction of £-Tolyllithium with p-Tolyl Sulfoxide...... 37
D. The Reaction of p-Mesityllithium with Mesityl Sulfoxide...... 41
E. Gas Chromatographic Analyses...... 44
1. Purification of m-jp’ -Bitolyl...... 44
2. Product Analysis of the Reaction of p- Tolyllithium with £-Tolyl Sulfoxide...... 45
IV. SUMMARY...... 51
V. BIBLIOGRAPHY...... 65
v
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES
Page
1. Substituted Diphenyl Sulfoxides and Derivatives...... 32
2. Determination of Weight Factors for Quantitative Gas Chromatographic Analysis...... 49
3. Product Analysis of the Reaction of p-Tolyllithium with £-Tolyl Sulfoxide...... T ...... 50
vi
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES
Page
1. Nuclear Magnetic Resonance Spectrum of ^
2. Nuclear Magnetic Resonance Spectrum of C20H26SO...... 57
3. Nuclear Magnetic Resonance Spectrum of m,p-Bitolyl....58
4. Nuclear Magnetic Resonance Spectrum of Mesityl Sulfide...... 59
5. Infrared Spectrum of C27H32S...... 60
6. Infrared Spectrum of C20H26S^...... ^ 7. Infrared Spectrum of m,£! -Bitolyl...... 62
8. Infrared Spectrum of Mesityl Sulfide...... 63
9. Infrared Spectrum of Di(£-trifluoromethyl)biphenyl. .. .64
vii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT
SOME REACTIONS OF ARYLLITHIUMS WITH ARYL SULFOXIDES
by
SANDRA YEAGER BAST
The mechanism of the reaction of sulfoxides with
organolithium reagents is now known with certainty. Various
mechanisms have been invoked to explain the products ob
served depending on whether the sulfoxide is dialkyl,
aralkyl or diaryl. Previous work by the author concerning
the reaction of phenyllithium with phenyl sulfoxide had
indicated that a sulfonium salt and benzyne were intermedi
ates in the reaction. Other workers had argued in favor of
the formation of a tetracovalent intermediate which then
collapsed to products. The present work was carried out in
an attempt to clarify the mechanism of the reaction of
aryllithium reagents with aryl sulfoxides.
The same para substituent was used on both the aryl
lithium reagent and on the diaryl sulfoxide. If the mechanism
follows a benzyne pathway, then a 4-substituted benzyne
would be expected to be formed and subsequent reaction of
Vlll• • •
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. this aryne with excess aryllithium would lead to two isomeric
biaryls, £,£* -disubstituted and m,£’ -disubstituted. The
m,£’ -isomer could arise only from a 4-substituted benzyne
and not from collapse of a tetracovalent intermediate nor
by a direct nucleophilic displacement of the aryllithium
reagent on an intermediate sulfonium salt nor on the original
sulfoxide. Any of these latter mechanisms would give rise
to only the £,£' -isomer. Generation of a 4-substituted
benzyne was shown to occur in the reaction of £-tolyllithium
with £-tolylsulfoxide. The major products were toluene, £-
tolyl sulfide (98.97o), £,£’ -bitolyl (48.4-607o) and m,£'-
bitolyl (19.7-27.67o) . The formation of m,£'-bitolyl in
significant amounts indicates a predominate aryne mechanism
and excludes a tetracovalent intermediate or nucleophilic
displacement as the only pathway.
For reactions in the literature known to proceed
through an aryne mechanism, the isomer ratios for substitu
tion of a given aryne are virtually constant. With 4-methyl-
benzyne, meta substitution is favored somewhat over para
substitution (58 meta/42 para). The fact that the isomer
ratio obtained in this study is 28 meta/72 para certainly
does not discredit a benzyne mechanism here as well. It,
instead, suggests that although a benzyne mechanism
ix
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. predominates (calculated to be greater than 507,) , an alternate
mechanism may also be taking place. These alternate possi
bilities are discussed.
When there are no ortho-hydrogens on the sulfoxide
or on the lithium reagent, as in the case of mesityl sulfoxide
and mesityllithium, an aryne mechanism cannot occur and
completely different types of products are obtained. The
major products are mesitylene, C20H26SO an°* C27H32S * Gom" plete identification of the last two substances was not
achieved, but possible structures are suggested as well as
possible mechanisms for their formation. Failure to obtain
mesityl sulfide and bimesityl as products serves as evidence
against collapse of a tetracovalent intermediate or a nucleo
philic displacement reaction on mesityl sulfoxide or on an
intermediate trimesityl sulfonium salt.
A new preparation of symmetrical diaryl sulfoxides
has been devised employing the reaction of a Grignard
reagent with N,N' -thionyldiimidazole. This method offers
a convenient synthesis of symmetrical diaryl sulfoxides,
provided the desired Grignard reagent can be made, and may
well be the method of choice for the preparation of some
sulfoxides heretofore unattainable.
x
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION
The reaction of organometallic reagents with sulfox
ides has been shown to result in a variety of products
depending on the nature of the sulfoxide, the particular
organometallic reagent employed, and in some instances, on
the experimental conditions.
When diaryl sulfoxides are treated with sodium
reagents such as phenylsodium, benzylsodium, diphenylmethyl-
sodium, or anthracenyldisodium, the principal products are
those resulting from cleavage of the sulfoxide to a new 1 2 3 sulfoxide (eq. 1) or reduction * to the sulfide accompanied 3b by cleavage ofthe carbon-sulfur bond toform mercaptans ,
disulfides^a,c,c^, or sulfinic acids^c,c* (eq. 2).
0 0 0
W C6H5 + C6H5CH2Na * W C6E5 + C6V CH2C6H5 (1) 0 C6H5L 6H5 + C.HLSH + C.HcSSC.Hc + C,H,.S0oH (2) 6 5 6565 652 Diphenyl sulfoxidewhen treated with sodium amide undergoes cyclization as well as reduction to dibenzothio- phene^’^ (eq. 3). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 + N a ™ 2 ■* + c 6 " 5 n h 2 u s (c 6h 5)2s + C6H5SSC6H5 + C6H5S02H ^ This concommitant reduction and cyclization is the same as 3a that observed by Fuchs and Gross when di-£-tolyl-sulfoxide was treated with potassium metal resulting in dimethyldibenzo thiophene. These same workers also observed molecular 3a complex formation between several diaryl sulfoxides and tritylsodium. Early workers 4 found both alkyl and aryl Grignard reagents to be inert towards aromatic sulfoxides but found them to cause reduction of aliphatic sulfoxides to the /[ a sulfides with olefins formed as by-products (eq. 4). 0 C2H5L 2H5 + C2H5MgBr -» ( C ^ H ^ S + CH2=CH2 (4) 5 Later, Hepworth showed that sulfoxides in general were capable of forming complexes with various Grignard reagents and that the sulfoxides actually accelerated the formation of Grignard reagent. Because these complexes could not be obtained in crystalline form, their exact structure is uncertain but is believed to be [ZR^SO’R'MgX]. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Hepworth also demonstrated the reduction of diphenyl sul foxide, di-isoamylsulfide, and phenylbenzylsulfoxide to the corresponding sulfides by methylmagnesiuiii iodide or phenyl- magnesium bromide. In the hope of observing a 1,4-addition of a Grignard reagent to an a,p-unsaturated sulfoxide analogous to that observed for a,p-unsaturated ketones, Kohler and Potter^ treated benzalmethyl-jD-tolyl sulfoxide with ethylmagnesium bromide (eq. 5). They observed only reductive cleavage to ethyl-£-tolyl sulfide, butane, and 1,4-diphenyl-1,3-buta diene . 0 2C6H5CH=CHSC7H7 + 3C2H5MgBr -> C4H10 + C7H7SC2H5 + C6H5 ^ C6H5 (5) 0 II 2C6H5CH=CHSC7H7 + 3C6H5MgBr C6H5C6H5 + C ^ S C ^ + 0 n n (C6H5)3CCH2SC7H7 + C6H5 C6H5 (6) With phenylmagnesium bromide a small amount of 2,2,2-tri- phenylethyl-£-tolyl sulfoxide was also obtained which con ceivably arose through the expected 1,4-addition product 2,2- diphenylethyl-£-tolyl sulfoxide (eq. 6). When the p-position Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. of the a,p-unsaturated sulfoxide is more sterically hindered g as in the case of 2 ,2-diphenylethylene-£-tolyl sulfoxide , no addition of phenylmagnesium bromide occurs but rather reduction and cleavage to £-tolylphenyl sulfide and 2,2- diphenylethylene £-tolyl sulfide (eq. 7). 0 11 (C6Hs) 2C=CHSC7H7 + CgH^MgBr CgH^SC^ + (C6H5)2C=CHSC7H7 (7) The reduction of dialkyl or aralkyl sulfoxides to 9 10 11 sulfides by Grignard reagents * ’ appears to be a general reaction in which the major products are sulfides derived from the parent sulfoxide but where substitution of the hydrocarbon radical of the Grignard reagent has occurred on the carbon alpha to the sulfur (eq. 8). 0 RSCH3 + R'MgX RSCH2R' (8) R = CH3, C6H5 , 2.-CH30C6H4 , or £-CH3C6H4 R> = alkyl, aryl or aralkyl With dimethylsulfoxide and phenylmagnesium bromide, Sekera et. al.^^a ’C have observed in addition to the expected benzylmethyl sulfide, some cleavage to phenylmethyl sulfide as well as rearranged products, phenylethyl sulfide and £- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. tolylmethyl sulfide. They seem to indicate that the cleavage reaction is caused by impurities present in the 11c magnesium. Their proposed mechanism for the cleavage reaction involves an intermediate salt of a sulfenic acid, its con version to a disulfide and its subsequent reaction with another mole of Grignard reagent (eq. 9 and 10). 0|| j. + j.+ - 2RSCEL + 2R' MgX -> 2R-S-CH0 -> 2R-S-CH0 + R'H (9) 3 ^ | \.\ 2 | 2 ,ii ? 0 M SX si\ \ .Mg-R' X + - 2R-S-CH2 -> 2CH2 + 2RS0MgX 0MgX I---- > RSSR — ' ^ X» RSR' + RSMgX (10) This same mechanism would explain the formation of disulfides, mercaptans, and sulfinic acids obtained by earlier workers. 