University of the Pacific Scholarly Commons University of the Pacific Theses and Dissertations Graduate School 1972 Birch reduction of benzenesulfonamide, N,N- dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide, and 2-mesitylenesulfonamide Vishnubhai V. Patel University of the Pacific Follow this and additional works at: https://scholarlycommons.pacific.edu/uop_etds Part of the Chemistry Commons Recommended Citation Patel, Vishnubhai V.. (1972). Birch reduction of benzenesulfonamide, N,N-dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide, and 2-mesitylenesulfonamide. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/420 This Thesis is brought to you for free and open access by the Graduate School at Scholarly Commons. It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. BIRCH REDUCTION OF BENZENESULFONAMIDE, N,N-DIMETHYLBENZENESULFONAMIDE, N,N-DIISOBUTYLBENZENESULFONAMIDE AND 2-MESITYIENESULFONAMIDE. A Thesis Presented to the Faculty of the Graduate School -1 University of the Pacific I I -i In Partial Fulfillrnent of _j the Requirement for the Degree Master of Science by Vishnubhai V. Patel June 1972 ACKNOWLEDGEMENT The author wishes to express his sincere gratitude to Dr. Charles A. Matuszak for his unceasing encouragement and help during the course of-this research. My grateful thanks to Dr. Herschel G. Frye and Dr. Donald K. Wedegaertner for their kind suggestions. I would like to thank Dr. E.G. Cobb, Chainnan of the Chemistry Department, for his help and facilities. Finally, rey sincere appreciation to Mrs. Dawn Mallard for an excellent job of typing. --j j TABLE OF CONTENTS ,PAGE INTRODUC'J1ION . • • • . I 1 RESULTS AND DISCUSSION . \u I SUMMARY AND CONCLUSION . \25 EXPERTIVIENTAL • • • • • .!27 ! A. Summary of General Experimental Procedure i27 B. Preparation of Benzenesulfonamide ~7 I C. Reduction of Benzenesulfonamide 28 1. First Reduction . 28 2. ·Second Reduction . 29 3. Third Reduction . ~3 4 . Fourth Reduction 33 5. Fifth Reduction • 33 6. Sixth Reduction . 33 7. Seventh Reduction 33 8. Eighth Heduction 34 9. Ninth Reduction . 34 10. Terith Reduction . 34 11. Eleventh Reduction 34 12. Twelfth Reduction • 35 13. Thirteenth Reduction 35 14. Fourteenth Reduction 35 15. Fifteenth Reduction • 36 16. Sixteenth Reduction . 36 17. Seventeenth Reduction 36 D. Preparation of N,N-D:imethylbenzenesulfonamide 38 E. Reduction of N,N-D:imethylbenzenesulfonamide 38 1. First fuduction . 38 2. Second Reduction 39 3. Third Reduction . 39 4. Fourth Reduction 39 5. Fifth Reduction . 40 6. Sixth Reduction . lJO 7. Seventh Reduction .. 40 8. Eighth Reduction 40 PAGE F. Preparation of N,N-Diisobutylbenzenesulfonamide 41 G. Reduction of N,N-Diisobutylbenzenesulfonamide . i, 41 1. First Reduction . ~ . .' . : 41 2. Second Reduction :. 42 3. Third Reduction 1'. 43 4. Fourth Reduction . 43 5. Fifth Reduction • 44 6. Sixth Reduction 1i• 44 H. Reduction of 2-Mesitylenesulfonamide i• 45 (2,4,6-Trimethylbenzenesulfonamide) ' 1. First Reduction • 45 2. Second Reduction ~ 46 3. Third Reduction 51 4 , Fourth Reduction 52 BIBLIOGRAPHY 53 LIST OF FIGURES FIGURE NO. PAGE l. Reduction Products of Toluene, Anisole, Dimethylaniline and Benzoic Acid • • • • . · 4 2. Reduction Products of p-Toluenesulfonamide 7 3. Dimerization of Phenylsulfur Radical to Diphenyldisulfide ll 4. Reduction Products of Substituted Benzenesulfonamide 13 5. Reduction Products of 2-Mesitylenesulfonamide • • • . 22 6. IR Spectrum of Thiophenol from First Reduction Product of Benzenesulfonamide . • . 30 7. IR Spectrum of known Thiophenol • • . • . • . 31 8. IR Spectrum of known Mixture of Thiophenol and Diphenyldisulfide ••• . 32 9. IR Spectrum of Mesitylene • • • . • . • • . 47 I -,' 10. IR Spectrum of Mesitylene from First Reduction Product of 2-Mesitylenesulfonamide • . • • • . • • • 48 ll. IR Spectrum of 2,4,6-Trimethylthiophenol from First Reduction Product of 2-Mesitylenesulfonamide . • • • • . 49 LIST OF SCHEMES SClJEI'IIE NO. PAGE I. Reaction Mechanism of Birch Reduction . 2 II. Birch Reduction Cleavage of Supstituted Tosylsulfonamide 7 III. Reaction Mechanism for Sulfonamide Cleavage by Arene Anion 9 IV. Reductive Cleavage of Alkyl Substituted Benzenesulfonamide 12 LIST OF TABLES TABLE NO. PAGE I. Comparative Yield of Reduced N-Alkylated Benzamides 5 II. Comparative Acidity Tabulation . 