1-3 ’ 7 ’ 8 This mechanism, however, does not account for the formation of phenylethyl sulfide or £-tolylmethyl sulfide unless it is to be assumed that these arise through an insertion of the carbene into a C-H bond. When R is phenyl or £-anisyl, only sulfides described by eq. 8 are reported. Their proposed mechanism to explain this a-substitution includes a sulfonium ylid (eq. 11). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Although a sulfonium salt might be expected as an intermediate in the reduction followed by a Stevens rearrange- ment 12 to give the product sulfide, Manya 11 and co-workers have shown this not to be the case by the failure of di- methylphenylsulfonium tosylate to yield phenylbenzyl sulfide when treated with phenylmagnesium bromide (eq. 12). -r^ °Ts“ C,H.-S-CH3 + CgHjMgBr - / / - > CgHjSCH^Hj (12) The addition of Grignard reagents to an aromatic 13 sulfoxide was successfully accomplished by Wildi using re- fluxing butyl ether or benzene as solvent in the reaction of arylmagnesium bromides with diphenyl sulfoxide to give triaryl- sulfonium salts (eq. 13). When phenyllithium was used, how ever, the yield of sulfonium salt was almost negligible. nII OtlTJi- + « ArMgBr + C ^ S C ^ — ArS (C g H ^ ,Br Ar = C6H5, m-CH3C6H4, £-CH3C6H4, o,£-(CH^C^ (13) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Organolithium reagents, in contrast to the action of other organometallics, have resulted not only in reduction^ 1 / 1 C 1 /* to the sulfide but to a large extent in metalation * ’ lA'b d 6 16 and some cleavage. ’ ’ ’ From the reaction of thian- 14b threne-5-oxide with butyllithium followed by carbonation, dibenzothiophene and its 1-carboxylic acid were isolated along with thianthrene (eq. 14). 0 1) n-C4HgLi + 2) C0o + 3) H20,H COOH COOH + d - o (14) Under certain conditions some 2,2*-dicarboxydiphenyl sulfide was isolated. It was shown that metalation must have pre ceded reduction since neither dibenzothiophene^a nor 1 A.£ thianthrene . is metalated by butyllithium. Similar results were also obtained when phenoxanthin-10-oxide 1 ^ g c ’ d was treated with butyllithium (eq. 15). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8 COOH 3) H20,H Q “ °“® + Q - ^ Q + C 6H50C6H5 + rnnw — — \ ' — LU(JH COOH COOH n-C^HgSH (15) g Potter observed reduction and cleavage of 2,2- diphenylethylene-jo-tolyl sulfoxide by phenyllithium to give the same products he obtained from the reaction of this sulfoxide with phenylmagnesium bromide, jo-tolylphenyl sulfide and 2 ,2-diphenylethylene-jo-tolyl sulfide (eq. 7). The treatment of optically active arylmethyl sul- foxides with methyllithium16 by Mislow, resulted in recovery of ra'cemic sulfoxide and aromatic hydrocarbon. The racemiza- tion of the sulfoxides is explained by the initial formation of an a-sulfinyl carbanion by the methyllithium, decomposition of this carbanion to^sulfine and aryllithium, followed by re combination of the latter two (eq. 16). The initial anion formation was demonstrated by both carbonation and hydrolysis with deuterium oxide. 0 0 II .+ C6H5SCH3 + CH3Li -> C6H5-S-CH2 ,Li -* CgHjLi + 0 0 II II CH2=S: -» C6H5SCH3 (16) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9 In the only reported instance of reaction of an 17 aryllithium reagent with a diaryl sulfoxide , Andersen has obtained diphenyl sulfide and biphenyl in almost equal amounts when diphenyl sulfoxide is treated with four to five molar equivalents of phenyllithium in ethyl ether (eq. 17-19). The reaction is believed to involve a sulfonium salt intermediate as shown by the reaction of triphenyl- sulfonium bromide with phenyllithium to give the same products and product ratios (eq. 18-19). 0 II + (C6H5)3S OLi“ (17) C.Hc-Li6 5 + C,H,-SC^Hn 6 5 6 5 1 h 2o * 6 5 6 5 + LiOH (19) » C.H,SCcH, + LiOH 6 5 6 5 (2Q) That benzyne was also an intermediate in the reaction was shown by the isolation of 2-phenylbenzoic acid on carbona- tion. It was also shown by the sharp increase in yield of phenyl sulfide with a corresponding decrease in yield of bi- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10 phenyl when the reaction was run in the presence of 1.2 molar equivalents of lithium thiophenoxide (eq. 20). The lithium thiophenoxide successfully competes with phenyl- lithium for the benzyne. 18 Further evidence 19 for the benzyne as an intermediate was obtained by the isolation of triptycene in 357> yield when the reaction was run in the presence of anthracene (eq. 21). Triptycene 19 was also isolated from the reaction of triphenylsulfonium bromide with phenyllithium in the presence of anthracene. + (21) O Franzen 20 et aT. have presented evidence that tri phenylsulfonium bromide and tri(2-methoxyphenyl)sulfonium chloride react with phenyllithium to give the corresponding arynes, but in poor yields. They state that the principal reaction is the formation of an unstable intermediate involv- 21 ing tetravalent sulfur and an exchange reaction (eq. 22) of the aryl groups of the sulfonium salt with the aryl lithium. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11 + + (o -CH30C6H4) 3S + C6H5LiS=± (o-CHgOCgH^SC^ + o-CH3OC6H4Li (22) Other workers have also postulated a similar tetra covalent sulfur intermediate^C ’^,■^a,'^,^, but all these are not concerned with the reaction in question, namely the reaction of sulfoxides with organometallic reagents. Manya lib has shown that the reaction of a Grignard reagent with sulfoxides probably does not involve a tetracovalent inter mediate (eq. 9, 10, 11). The only definitive work on the mechanism of sulfoxides with lithium reagents has been carried out by Andersen^, and his results do not support this conclusion. The present work was carried out in an effort to clarify the mechanism of the reaction of aryl lithium reagents with diaryl sulfoxides. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12 DISCUSSION Preparation of Sulfoxides A variety of methods exist for the preparation of 23 symmetrical diaryl sulfoxides. Oxidation of a diaryl 24 sulfide to the corresponding sulfoxide has been carried 25 out using nitric acid , hydrogen peroxide in glacial acetic 26 27 28 29 29 acid y , ozone , sodium metaperiodate , iodosobenzene , 27 31 potassium permanganate , and N-bromosuccinimide. The oxidation method depends primarily on the availability of the desired sulfide and on the absence of other functional groups which might be readily oxidized as well as the sulfur. Sulfides have been made from the reaction of a Grignard 32 33 reagent with a disulfide or with a sulfenyl halide } and 3 / other workers have utilized the reaction of a sodium thiophenolate with an aryl halide. The latter method re quires refluxing for long periods of time giving only poor to moderate yields and again depends on the availability of the desired thiophenol. The Friedel-Crafts synthesis of sulfoxides has been used extensively by earlier workers using an aromatic hydro carbon, aluminum chloride and either thionyl chloride or sulfur dioxide.^325a,27,35,36 some cases the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13 sulfide^>25a,35,36d^ sulfonic salt^^, or sulfinic acid"^^ in addition to or rather than the sulfoxide is obtained. The action of a Grignard reagent with thionyl , 4,37,38 -t , 6,37 37,38,39 chloride , sulfonyl chlorides * , or sulfites has also led to the production of sulfoxides. Again sulfides are frequently obtained as by-products. Because none of these methods were found to be wholly satisfactory, a new synthesis was devised using N,N’- 40 thionyl-di-imidazole, an intermediate described by Staab , which affords reasonable to good yields of sulfoxide when treated with aryl Grignard reagents (eq. 23). Neither the Grignard reagent nor the N,N*-thionyl- di-imidazole requires isolation or further purification but can be used directly in solution. Because of this, in com parison with other syntheses of diaryl sulfoxides, the method offers a greater ease of work-up and an overall decrease in the time required to obtain product. In most cases merely washing the crude product with cold chloroform or ether gave pure product eliminating the necessity of recrystallization. Seven para substituted diaryl sulfoxides have been made, but the method appears to be generally applicable to the prepara tion of symmetrical diaryl sulfoxides. The only requirement is that the desired aryl halide be capable of forming a Grignard reagent and that the resulting sulfoxide will not Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. react further with the Grignard reagent as in the case of aliphatic sulfoxides. The sulfoxides prepared by this method are listed in Table I. N = \ N = \ ? / = N 0 | N — S-N__ + 2 ArMgBr -> Ar&Ar +2 NMgBr (23) The Reaction of £-Tolyllithium with jj-Tolyl Sulfoxide The reaction of aryllithium reagents with diaryl sulfoxides was carried out using a para substituent on both the sulfoxide and the aryllithium reagent. The stoichiometry of the reaction is considered to be the same as in the unsub stituted case, namely, phenyl sulfoxide and phenyllithium, where three equivalents of phenyllithium are required for one equivalent of phenyl sulfoxide. Under these conditions, a substituted benzyne is produced and two isomeric biphenyls result from the reaction of lithium reagent with the aryne (eq. 24 and 25). R + (24) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15 Li ■> R + R «c k > (25) For the reaction of £-tolyllithium with £-tolyl sulfoxide, preliminary studies showed the best method of analysis to be gas chromatography. In order to establish clearly the identity of the products, it was necessary to synthesize the expected products for comparison of glpc retention times. £-Tolyl sulfide was prepared from the 41 known sulfoxide by iodide reduction. E jE* -Bitolyl* was commercially available and m,£f -bitolyl was synthesized by the reaction of £-tolylmagnesium bromide with 3-methyl- cyclohexanone followed by dehydration and dehydrogenation (eq. 26). (26) *The Chemical Abstracts nomenclature for the bitolyls is 4,4’- dimethyldiphenyl and 3,4'-dimethyldiphenyl. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16 The yields of products were obtained by glpc on Apiezon L using the method of area to weight ratios obtained from known mixtures. With £-tolyllithium and £-tolyl sul foxide, based on the amount of sulfoxide used, £-tolyl sulfide was obtained in 86-98.57. yield, £,£’ -bitolyl in 55- 67.87. yield, and m,£'-bitolyl in 19.7-27.67. yield. It was found by hydrolyzing an aliquot of £-tolyllithium, that as much as 11% £,£’ -bitolyl is formed in the preparation of the lithium reagent. Correction of the yields of £,£* -bitolyl for this amount decreases the value of the £,£’ -bitolyl actually formed by the reaction to 48.4-60% yield. The formation of m,£' -bitolyl could only have arisen through reaction of the lithium reagent with 4-methylbenzyne, thus giving conclusive evidence for the formation of 4- methylbenzyne and definitely excluding a tetracovalent inter mediate as the only pathway. The latter intermediate would have given rise to toluene, £-tolyl sulfide and £,£’ -bitolyl and not m,£’-bitolyl. The predominance of para substitution of the lithium reagent on the aryne, 70-76% para: 24-307. meta or 2.7 £/m, (for corrected yields of £,£> -bitolyl, 69-747. para: 26-317. meta, 2.4 £/m) is not paralled in studies where the same aryne was generated from a £-tolyl halide and amide ion in 43 44 liquid ammonia or piperdide ion in piperdine-ether ; the' Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. observed ratios were 68 meta: 38 para for the amide ion case and ^st 55 meta: « 45 para for piperdide ion case depending somewhat on the particular halide leaving group. Similar ratios of higher meta to para substitution (55 meta: 45 para) were observed for the reaction of 4-methylbenzyne 45 46 with triphenylphosphine or ethanol , where the aryne was generated from a substituted 1,2,3-benzothiadiazole-l,1- dioxide or a substituted arylazoderivative. With potassium phenylacetylide 18 or potassium phenolate 47 the ratio of meta to para substitution is 57:43 and with potassium 48 anilide the ratio is 53 meta: 47 para. Potassium tert- butoxide with jo-tolyl bromide 49 gives a ratio 51 meta: 49 para. The silver salt of 2-chloro-4-methylbenzoic acid reacts with the 4-methylbenzyne derived from it giving an isomer ratio of 62 para: 38 meta The 5-methyl derivative gives the same isomer ratio as well. When various tolyl 51 halides are treated with aqueous sodium hydroxide , the reaction mechanism varies from complete Sn^ to exclusive benzyne depending on the halide leaving group, the concentra tion of hydroxide ion, and the temperature employed. The most favorable case for benzyne formation for para substi tuted halides gives an isomer ratio of 54.5 meta: 45.5 para. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18 It has been reported that when £-tolylfluoride undergoes reaction with sodium hydrazide or sodium methylhydrazide, 52 almost exclusive para substitution results. In these cases it appears that an addition-elimination mechanism is operating rather than an aryne mechanism. With sodium 1,1- dimethylhydrazide, however, the results support an aryne mechanism and again meta substitution is favored over para substitution, 58:42. An aryne mechanism does occur when these hydrazides undergo reaction with £-tolylbromide or £-tolyl chloride with an isomer ratio of 62 para: 38 meta. Although for a benzyne mechanism the isomer ratios are almost constant and essentially independent of the nature of the leaving group, the fact that the isomer ratios obtained for the reaction under study are in essence the reverse of that quoted in the literature does not discredit a benzyne mechanism operating here as well. It instead suggests that although a benzyne mechanism predominates, an alternate mechanism may also be taking place. Assuming that more than one mechanism is taking place, a comparison of our isomer ratios with the average literature value for the isomer ratio of products obtained from nucleophilic substi tution of 4-methylbenzyne (58 meta: 42 para) indicates a 217, yield of £,£’ -bitolyl arising from a benzyne. This suggests that at least 507, of the £,£* -bitolyl is formed by Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 19 a benzyne mechanism. An alternate mechanism would most likely involve a nucleophilic attack of £-tolyllithium on the sulfoxide directly or on the intermediate sulfonium salt. Collapse of a tetracovalent intermediate also cannot be ex cluded. The latter two intermediates would both give all the products observed except m,£'-bitolyl. Attack of £-tolyllithium on a carbon adjacent to the electron-withdrawing sulfoxide or sulfonium group is not un reasonable since £-tolyllithium is a good nucleophile as well as a strong base. A direct substitution of the aryl- lithium reagent on the sulfoxide would lead to a sulfenate anion. Since sulfenic acids are too unstable to be isolated, the resulting products might be in the form of the disulfide, CH 3 - C M ^ O > ™ 3 L 1 > c h 3 ^ Q H O >~C H 3 + (27) 'o' C H s ^ - r «-» CH3- thiol, sulfinic acid, thiosulfonate ester, thiosulfinate 53 ester or sulfonic acid. None of these compounds were obtained. Attack of the aryllithium reagent on a tri-£-tolyl- sulfonium salt could lead to a tetracovalent intermediate Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 20 21 described by Franzen which would collapse to give £-tolyl- sulfide and £,£’ -bitolyl (eq. 28). It could also be expected that a direct nucleophilic attack of £-tolyllithium on an intermediate sulfonium salt displac ing the neutral £-tolyl sulfide and forming £,£’ -bitolyl (eq. 29) could compete with abstraction of an ortho hydrogen by the aryllithium reagent from the same sulfonium salt inter mediate which leads to the expected aryne (eq. 24 and 25). p 3 P ci CH He (29) £-tolyl Li + c h ?<0 ^ Several workers have reported the reaction of dimethyl 5 3 c/. sulfoxide with benzyne to give 2-dimethylsulfoniophenoxide, a (isolated as the picrate), (eq. 30) or £-methylmercaptophenol and £-methylmercaptophenyl ether (eq. 31). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Although this reaction has not been reported for sulfoxides other than dimethyl sulfoxide, no products of this type were observed from the reaction of £-tolyllithium with £-tolyl sulfoxide. It appears quite reasonable that £-tolyllithium would react much faster than £-tolyl sulfox ide with the methylbenzyne formed in the reaction. Also, in no case was unreacted £-tolyl sulfoxide isolated. It .was originally intended to carry out the general reaction indicated by eq. 24 and 25 using both electron- withdrawing (CF^-) and other electron-donating [(CHg^N- ,CHgO substituents as well as using a heterocyclic sulfoxide (3- pyridyl). Unfortunately, the original difficulties en countered in the sulfoxide syntheses and the problems in volved in the analysis of the reaction mixtures precluded this study. Since virtually all of the expected biaryls and some of the sulfides are unknown, authentic samples of all these compounds would have had to be synthesized. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 22 The Reaction of Mesityllithium with Mesityl Sulfoxide The reaction was carried out using a sulfoxide, mesityl sulfoxide, in which a benzyne mechanism could not operate, and it was hoped that the reaction might proceed only as far as formation of a trimesitylsulfonium salt. This was found not to be the case as no sulfonium salt was isolated nor could be detected by the cobalt test for sul- fonium salts. 55 Here, the stoichiometry of the reaction was not actually determined; however, five molar equivalents of mesityllithium were used for each equivalent of sulfoxide. Column chromatography on alumina of the crude reac tion mixture gave three major fractions, mesitylene and two white solids, C2yH22S(I) an^ ^20H2 6 ^ * Fraction I from the nmr (Fig. 1) and ir spectra (Fig. 5) as well as osmometric molecular weight determination. (390) , is believed to have the structure 3_. As in the mechanism proposed for the reaction indicated by eq. 24 and 25, it is possible that Fraction I from the mesityl reaction could have arisen from a sulfonium salt intermediate as well. A Smiles rearrangement^^ of the betaine 2_ would lead to 3. (eq. 32) . Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23 CH CH mesityl L\ CH CH CH3 1 2 CH CHo (32) CH, CH 3 Unfortunately, a trimesitylsulfonium salt has not been reported in the literature, and we were unsuccessful in synthesizing a trimesitylsulfonium salt from mesityl sulfox 36d ide and mesitylene using phosphorus pentoxide. Attempts at preparing a dimesitylsulfonium salt from dimesitylethoxy- 57 sulfonium salt and phenylmagnesium bromide (eq. 33) by other workers 5 8 in this lab resulted in recovery of starting materials. This does not mean that a trimesitylsulfonium salt is incapable of being synthesized nor that it cannot appear as a transitory intermediate during the course of the reaction. Since lithium reagents in their reactions differ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24 CH CH CHS + CH s —CH 3 + 0MgBr --- > rH3 \ Q ) — S-0 tHa/2 (33) somewhat from the behavior of Grignard reagents, it is quite possible that such a salt could have been formed and rapidly disappeared to products, thus escaping detection. Another possible mechanism for the formation of 3_ would involve the sulfoxide directly (eq. 34 and 35). CHol CH mesityl mesityl Li sulfoxide ‘CH, CH CH CH (34) ch3° ch3 mesityl Li OTT 5 1-----> CH^ - S -<0)-CH3 (35) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25 The presumed initial anion formation (4) on one of the ortho methyl groups of mesityl sulfoxide is quite reasonable in light of the electron-withdrawing nature of the sulfoxide group. Oae et al.59 found that deuterium was incorporated in the para methyl group of £-tolylmethyl sulfoxide when it was treated with sodium ethoxide in ethanol (OD) or potassium tert-butyl alcohol (OD), eq. 36. OK That the hydrogens on an ortho methyl group are more acidic than those of a para methyl group is to be expected and is supported by the work of Truce 60 who presumed such ortho carbanion formation when certain mesityl sulfones were treated with n-butyllithium. A Smiles rearrangement^^ follows to give a sulfinic acid (eq. 37). S-£-Tolyl O)— frR'Tolyl <37> IH2-£-Tolyl Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26 Although the sulfone group is considerably more electron-withdrawing than the sulfoxide, anion formation is certainly possible for the sulfoxide as well (eq. 34) and is even greater if a sulfonium salt is the intermediate (eq. 32). In the case of dimesityl sulfoxide with mesityllithium, no analogous sulfenic acid was observed. Since sulfenic acids are too unstable to be isolated, the resulting products might be in the form of the disulfide, thiol, sulfinic acid, 53 thiosulfonate ester, thiosulfinate ester or sulfonic acid. None of these compounds were found upon analysis of the organic layer of the hydrolyzed reaction mixture, although small amounts of oils (total 0.07 g) were obtained which were not characterized. The aqueous layer on acidification with hydrochloric acid produced a small amount of tarry substance and the filtrate had a definite "sulfur compound" odor. No products other than the two white solids previously named were able to be identified from the reaction mixture. The identity of Fraction II is discussed later. With reference to the second mechanism postulated for the formation of 3^ (eq. 34 and 35), resonance stabiliza tion of the anion 4 is conceivable involving structure jj. The product can then be explained by attack of a second molecule of mesityllithium on the intermediate with subse quent loss of the sulfoxide oxygen. Just how this oxygen Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27 is lost is not readily explained by this author nor by authors who suggest a mechanism for the loss of oxygen from sulfoxides when treated with Grignard reagents^^a,^> (eq. 9, 10, 11 and 38). 0 OMgBr CH3S0 + CH30H II CH3SCH3 + 0MgBr -> CH3-S-CH3 (38) A CH3SCH3 + 0OH The only explanation to be offered by any of the authors is the possible formation of a lithium salt or of mesitol. Yet a third mechanism similar to that described by fi 0 Truce (eq. 37) could be invoked to explain the formation of 2 (e9 • 39). ch3 ch3 CH - CH, OLi CH, CH 6 mesityl Li (39) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28 Initial anion formation 4, is reasonable as previously explained and it is also quite reasonable that mesityllithium would react with the sulfenic acid salt 6_ to give 3^ This last step is analogous to the displacement of halide or alkoxide from sulfenyl compounds by nucleophiles. 53 Alternate structures for Fraction I can also be postulated. ch3 ch3 CH CHr 8 chI ^ cHc CH CH — s— c: CH CH CH CH Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29 The nmr spectrum of Fraction I indicates three aromatic methyl peaks 2.24,15; & 2.13,3; & 1.99,6), a benzyl peak (S 3.98,2), and two aromatic peaks ( S 6.79,5; S 6.09,1). Compounds 8^ and 9_ can be ruled out since they contain four and one benzyl protons respectively. Comparison of methyl peak positions for mesityl sulfide [ortho ( S 2.17) and para ( & 2.22)], mesitylene (^> 2.22) and ditolylmethane (S 2.27) would lead one to expect only two methyl peaks in the nmr spectrum for compound ]_. On the basis of the data obtained, structure 3_ is favored. Fraction II from the reaction was not able to be characterized other than it is a sulfoxide having the elemen tal analysis given and a molecular weight of 314 (mass spec trum) . Because of the large number of alkyl protons shown in the nmr spectrum (Fig. 2), the possibility of reduction of an aromatic ring may be indicated. The products obtained from the reaction clearly in dicate that a tetracovalent intermediate is not operating here as this intermediate would lead to mesityl sulfide and bimesityl, neither of which were found. It is also clear from the structures of the reactants that a benzyne mecha nism cannot occur. With certainty this reaction must follow an altogether different course of reaction and further work is necessary to determine the mechanism. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 30 EXPERIMENTAL The infrared absorption spectra were obtained using a Perkin-Elmer Model 337 grating infrared spectrophotometer. The nuclear magnetic resonance spectra were obtained using a Varian Model A-60 nuclear magnetic resonance spectrometer. Microanalyses were determined by M-H-W Laboratories, Garden City, Michigan. The boiling points and melting points are in degrees centrigrade and are uncorrected. Gas chromatographic data are listed separately under that section. Preparation of Symmetrical Diaryl Sulfoxides All of the sulfoxides in Table I were prepared by the addition of a solution of N,N’-thionyl-di-imidazole to a previously prepared solution of the desired Grignard reagent according to the following general directions. Thionyl chloride (12 g, 0.10 mole) was added drop- wise with stirring and cooling in an ice bath to a solution of imidazole (28 g, 0.41 mole) in 250 ml of anhydrous tetra- 40 hydrofuran. A white precipitate formed immediately. After cooling for several minutes, the reaction mixture was rapidly filtered by suction under a nitrogen atmosphere. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The clear filtrate was added dropwise over a fifteen-minute period at room temperature to a Grignard solution made from magnesium (9 g, 0.38 g at) in 50 ml of anhydrous tetrahydro- furan and 0.33 moles of the desired aromatic halide in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for an hour and then hydrolyzed by pouring into 400-ml of an ice-dilute hydrochloric acid mixture. The organic and aqueous layers were separated and the aqueous layer extracted with three 100 ml portions of diethyl ether or chloroform. The combined extracts were washed with 100-ml of saturated sodium bicarbonate solution, separated, and again washed with 100 ml of water. The organic solution was dried (MgSO^) and the solvent removed using a rotary evaporator. The residue crystallized on cooling and, in most cases, merely washing with cold ether yielded pure product. Recrystallization solvents are in cluded in Table I. Nmr and ir spectra and melting points were consistent for all the compounds listed. The sulfoxides were oxidized to the known sulfones using hydrogen peroxide in acetic 64 acid and reduced to the known sulfides using sodium iodide 41 in hydrochloric acid solution. The sulfoxides prepared by this method, their derivatives, and melting points are listed in Table I. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table I. Yields and Melting Points of Substituted Diphenyl Sulfoxides and Derivatives Recrystal Recrystal Recrystal Diaryl % Mp lization Sulfone lization Sulfide lization Solvent MP?°Ca ,_ Solvent Solvent Sulfoxide Yield °Ca Mp.,°Ca . Phenyl 35 69.5-70.5 ether 124.5-127 EtOH (70.5)36a (125)67 j)-Tolyl 40 94-95 ligroin 157-158 CCl, 56-57 MeOH 36b,68 (92)36b (159) (56)36b £-Anisyl 60 97-98.5 acetone 128-129 EtOH 43.5-44 EtOH (96)25a (129)36d (46)25a’34b Mesityl 84 153.5-154 acetone 201-202.5 EtOH 91.5-92.3 EtOH 36h 60a (153.5-154) (203.5-205) (91-92)60a acetone b b £-N,N-Di- 50 162 36c methyl- (151-152) aminophenyl 3-pyridyl 2 oil £-Trifluoro- 4 oil methyl- phenyl a) Literature mp are given in parentheses. b) The sulfoxide decomposes in acid solution to sulfur dioxide and N,N-dimethyl aniline. With £-trifluoromethylphenyl sulfoxide and 3- pyridyl sulfoxide, the Grignard reagent was prepared using a modification of the entrainment method described by Overhoff and Proost.^ Ethylene dibromide was used instead of ethyl bromide. Evidence of product formation was obtained for these two sulfoxides; 3-pyridyl sulfoxide Showed a band for sulfoxide (1060 cm in the ir spectrum. (For £-tri- fluoromethylphenyl sulfoxide, the trifluoromethyl absorption occurs in the same region of the ir spectrum as the sulfoxide absorption). Both sulfoxides gave a positive test with Dragendorff solution. 