6 III. L~quid Ammonia Cleavage of p-Toluenesulfonamide 8 rr. N-Ethyl-N-Phenyl-p-Toluenesulfonamide Cleavage 8 V. Birch Reduction of Benzenesulfonamide • • • • • 14 VI. Birch Reduction of N,N-Dimethylbenzenesulfonamide 19 VII. Birch Reduction of N,N-Diisobutylbenzenesulfonamide 21 VIII. Birch Reduction of 2-Mesitylenesulfonamide •••• 23 _j' Chapter I INTRODUariON The use of active metal-liquid ammonia-alcohol reagents in the reduction of aromatic compounds dates from 1937, when Wooster (1) showed that the presence of alcohol in active metal-liquid ammonia allowed the reduction of benzene to its dihydro derivative, Whereas~ in· the absence of the alcohol there was no reduction. He did not examine the reduction product in detail (1). In later - l years Arthur J. Birch (2,4,5,7,12) reexamined the method, improved it and utilized it extensively in the reduction of a variety of aromatic compounds and this type of reduction often is called "Birch Reduction". The Birch method (2,4,5) has great synthetiq usefulness because it proVides a simple route to 19-nor-analogues of steroidal hormones (37 and in peptide chemistry (19,20) to remove tosyl blocking groups. ·.The extensive modifications of this method by variation of experimental conditions have proven its versatility. The original method used an alkali metal, liquid ammonia and an acid or proton source (1). The most commonly used metal is sodium, although lithium and potassium have also been used. The proton source is usually an a~cohol (methyl or ethyl) or an amnonium salt e.g. NH Cl. 4 Sometimes cosolvents such as anhydrous tetrahydrofuran and ether are used when the compounds are not very soluble in liquid anmonia. The 1 primary function of the alcohol is that of a proton donor, but it also facilitates the process by buffering the reaction mixture, thus preventing the accU!Illllation of strongly basic li!H ion. Thus the base catalysed 2 rearrangements can be minimized. The acidity of the proton source is an important factor in determining the nature of the reduction product ( 6). If the acidity is very high, the proton donor will react readily with the alkali metal and gaseous hydrogen will be the main product. Alcohols have optimum pKa for the reduction of aromatic rings. The mechanism of Birch reduction (2,15,16,17,18,24) as established for most benzenoid compounds is depicted in Scheme I. Scheme I [A] (?olvated catio'11 a.md <;,olvcded eleci;to'Yl) CBJ .. MQ) e + CNH ')------ e CNH) " e 0-----M~""Y 3 3 0 -e e(NH~) ( il.+e'l'le "-'1'1 i 01'\ "1'-o.d i ca. I ) 2 CCJ .. pKc.;: 16-1~ ------MEFJ +ROH -~ ( NH~) 0• • CNH) e :; CD] ·•- .. -. Q H H ... -j . ! C.E1 H H +ROMCNH) 3 3 It can be noted that .ammonia can not furnish proton due to its low acidity (pKa about 34) . Therefore, more acidic proton sources such as alcohols (pKa about 16-18) are required. Wilds and Nelson (3) modified this method by using lithium instead of sodium or potassium and adding alcohol last. This procedure has improved the yields in many cases and therefore is widely used. The nature of substituents in a benzene nucleus profoundly effect the mode of Birch reduction. Substitution of a benzene nucleus with electron releasing groups (e.g. alkyl and amino) generally decrease ease of Birch reduction and give 2,5-dihydroderivatives (6) ~ Electron with­ drawing groups (COOH, amide) give increased ease of reduction and give -, 1,4-dihydroderivatives as illustrated in Fig. 1. R. R M r L,[q_ NH3 ---~ ROH - 1--1 0 -N ..- cH, H R= -cH -oc.H . 3 I ~I -.. Gf-3 cooH H cooH M+ Liq NH3 I. 0 :ROH \-\ \-\ Figure 1 4 Kuehne and Lambert (6) reported the reduction of the ring of ben- zarnide in high yields using :!2_-butanol but not using ethanol. However, Niem (10), Dickson (27) and Qazi ( 36) found that reduction of the ring rather than amide group occurred using either ethanol or :!2_-butanol. The following 1,4-dihydro-3,5-dimethoxybenzarnides (Table I) were obtained from Birch reduction of 3,5-dimethoxybenzamide, 3,4,5-trimethoxy­ benzarnide or N-alkyl-3,4,5-trimethoxybenzarnides (6). TABLE I A B %yield -~ 1\ R2 OCH OCH H H 90* 3 3 OCH OCH H 90 3 3 c2~ 1\ 13 OCH OCH H CH(CH ) 74 d H H 3 3 3 2 OCH OCH CH 6 3 3 CH3 3 OCH OCH H 8 3 3 C(CH3)3 * About the same yield of 1,4-dihydro-3,5-dimethoxybenzamide was obtained from 3,5-dimethoxy benzarnide as from 3,4,5-trimethoxybenzarnide. The yield of the substituted 1,4-dihydro-N-:!2_-butyl-3,4,5-trimethoxy- benzamide was much lower than that obtained from the other mono-N-substi- tuted trimethoxybenzamides . Thus, in that compound the amide apparently behaves as one which can not be stabilized by a negative ion (N,N-dimethyl compound). Since methyl, ethyl and isopropyl groups have no similar large effect, the size of the single substituent on the nitrogen may be :important. 5 The acidity factor plays a great role in the protection of amide groups (6~ 10, 27). A comparative tabulation of the acidities of benzoic acid, benzamide and benzenesulfonamide showed (Table II) that the order of acidity is ~co 2H) ~S0 2NH 2 ) ~CONH2 , (36) • TABLE II -K P a Benzoic acid 4.5 Benzamide 15-16 Benzenesulfonamide 10 l Ethanol 18 t-Butanol 19 Benzoic acid is highly acldic, so anionic form of carboxyl group L is protected during Birch reduction. According to Lambert and Kuebne (6) benzamide is a weak acid so it does not exist in anion form and the amide group undergoes Birch reduction in presence of ethanol.