66 It should be noted that Dragendorff solution also gives a positive test with 3-bromopyridine and other amines (pyridine, £-bromo-N,N*-dimethylaniline). Con sequently, only the ir spectrum is conclusive for the 3- pyridyl sulfoxide. These sulfoxides could not be obtained pure from contaminating oils either by distillation under reduced pressure or recrystallization from a variety of solvents. Column chromatography on alumina of the crude £- trifluoromethylphenyl sulfoxide gave four fractions. Frac tion I, mp 91-93 (methanol), gave a negative test for sulfoxide with Dragendorff solution 66 and was shown to be £,£* -ditrifluoromethyldiphenyl, presumably formed during preparation of £-trifluoromethylmagnesiumbromide. Nmr Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (CCl^) b 7.7 (s, aromatic H). Anal, calcd. for C^HgFg: C, 57.967,; H, 2.767,; F, 39.3%. Found: C, 58.66%; H, 2.81%. Fraction II (mp 85-91) gave an amorphous powder on attempted recrystallization. The test with Dragendorff solution 66 was negative indicating the absence of sulfoxide. Further identification was not carried out. Fraction III was a yellow oil which could not be obtained solid but which did give a positive test with < Dragendorff solution indicating it was the sulfoxide. Fraction IV produced a water soluble white solid (mp 330°) which gave a negative test for sulfonium salt with cobalt solution. 64 Oxidation of Sulfoxides to Sulfones To 0.007 mole sulfoxide dissolved in glacial acetic acid was added 10 ml 30% hydrogen peroxide and the mixture was heated until the volume was reduced to one-half its original volume or to 50 ml, whichever was the smaller volume,. Water was added to precipitate the sulfone which on recrystallization from the appropriate solvent (listed in Table I) gave pure product. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 41 Reduction of Sulfoxides to Sulfides To 0.015 mole sulfoxide in 30 ml glacial acetic acid and 10 ml concentrated hydrochloric acid was added sodium iodide (9 g, 0.06 mole). The mixture was stirred at 100°C for four hours, cooled, and decolorized with a saturated sodium metabisulfite solution. The sulfides reported were all recrystallized from ethanol. Preparation of m,£' -Bitolyl An attempt to prepare m.,2/ -bitolyl by a diazonium coupling reaction was made using the method of Gomberg and 69 Pernert. m-Toluidine (13.5 g, 0.125 mole) dissolved in 32 ml concentrated hydrochloric acid and 32 ml water was cooled to 0-5°C by the addition of ice. A solution of sodium nitrite (9.3 g, 0.135 mole) in 20 ml water was slowly added to this. This solution was added all at once to toluene (90.3 ml, 78 g, 0.85 mole) in 35 ml 10 M sodium hydroxide. The temperature was kept at 0-5°C for one hour; then the mixture was stirred at room temperature for 5 hrs. The organic and aqueous layers were separated and the organic layer was steam distilled. The organic and aqueous layers of the distillate were separated, the organic layer dried (MgSO^) and distilled under reduced pressure. No clear separation was obtained. Glpc on 207o carbowax 20 M showed at least two distinct materials to be present. It was later Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 36. found using authentic samples of -bitolyl and £,£' - bitolyl, that these two bitolyls cannot be separated on a 207c carbowax 20 M column. Density measurements and refrac- tive indices 70 of fractions collected did not provide a distinction between m,£'-bitolyl and n^m'-bitolyl. Glpc on 207. SE-30 column also gave 2 major peaks. The reaction was repeated using £-toluidine and again no good separation and identification of products could be obtained. An unambiguous synthesis of m,£’ -bitolyl was carried 42 out according to the method of Ito and Hey. 3-Methylcyclohexanone (16.4 g, 0.146 mole) in an equal volume of anhydrous ether was added dropwise to a solution of £-tolylmagnesium bromide made from £-tolyl- bromide (25 g, 0.145 mole) and magnesium (3.6 g, 0.15 mole) in 200 ml of anhydrous ether. The reaction mixture was" heated on a steam bath for one-half hour and then hydrolyzed with 150 ml of 6 M sulfuric acid. The layers were separated, the organic layer dried (MgSO^), and the solvent removed using a rotary evaporator. Vacuum distillation of the residue gave 16 g of the cyclohexene derivative (bp 130- 144/3.5 mm, 0.087 mole, 59.67o yield). The appearance of a vinyl proton in the nmr indicated dehydration to have already occurred. The derivative was heated with sulfur Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (5.3 g, 0.165 mole) in an equal volume of quinoline at 250°C for 2 hrs, then the mixture was hydrolyzed with 150 ml 1 M sulfuric acid. The hydrolyzed mixture was extracted with five 100-ml portions of ether and the extracts washed with 100 ml of 1 M sulfuric acid followed by 100 ml of water. The organic extracts were dried (MgSO^) and the solvent removed using a rotary evaporator. The residue was distilled under reduced pressure three times and a fourth time at atmospheric pressure. The fraction boiling at 260-263° was further purified by preparative glpc using a 20* x 3/8" 207. carbowax 20 M on Chromsorb W (80/100) column. For details see the section on gas chromatographic analyses. The yield of m,£'- bitolyl was 2.17 g (0.012 mole, 27.67.); n ^ 1.5900 (lit. value n ^ 1.5968)^; uv max (95% C2H^0H) 253 rn^i (£ 20400); ir (neat) 1780 (meta), 780 (meta) and 822 cm ^ (para) (Fig. 7); nmr (CCl^) & 7.2 (m,8) and h 2.28 ppm (s,6) with a shoulder at S 2.25 ppm (Fig. 3). The Reaction of £-Tolyllithium with £-Tolyl Sulfoxide The preparation of £-tolyllithium was carried out 71 according to the procedure described by Vogel. Lithium wire (1.6 g, 0.232 mole) cut in small pieces was added to 35 ml of anhydrous ether in a 250-ml three-neck round bottom flask fitted with a dropping funnel, stirrer and condenser. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.8 A solution of freshly distilled 4-bromotoluene (17.9 g, 0.105 mole) in 35 ml of anhydrous ether was added dropwise; the mixture was heated at reflux for 45 min after the addition. The flask was cooled to room temperature and £- tolyl sulfoxide (4.8 g, 0.021 mole) in 150 ml of anhydrous ether was added over a half-hour period. The reaction mixture was refluxed for an additional half hour, then hydrolyzed by pouring into 300 ml of an ice water mixture. The organic and aqueous layers were separated and the aqueous layer extracted with three 100-ml portions of ether. The extracts were dried (MgSO^) and the solvent removed using a rotary evaporator. Vacuum distillation afforded no clear separation of products. Column chromatography on alumina also gave mixtures of products. Tolyl sulfide and £,£’-bitolyl were separated and collected by preparative glpc using a 5’ x 1/4" column (207> SE-30) . See the section on gas chromatographic analyses for details. Fraction I contained a small amount of liquid which could not be characterized. It was later shown to be m,2.’ - bitolyl using a 20' x 1/4" column (5% Apiezon L). Fraction II (mp 115-119°) after recrystallization from methanol (mp 119-120°) was identified as £,£« -bitolyl; mixed melting point with an authentic sample, 119-120°. Fraction II (mp 43-53°) was partially contaminated with Fraction II because of Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. condensation and mixing in the collector. Oxidation with 64 hydrogen peroxide - acetic acid gave £-tolyl sulfone , mp 159-160°, lit. mp 159.^ Programming from 150-200° (10°/min), did not give a better separation of Fraction I from solvent. Repetition of the above gave 7.8 g product. Glpc on Apiezon L showed the mixture to consist of 53.3% tolyl sulfide (4.15 g, 0.018 mole, 86%), 33.2% £,£'-bitolyl (2.59 g, 0.0142 mole, 67.8%) and 13.5%, m,^-bitolyl (1.05 g, 0.0058 mole, 27.6%, yield). The final yields are based on sulfoxide reacted. Subsequent runs were made using lithium dispersion (200 ji) instead of lithium wire. The exact amount of lithium used in each case was not; known; however, an excess was always used as shown by the presence of unreacted lithium. A third run gave 7.9 g of product. Glpc on Apiezon L indicated 60.4%, of tolyl sulfide (4.77 g, 0.021 mole, 98.9%,), 30.3%, £,£’ -bitolyl (2.4 g, 0.013 mole, 63%) and 9.3% m,£'- bitolyl (0.75 g, 0.004 mole, 19.7%, yield). Runs 4 and 5 were carried out as previously described using half-molar quantities of reagents with the same quantity of solvent. Analysis of 4 (3.6 g) by glpc on Apiezon L showed 59%, tolyl sulfide (2.32 g, 0.010 mole, 97.2%, yield) 29.4% £,£' -bitolyl (1.04 g, 0.0057 mole, 55% yield) and 11.6% m,^-bitolyl (0.42 g, 0.0023 mole, 22.1%, yield). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 40 The reaction mixture from run 5 was sublimed to give a partial separation. Both tolyl sulfide and £,£* -bitolyl sublimed and the sublimate also contained a small amount of m,]}’ -bitolyl. The sublimate (1.05 g) was analyzed by glpc on Apiezon L and was shown to contain 60.4% tolyl sulfide (0.63 g, 0.0027 mole, 26.5%, yield) and 39.67. £,£' -bitolyl (0.42 g, 0.0023 mole, 22% yield). The residue was identified as m,£' -bitolyl from its ir spectrum (0.08 g, 0.0004 mole, 4.23% yield). On hydrolyzing an aliquot of £-tolyllithium, as much as 11% £ , £ ’ -bitolyl was formed in the preparation of the lithium reagent. Corrected yields of £,£* -bitolyl are listed in Table III. The results from run 5 are not as reliable as those from runs 2 through 4 because of greater possibility of material loss through multiple operations. Consequently only runs 2 through 4 were considered in determining the ratio of addition of £-tolyllithium to 1-methyl-3,4-benzyne. Substitution in the 4 position is favored over the 3 position 2.7 to 1 or 70-76% 4 substitution to 24-30% 3 substitution. The corrected ratio is 2.4 or 69-74%, 4 substitution to 26-31%, 3 substitution. All these results are collected in Table III in the section on gas chromatographic analyses. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 41 The Reaction of Mesityllithium with Mesityl Sulfoxide The same apparatus and general procedure as used for the reaction of jo-tolyllithium with £-tolyl sulfoxid£ were employed. Mesityl sulfoxide (6.0 g, 0.021 mole) in 100 ml anhydrous ether and 50 ml of anhydrous tetrahydrofuran was added dropwise over a half-hour period to an ether solution of mesityllithium made from freshly distilled mesityl bromide (20.9 g, 0.105 mole) in 35 ml of anhydrous ether and excess lithium dispersion in 35 ml of anhydrous ether. The solu tion immediately turned red-orange. The reaction mixture was stirred at room temperature for two hours and then hydrolyzed by pouring into 400 ml of an ice-water mixture. The organic and aqueous layers were separated and extracted with two 100 ml portions of ether and two 100-ml portions of chloroform. The combined organic layers were dried (MgSO^) and the solvent removed using a rotary evaporator to give 17.9 g of a yellow oil. The cobalt test for sulfonium salts 55 was negative for both the aqueous layer and the yellow oil. The residual oil was chromatographed on 250 g of neutral alumina. Rinsing the flask with acetone caused the formation of a yellow precipitate (mp 200°) which was shown to contain sulfur by a sodium fusion test. Infrared and nmr spectra indicated the presence of aromatic protons ( b 6.84 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 42 ppm) and aromatic methyl groups ( & 2.25 ppm) but further identification could not be made. Tic on alumina G (chloro form) of both the yellow precipitate and the residual oil (three spots each) clearly indicated the absence of mesityl sulfide and mesityl sulfoxide. Attempts to recrystallize the yellow solid using various solvents failed. Column chromatography of the oil gave two distinct fractions and varying amounts of oils. Fraction I (8.9 g) was shown by comparison of retention times with knowns using glpc (20* x 1/4" 5% Apiezon L on Chromsorb W 80/100, column temperature, 160°) to contain mesitylbromide, mesi- tylene and small amounts of n-hexane, the eluent- Fraction II gave 1.01 g of white solid, mp 155.5-159°. After two recrystallizations from acetone, the mp was 160-161°; osmometric molecular weight determination in toluene, 390 (calcd. 388). Anal. calcd. for C27H22S: C, 83.51; H, 8.25, S, 8.25. Found: C, 83.50; H, 8.42, S, 7.98. The ir spectrum (Fig. 5) (CCl^) showed no sulfoxide or sulfone absorption. Oxidation of a small portion with hydrogen peroxide-glacial acetic acid gave the sulfone [ir (CC14) 1330 cm-1 and 1140 cm"1 ( > S02); mp 142-166°] thus indicating the initial presence of a sulfide. The nmr (Fig. 1) (CCl^) spectrum gave six peaks: & 2.24 (s,15), k 2.13 (s,3) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 43 ^1.99 (s,6 ) all aromatic CH^; <$3.98 (m,2, 0CH^); 8 6.79 (m,5) and£ 6 .09 (m,l) both aromatic protons. The above reaction was repeated using one-half the molar quantities and adding the sulfoxide to the mesityl- lithium as a slurry in 100 ml of ether. Three fractions as well as small amounts of oil were obtained after column chromatography on 200 g of neutral alumina. Fraction I was shown to be mesitylene with some n-hexane by glpc, yield 5.53 g. Fraction II gave 0.64 g of the white solid des cribed above, mp 160°, (0.0017 mole, 15.77o yield). Fraction III contained 0.21 g of a white solid, mp 133.5-134.5°. The nmr spectrum (Fig. 2) indicated several different kinds of alkyl protons in the ratio of 10 alkyl to 1 aryl proton. The ir spectrum (Fig. 6) indicated the presence of a mesityl group ir (CC14) 2000, 1720, 1270, 1250, 1070, 1030, 850 and 700 cm ■*") and possible sulfoxide or ether linkage (1070 and 1030 cm ). A positive sulfoxide test was obtained with Dragendorff solution. 66 From the relative intensities and positive sulfoxide test the 1070 cm ^ band in the ir spectrum -1 must be due to the mesityl group and the 1030 cm band due to the sulfoxide group. Anal, calcd. for C2QH26SO: C, 76.43; H, 8.28; S, 10.18; 0, 5.09. Found: C, 76.57; H, 8.17. Mol. wt. (mass spectrum) 314. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Neither Fraction II nor III was further identified, although a possible structure for II is suggested. 72 Gas Chromatographic Analyses All glpc analyses were carried out using an Aerograph A90-P3 gas chromatograph with helium carried gas at a pressure of 65 lb/in. Because of the rather high boiling points of all the compounds analyzed, it was necessary to employ high injector and detector temperatures to prevent condensation of these compounds. In preparative work, on- column injection of the samples was used. Fractions were collected using no additional cooling other than air cool ing as an ice bath or Dry Ice-acetone bath caused aerosol formation. For comparison of retention times for identifi cation, known £,£’ -bitolyl was commercially available, and £-tolyl sulfide and m,£’-bitolyl were synthesized as des cribed in earlier sections. Purification of m , £ ’ -Bitolyl Repeated distillation of m , £ ’ -bitolyl, prepared as described in an earlier section, failed to give a single product. Preparative scale glpc of the fraction boiling 260-263° on a 20' x 3/8" column packed with 207o Carbowax 20 M on Chromsorb W (80/100) afforded pure material. The conditions employed were: Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 45 Injector 260°C, Detector 285°C, Column 200°C Collector 245°C, Flow rate 300 ml/min, Current 190 ma, Attenuator 32, Sample size 300 p i The adjusted retention time of m,£J-bitolyl was 90 minutes. Product Analysis of the Reaction of Tolyllithium with Tolyl Sulfoxide Difficulty was encountered in finding a column suitable for both qualitative and quantitative work. At best only partial separation of m.,2 * -bitolyl and £,£’ - bitolyl could be obtained. Using several columns, the reaction products were identified and the yields of each were obtained. In analyzing product mixtures, sufficient toluene was added to dissolve the solid residue. Work on an analytical scale with a 5’ x 1/8" column packed with 20% carbowax 20 M on Chromsorb W (80/100) gave a good separation into two major peaks when manually programmed from 150°C to 200°C (10°/min). On a preparative scale (20* x 3/8" or 10» x 1/4") however, the long retention time (2 hr. 45 min) seemed prohibitive. By comparison of retention times with knowns, the latter peak was shown to be £-tolyl sulfide. Since m,^-bitolyl and £,£' -bitolyl have identical retention times under the conditions used, the identity of the earlier peak could not be determined. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 46 It is important to note that for a known mixture of m,£’ -bitolyl, £,£» -bitolyl and £-tolyl sulfide, the sulfide has a smaller area to weight ratio than the bitolyls necessi tating either a larger quantity of sulfide in the mixture or a larger sample size to ensure its appearance on the chromat ogram. More positive identification of the products was obtained using a 5’ x 1/4" column (20% SE-30 on Chromsorb W (60/80). The following conditions were used: Injector 320°C, Detector 355°C, Column 230°C, Collector 310°C, Flow rate 60 ml/min, Current 180 ma, Attenuator 128, Sample size 200 j i l . Preparative scale gave three major fractions: adjusted retention times - 6 min, 10 min, and 18 min. The first fraction was a colorless liquid which could not be efficiently collected. It was also highly contaminated with toluene used as solvent. The other two fractions were collected and identified by melting point, infrared and nmr spectra. Tolyl sulfide was also converted to the sulfone. The second fraction was the £,£’ -bitolyl and the last fraction the £-tolyl sulfide. In an attempt to prove the identity of m,£'-bitolyl and to find a column which would separate all three compo nents and thus allow for quantitative analysis of the reac tion mixtures, several columns were tried. Virtually no separation was obtained using a 10> x 1/4" column packed Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 47. with 107o Bentone 34 on Chromsorb W (60/80) employing a variety of conditions and it appeared that some material remained on the column. This may have been due in part to the lower column temperature necessitated by the column substrate (max temp. 200°C). The maximum temperature used was 180°. Only partial separation and very long retention times were obtained using a 10’ x 1/4" column packed with 107. Apiezon M on Chromsorb W (60/80) . The isomeric bitolyls were not completely resolved but were separated sufficiently from each other and from tolyl sulfide to allow identification and yield analysis using a 20' x 1/4" Column packed with 57o Apiezon L on Chromsorb W (80/100). Conditions: Injector 325°C, Detector 345°, Column 220°, Flow rate 125 ml/min, Current 180 ma, Attenuator 2, Sample size 1 j i l . Adjusted retention times: m,]}' -bitolyl 21.2 min, £,£’ -bitolyl 22.2 min, £- tolyl sulfide 47.8 min. Positive identification was shown by comparison of retention times with knowns. Quantitative analyses of the reaction mixtures were carried out using the method of area to weight ratios and employing correction factors, K, predetermined from knowns. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 48 An TJe -r- = K rrr- where A = area of component Ab Wb r W = weight of compound s = sulfide standard b = bitolyl Peak areas were measured by height times the half-height width. Normalization gave the weight precentage of each component. The results are summarized in Tables II and III. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced Table II. Determination of Weight Factor co Ptt •rl rP C +J £ o 4-1 rH cd u o o co 4-1 U ov O m o iH CO r-l CO as CO o CTv •H pq 4-1 CM 0 ai 1 n 49 ) 4 . 2 ( (2.18) (2.79) Substi- (2.18) (4.6) 2.7 27.6% 27.6% 2.5 19.7% 19.7% 3.2 22.1% 22.1% 2.5 4.23% 5.2 13.5%(1.05g) 13.5%(1.05g) 9.3%(0.75g) 9.3%(0.75g) 11.6%(0.42g) 11.6%(0.42g) 0.08g (60%) (55.3%) (48.4%) 67.8% 67.8% mole 0.0058 (19.4%) 63% 63% mole 0.004 55% 55% mole 0.0023 . 22% 22% mole 0.004 4 mole) through 2 0.0020 (0.0126 mole) (0.0126 (0.0116 mole) (0.0116 33.2%(2.59g) 0.0142 mole 0.0142 (0.0051 mole) (0.0051 0.013 mole 0.013 ( 30.3%(2.4g) 30.3%(2.4g) 0.0057 mole 0.0057 29.4%(1.04g) 29.4%(1.04g) 39.6%(0.42g) 39.6%(0.42g) mole 0.0023 h h tution^ % 86 Yield £,£r-Bitolyl Yield0 nbp*-Bitolyl Yield Ratios p/m 0.018 mole 0.018 0.021 mole 0.021 98.9% 0.010 mole 0.010 97.2% 0.0027 mole 0.0027 26.5% Table III. Product Analysis jo-Tolyllithium. with jo-Tolyl Sulfoxide withjo-Tolyl Table III. Analysis jo-Tolyllithium. Product Total Total £-Tolyl 7.8 g 7.8 53.3%C4.15g) 7.9 g 7.9 60.4%(4.77g) Yield Sulfide3 3.6 3.6 g 59%(2.32g) 1.05 g 1.05 60.4%(0.63g) Run Ratio of para substitution to meta substitution: meta Ratio para substitution to substitution: of corrected ; (70-76%)p/(24-30%)m (69-74)p/(26-31)m mixture, Weight glpc a) percent in present component each of £-tolyl- preparation in the formed of -bitolyl the Yields based b) on reacted, sulfoxide £,£* are Yields corrected c) parentheses in for lithium. -bitolyl. £,£r Ratios yields are corrected parentheses in of Order d) e) for sample; some m,£’-bitolyl may well have been lost on standing, well may have werem,£’-bitolyl been some on standing, lost -bitolyl £-Tolyl £,£* and f) sulfide mixture. reaction the fromsublimed was analyzed Only by sublimate the glpc. of Because loss Meanvalue ratios of encountered through multiple operations and possible loss of m,£’ -bitolyl during the sublimation, during sublimation, the -bitolyl multiple m,£’ and possible encountered operations through of loss these yields not are yields as considered as reliable these Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 51 SUMMARY During the course of this study of the reaction of aryllithium reagents with diaryl sulfoxides, because many of the starting sulfoxides were unavailable or not readily ob tainable from existing synthetic methods, a new preparation for symmetrical diaryl sulfoxides was devised employing the reaction of a Grignard reagent with N,N’-thionyl-di-imidazole. This method offers a convenient synthesis of symmetrical diaryl sulfoxides, provided the desired Grignard reagent can be made, and may well be the method of choice for the prep aration of some sulfoxides heretofore unattainable. Although it was not possible to elucidate completely the mechanism of the reaction of aryllithium reagents with diaryl sulfoxides, considerable groundwork has been laid for further work on this question. It is clear that an aryne mechanism, although perhaps not exclusive, predominates when there are ortho hydrogens available on the sulfoxide. The fact that mesityllithium with mesityl sulfoxide, which cannot undergo a benzyne mechanism, gives altogether differ ent types of products further supports this finding. From the isomer ratios of substituted biphenyls obtained from the reaction of £-tolyllithium with £-tolylsulfoxide, a substitu Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 52 tion of aryllithium on an intermediate sulfonium salt or the involvement of a tetracovalent intermediate can, at most, play only a small part in the reaction. A direct substitu tion of the aryllithium reagent on the sulfoxide has been logically ruled out. This method of generating arynes may prove quite useful synthetically especially since it has the added advantage that one of the products, the diaryl sulfide, can be readily oxidized back to starting material. This reac tion would be of particular value in Diels-Alder type reac tions in which the possibility of isomer formation is less than that for a substitution reaction. 49 Except for one reported case where substituted 6 X triptycenes have been made using an aryne mechanism, benzyne and substituted anthracenes have always been used. For certain substituents and particular substitution patterns, it may well be more convenient to use a substituted benzyne instead of a substituted anthracene. This is the method Cadogen has used 49 , however, his yields of substituted triptycenes are low. Perhaps the only easier synthesis of benzyne is through the diazotization of anthranilic acid and subsequent decomposition of the benzenediazonium carboxylate; however, little work has been done using substituted anthranilic acids. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. It would seem that the desired substituted halides would be more readily obtainable than the desired anthranilic acids. It is evident that the reaction of mesityllithium with mesityl sulfoxide follows neither a benzyne nor tetra- covalent intermediate mechanism. Several possible mechanisms are suggested to explain the observed products. Further work is necessary to establish the mechanisms of this reac tion. Suggestions for further work in this area: 1. The reaction could be run with the other sul foxides originally intended to be studied and the isomer ratios obtained compared with those in the literature. For analysis of these reactions the expected biaryls would have to be synthesized. Presumably the same method as used for the preparation of m,£’ -bitolyl could also be used. In some cases it would also be necessary to synthesize the desired substituted cyclohexanones. An alternate method for the preparation of the unsymmetrical biaryls using a monoether of dihydroresorcinol might be more convenient for the 62 preparation of some m,]!’ -disubstituted biphenyls (eq. 40). OEt 5% R-M 0 r 2m > (40) 9 * R 1 Ri Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 54 2. The reaction of £-tolyllithium with a tri-£- tolylsulfonium salt would serve as a further check on the appearance of a sulfonium salt intermediate in the reaction of £-tolyllithium with £-tolyl sulfoxide. If the same isomer ratio of bitolyls is produced in each case, then if a mechanism other than an aryne mechanism is operating, it must occur past the sulfonium salt stage. If different ratios are obtained, then the possibility of a second mechan ism operating in the sulfoxide case must occur before the sulfonium salt stage or may indicate that a sulfonium salt may not be an intermediate in the reaction. 3. The extent to which an aryne mechanism operates in the reaction of aryllithium with diaryl sulfoxides could be shown by trapping the aryne as a Diels-Alder adduct. Both furan and 1,3-diphenylisobenzofuran are known to be better 63 trapping agents than anthracene for benzyne. The adducts with furan could readily be converted to substituted naphthalenes and the isobenzofuran adducts to substituted anthracenes. Host of these products should be known or readily identified. 4. For the reaction of mesityllithium with mesityl sulfoxide, a complete product analysis should be made in cluding those products not previously isolated from the acidified aqueous layer. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 55 5. The reaction of phenyllithium with mesityl sulfoxide could conceivably shed light on the reaction mechanism. If a sulfonium salt is formed, it would now be possible for a benzyne mechanism to occur and the major expected products would be benzene, mesityl sulfide, ~ bitolyl and m,£’ -bitolyl. Because of possible exchange of aryl groups of the phenyllithium with the dimesitylphenyl- sulfonium salt, it might also be expected that mesitylene, mesitylphenyl sulfide, diphenyl sulfide, and mesitylbenzene would be formed. If no exchange occurs before the reaction takes place, analysis of the reaction mixture should pose no particular problem. If exchange does occur, then the wider variety of products may make the product analysis difficult to carry out. There is the advantage that all of these products are known. 6 . A check for initial anion formation when dimesityl sulfoxide is treated with mesityllithium could be made by hydrolyzing the reaction after a very short reaction time with deuterium oxide. The position of deuteration could be determined by nmr spectroscopy. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 56 o CM CO CO COCM P'. CM •rl r-l 00 i Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 57 o CM O CO CO VO pTo aCM o •Uu O a) coa a) o c cd o« CO(U Pc3 CJ •rl 4-10) a VO bO 3 M cd0) iH o 5§ CM cu u 3 bO •rl PH CO Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 58 CM 1—I i—I 0 •H4-J M1 P4•\ si m o •Mu o a) a co ocd ccJa G o CO (U ft o •H 4-1 aCD VO t>0 u CD CD rHO 3 53 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 59 o CM CO VO Figure Figure 4. Nuclear Magnetic Resonance Mesityl Spectrum of Sulfide Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 60 »n <± 00 o o o o o oo o O CT\ O o o tn iry (N m a) ooQ O •H CO 0 0 P>4 aoNvsraosav Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CM VO 0 0 O oo o o O o oo o Ov O O o CM 2 0 ^ 2 6 O O m ra.ir© CO Figuire Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 62 oo o. o o o CO o o 0 0 o o CT\ o o o CM T"“J * -Bitolyl * 2 o o u> O CO CM 0 0 Figure 7. m., Infrared Spectrum of O aoHveraosav Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. VO 0 0 o o o t"- o 0 0 o o o\ o o o o o 3 ro Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. VO 0 0 • ,* o o o CO o -trifluorometh.yl) biphenyl -trifluorometh.yl) I 3 1500 1200 1000 900 800 700 ZwV o i m CO__ 0 0 Figure 9. Di(j Spectrum of Infrared o' 4(JUU 4(JUU Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 65 BIBLIOGRAPHY 1. K. Fuchs, Monatsh. Chem., 53/54, 438 (1929). 2. A. Schdnberg, Chem. Ber., S6 , 2275 (1923). 3. a) K. Fuchs and P. Gross, ibid., 63, 1009 (1930); b) E. Bergmann and M. Tschudnowsky, ibid., 613, 457 (1932); c) A. Schdnberg and A. Stephenson, ibid., 66^, 250 (1933); d) C. Courtot, M. Chaix and L. Nicolas, C. R. Acad. Sci., Paris, Ser. C, 194, 1660 (1932); C. Courtot, M. Chaix and J. Kelner, ibid., 194, 1837 (1332). 4. a) V. Grignard and L. Zorn, ibid., 150, 1177 (1910); b) C. Courtot and C. Pomonis, ibid., 182, 893 (1926). 5. H. Hepworth, J. Chem. Soc., 119, 1249 (1921). 6 . H. Hepworth and H. Clapham, ibid., 119, 1188 (1921). 7. E. Kohler and H. Potter, J. Amer. Chem. Soc., 57, 1316 (1935). 8 . H. Potter, ibid., 76, 5472 (1954). 9. H. Potter, Abstracts of Papers, 137th National Meeting of the American Chemical Society, Cleveland, Ohio, April, 1960, p. 3-0. 10. R. Oda and K. Yamamoto, J. Org. Chem., 26, 4679 (1961). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 66 11. a) A. Sekera, J. Fauvet and P. Rumpf, Ann. Chim. (Paris), 10, 413 (1965); b) P. Manya, A. Sekera and P. Rumpf, C. R. Acad. Sci., Paris, Ser. C, 264, 1196 (1967). c) T. Chaudron and A. Sekera, ibid., 265, 277 (1967). 12. T. Thomas and T. Stevens, J. Chem. Soc., 69 (1932). 13. B. Wildi, S. Taylor and H. Potratz, J. Amer. Chem. Soc., 73, 1965 (1951). 14. a) H. Gilman and D. Esmay, ibid., 74, 266 (1952); b) H. Gilman and D. Swayampati, ibid., !!_, 3387 (1955); c) D. Shirley and E. Lehto, ibid., 77, 1841 (1955); d) H. Gilman and S. Eidt, ibid., 7j8, 3848 (1956); e) H. Gilman and D. Swayampati, ibid., 7£, 208 (1966). 15. J. Braumen and N. Nelson, ibid., 8J3, 2332 (1966). 16. J. Jacobus and K. Mislow, ibid., 8£, 5228 (1967); K. Mislow, Rec. Chem. Progr., 28^, 217 (1967). 17. K. Andersen and S. Yeager, J. Org. Chem., 28_, 865 (1963); S. Yeager, M. S. Thesis, University of New Hampshire, Durham, N. H., 1963. 18. F. Scardiglia and J. Roberts, Tetrahedron, 3_, 197 (1958); J. Bunnett and T. Brotherton, J. Org. Chem., 23, 904 (1958). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 67 19. B. Knapp, unpublished work, Hudson Valley Community College, Troy, New York. 20. V. Franzen, H. Joschek and C. Mertz, Justus Liebigs Ann. Chem., 654, 82 (1962). 21. V. Franzen and C. Mertz, ibid., 643, 24 (1961). 22. J. Bornstein and J. Supple, Chem. Ind. (London), 1333 (1960). 23. H. H. Szmant in "Organic Sulfur Compounds", Vol. I, N. Kharasch, Ed., Pergamon Press, New York, N. Y., 1961, Chapter 16. 24. D. Barnard, L. Bateman and J. D. Cunneen, ibid., Chapter 21. 25. a) F. Loth and A. Michaelis, Chem. Ber., 27,, 2540 (1894); b) W. 0. Ranky and D. C. Nelson, in "Organic Sulfur Compounds", Vol. I, N. Kharasch, Ed., Pergamon Press, New York, N. Y., 1961, Chapter 17; c) B. Crocca and L. Cannonica, Gazz. Chim. Ital. 76,, 113 (1946); Chem. Abstr. 40, 71538 (1946). 26. H. H. Szmant and J. J. McIntosh, J. Amer. Chem. Soc., 73, 4356 (1951). 27. W. S. Gump and J. C. Vitucci, ibid., 61, 238 (1945). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28. L. Horner, H. Schaefer and W. Ludwig, Chem. Ber., 91, 75 (1958). 29. N. J. Leonard and C. R. Johnson, J. Org. Chem., 27, 282 (1962). 30. H. H. Szmant and G. Suld, J. Amer. Chem. Soc., 78, 3400 (1956); H. H. Szmant and R. Lapinski, ibid., 458 (1956). 31. W. Tagaki, K. Kikukawa, K. Ando and S. Oae, Chem. Ind., (London), 1624 (1964) . 32. F. G. Bordwell and P. J. Boutan, J. Amer. Chem. Soc., 2£, 717 (1957). 33. H. Lecher, F. Holschneider, K. Koberle, W. Speer and P. Stocklin, Chem. Ber., 58_, 409 (1925). 34. a) J. R. Campbell and R. E. Hatton, J. Org. Chem., 26, 2480 (1961); J. H. Uhlenbrock, Rec. Trav. Chim. Pays-Bas, 80, 1057 (1961); b) F. Mauthner, Chem. Ber., 39_, 3593 (1906). 35. C. Thomas in "Anhydrous Aluminum Chloride in Organic Chemistry", Reinhold Publishing Corp., New York, N. Y., 1941, pp. 263, 350. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 69 36. a) C. E. Colby and C. S. McLoughlin, Chem. Ber., 20, 195 (1887) ; b) H. C. Parker, ibid., 23, 1844 (1890); c) A. Michaelis and P. Schindler, Justus LiebigsAnn. Chem., 310, 137 (1900); d) S. Smiles and R. LeRossignol, J. Chem. Soc., 89, 696 (1906); ibid., 93, 745 (1908); e) G. Machek and H. Haas, J. Prakt. Chem., 160, 41 (1940); f) R. L. Shriner, H. C. Struck and W. J, Jorison, J. Amer. Chem. Soc., 52., 2060 (1930); g) S. Oae and C. Zalut, ibid., £52, 5359 (1960); h) S. Oae, T. Kitao, Y. Kitaoka and S. Kawamura, Bull. Chem. Soc. Jap., 38^, 546 (1965). 37. M. Kharasch and D. Reinmuth in "Grignard Reactions of Non-Metallic Substances", Prentice-Hall, New York, N. Y., 1954, pp. 1285, 1290, 1294. 38. W. Strecker, Chem. Ber., 43., 1131 (1910). 39. Ho H. Szmant and W. Emerson, J. Amer. Chem. Soc., 78, 454 (1956); Bert, C. R. Acad. Sci., Paris, Ser. C, 178, 1826 (1924). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 70 40. H. A. Staab and K. Wendel, Angew. Chem., 73_, 26 (1961); H. A. Staab, ibid., 74, 407 (1962); H. A. Staab, K. Wendel and A. Datta, Justus Liebigs Ann. Chem., 694, 78 (1966); H. A. Staab and K. Wendel, ibid., 694, 8 6 , 91 (1966). 41. E. N. Karaulova and G. D. Gal’pern, Zh. Obshch. Khim., 29, 3033 (1959); Chem. Abstr., 54, 12096d (1960). 42. R. Ito, I. Migita, N. Morikawa and 0. Simamura, Bull. Chem. Soc. Jap., 36, 992 (1963); D. H. Hey and E. R. B. Jackson, J. Chem. Soc., 645 (1934). 43. Jo D. Roberts, C. W. Vaughan, L. A. Carlsmith and D. A. Semenow, J. Amer. Chem. Soc., 78, 611 (1956); G. Graff, H. Hertog and W. Melger, Tetrahedron Lett., 15_, 963 (1965) . 44. R. Huisgen and J. Sauer, Chem. Ber., 91, 1453 (1958). 45. H. Matzura, Dissertation, University of Heidelberg, Heidelberg, Germany, 1964, in G. Wittig, Angew. Chem. (Int. Ed.), 4, 736 (1965). 46. R. Huisgen and K. Herbig in R. Huisgen and J. Sauer, Angew. Chem., 72_, 91 (1960); G. Wittig and R. W. Hoffmann, Chem. Ber., 95_, 2718 (1962); G. E. Vargas-Nunez in G. Wittig, Pure Appl. Chem., £, 173 (1963); R. W. Hoffmann Chem. Ber., 9_7, 2763 (1964); R. W. Hoffmann, G. E. Vargas- Nunez, G. Guhn and W. Sieber, ibid., £8 , 2074 (1965). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 47. R. W. Hoffmann, ibid., £7, 2772 (1964). 48. F. Scardiglia and J. D. Roberts, J. Org. Chem., 23, 629 (1958). 49. J. D. G. Cadogen, J. K. A. Hall and J. T. Sharp, J. Chem. Soc., Ser. C, 1880 (1967). 50. G. Kdbrich, Chem. Ber., 96_, 2544 (1964). 51. A. T. Bottini and J. D. Roberts, J. Amer. Chem. Soc., 79, 1459 (1957). 52. T. Kauffmann and H. Henkler, Chem. Ber., %_, 3159 (1963)j T. Kauffmann, H. Henkler, C. Kosel, H. F. Mdller and W. Schoeneck, Angew. Chem., 73, 540 (1961); T. Kauffmann, ibid., (Int. Ed.), 3_, 342 (1964). 53. N. Kharasch in "Organic Sulfur Compounds", Vol. I, N. Kharasch, Ed., Pergammon Press, New York, N. Y., 1961, Chapter 32. 54. a) H. H. Szmant and S. Vazquez, Chem. Ind. (London), 1000 (1967); b) M. Kise, T. Asari, N. Furukawa and S. Oae, ibid., 276 (1967); c) S. Oae, M. Kise, N. Furukawa and Y. H. Khim, Tetrahedron Lett., 15, 1415 (1967). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 72 55. H. A. Potratz and J. M. Rosen, Anal. Chem., 21, 1276 (1949). 56. J. F. Bunnett and R. E. Zahler, Chem. Rev., 49_, 362 (1951). 57. N. E. Papanikolaou, Ph.D. Thesis, University of New Hampshire, Durham, N. H., 1966. 58. N. E. Papanikolaou and M. Cinquini, private communica tion . 59. Y. H. Khim, W. Tagaki, M. Kise, N. Furukawa and S. Oae, Bull. Chem. Soc. Jap., 2556 (1966). 60. a) W. E. Truce, W. J. Ray, Jr., 0. L. Norman and D. B. Eickemeyer, J. Amer. Chem. Soc., 80_, 3625 (1958); b) W. E. Truce and 0. L. Norman, ibid. , 75, 6023 (1953); W. E. Truce and W. J. Ray, Jr., ibid., 81, 481 (1959); W. E. Truce, C. R. Robbins and E. M. Kreider, ibid., 88_, 4027 (1966). 61. E. Kornfield, P. Barney, J. Blankly and W. Faul, J. Med. Chem., 8_, 342 (1965); B. H. Klanderman, J. Amer. Chem. Soc., 87_, 4649 (1965). 62. G. Woods, A. Van Artsdale and F. Reed, ibid., 7j2, 3221 (1950). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 73 63. G. Wittig, W. Stilz and E. Knauss, Angew. Chem., 70, 166 (1958); G. Wittig and E. Knauss, Chem. Ber., 91, 895 (1958); G. Wittig and H. Hdrle, Ann., 623, 17 (1959); F. M. Beringer and S., J. Huang, J. Org. Chem., 29, 445 (1964). 64. W. E. Parham and J. D. Jones, J. Amer. Chem. Soc., 76, 1068 (1954). 65. J. Overhoff and W. Proost, Rec. Trav. Chim. Pays-Bas, 57, 179 (1938). 6 6 . L. Suchomelova, V. Horak and J. Myka, Microchem. J., 196 (1965); Chem. Abstr., 63., 9062b (1965). 67. M. J. Bdseken, Rec. Trav. Chim. Pays-Bas, 29_, 315 (1910) 6 8 . H. Meyer, Justus Liebigs Ann. Chem., 433, 327 (1923). 69. M. Gomberg and J. C. Pernert, J. Amer. Chem. Soc., 48., 1372 (1926). 70. E. A. Johnson, J. Chem. Soc., 4155 (1957). 71. A. I. Vogel, "A Textbook of Practical Organic Chemistry" 3rd ed., John Wiley and Sons, Inc., New York, N. Y., 1962, p. 930. 72. H. M. McNair and E. J. Bonelli, "Basic Chromatography", Consolidated Printers, Oakland, Calif., 1967. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 74 SECONDARY REFERENCES H. Heany, "The Benzyne and Related Intermediates", Chem. Rev., 62, 81 (1962). C. Price and S. Oae, "Sulfur Bonding", Ronald Press Co., New York, N. Y., 1962. A. Schdberl and A. Wagner, "Methoden der Organischer Chemie", (Houben-Weyl), 4th ed., Georg Thieme Verlag, Stuttgart, Germany, Vol. 9, 1955, p. 211. R. Huisgen in "Organometallic Chemistry", H. Zeiss, Ed., Reinhold Pub. Corp., New York, N. Y., 1960, p. 36. "G. C. Integration Methods", in Previews and Reviews, 7_, 1967, Varian Aerograph, Walnut Creek, Calif. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.- S- O' '