Post on 26-Feb-2023
transcript
University of the Pacific University of the Pacific
Scholarly Commons Scholarly Commons
University of the Pacific Theses and Dissertations Graduate School
1972
Birch reduction of benzenesulfonamide, N,N-Birch reduction of benzenesulfonamide, N,N-
dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide, dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide,
and 2-mesitylenesulfonamide 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 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 mgibney@pacific.edu.
-1
I I
-i
_j
BIRCH REDUCTION OF BENZENESULFONAMIDE, N,N-DIMETHYLBENZENESULFONAMIDE,
N ,N-DIISOBUTYLBENZENESULFONAMIDE AND 2-MESITYIENESULFONAMIDE.
A Thesis
Presented to
the Faculty of the Graduate School
University of the Pacific
In Partial Fulfillrnent of
the Requirement for the
Degree
Master of Science
by
Vishnubhai V. Patel
June 1972
--j j
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.
TABLE OF CONTENTS
INTRODUC'J1ION . • • • .
RESULTS AND DISCUSSION
SUMMARY AND CONCLUSION
EXPERTIVIENTAL • • • • •
A. Summary of General Experimental Procedure
B. Preparation of Benzenesulfonamide
C. Reduction of Benzenesulfonamide
1. First Reduction . 2. ·Second Reduction 3. Third Reduction . 4 . Fourth Reduction 5. Fifth Reduction • 6. Sixth Reduction . 7. Seventh Reduction 8. Eighth Heduction 9. Ninth Reduction .
10. Terith Reduction . 11. Eleventh Reduction 12. Twelfth Reduction • 13. Thirteenth Reduction 14. Fourteenth Reduction 15. Fifteenth Reduction • 16. Sixteenth Reduction . 17. Seventeenth Reduction
D. Preparation of N ,N-D:imethylbenzenesulfonamide
E. Reduction of N ,N-D:imethylbenzenesulfonamide
1. First fuduction . 2. Second Reduction 3. Third Reduction . 4. Fourth Reduction 5. Fifth Reduction . 6. Sixth Reduction . 7. Seventh Reduction .. 8. Eighth Reduction
,PAGE
. I 1
. \u I
. \25
.!27 !
i27
~7 I 28 28
. 29 ~3 33 33 33 33 34 34 34 34 35 35 35 36 36 36
38
38
38 39 39 39 40 lJO 40 40
PAGE
F. Preparation of N,N-Diisobutylbenzenesulfonamide 41
G. Reduction of N,N-Diisobutylbenzenesulfonamide . i, 41
H.
1. First Reduction . . . . . . . . . . . . ~ . . . .' . . . . : 41 2. Second Reduction :. 42 3. Third Reduction 1'. 43 4. Fourth Reduction . 43 5. Fifth Reduction 1• 44 6. Sixth Reduction i• 44
Reduction of 2-Mesitylenesulfonamide (2,4,6-Trimethylbenzenesulfonamide)
1. First Reduction 2. Second Reduction 3. Third Reduction 4 , Fourth Reduction
i • 45 '
• 45 ~ 46
51 52
BIBLIOGRAPHY 53
I ' -,
LIST OF FIGURES
FIGURE NO. PAGE
l. Reduction Products of Toluene, Anisole, Dimethylaniline and Benzoic Acid • • • • . · 4
7 2.
3. 4. 5. 6.
7. 8.
9. 10.
ll.
Reduction Products of p-Toluenesulfonamide
Dimerization of Phenylsulfur Radical to Diphenyldisulfide ll
Reduction Products of Substituted Benzenesulfonamide 13
Reduction Products of 2-Mesitylenesulfonamide • • • . 22
IR Spectrum of Thiophenol from First Reduction Product of Benzenesulfonamide . . • . 30
IR Spectrum of known Thiophenol • • . . • . • .
IR Spectrum of known Mixture of Thiophenol and Diphenyldisulfide •••
IR Spectrum of Mesitylene • • • . . . • . • • .
. . 31
32 47
IR Spectrum of Mesitylene from First Reduction Product of 2-Mesitylenesulfonamide • . • • • . . . . • • • 48
IR Spectrum of 2,4,6-Trimethylthiophenol from First Reduction Product of 2-Mesitylenesulfonamide . . . • • • • . 49
LIST OF SCHEMES
SClJEI'IIE NO. PAGE
I.
II.
III.
IV.
Reaction Mechanism of Birch Reduction . . . . . . . . . . Birch Reduction Cleavage of Supstituted Tosylsulfonamide
Reaction Mechanism for Sulfonamide Cleavage by Arene Anion
Reductive Cleavage of Alkyl Substituted Benzenesulfonamide
2
7
9 12
'
_j
LIST OF TABLES
TABLE NO.
I.
II.
III.
rr.
Comparative Yield of Reduced N-Alkylated Benzamides Comparative Acidity Tabulation . . . . . . . . L~quid Ammonia Cleavage of p-Toluenesulfonamide
N-Ethyl-N-Phenyl-p-Toluenesulfonamide Cleavage
V. Birch Reduction of Benzenesulfonamide • • • • •
VI. Birch Reduction of N,N-Dimethylbenzenesulfonamide
VII. Birch Reduction of N,N-Diisobutylbenzenesulfonamide
VIII. Birch Reduction of 2-Mesitylenesulfonamide ••••
PAGE
5 6 8 8
14 19 21 23
-l
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
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. NH4Cl.
Sometimes cosol vents 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!H2
ion. Thus the base catalysed
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) 3 3 0 " e -e
.. 0-----M~""Y
e(NH~)
( il.+e'l'le "-'1'1 i 01'\ "1'-o.d i ca. I )
2
-j .
!
CCJ
0.. pKc.;: 16-1~
------MEFJ +ROH -~ ( NH~)
• • C NH) e :;
CD]
·•- .. -.
Q H H ...
C.E1
3
H H
+ROMCNH) 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
0 M r L,[q_ NH3 -ROH 1--1
-N ..- cH, H R = -cH -oc.H . 3 I ~I -.. Gf-3
cooH H cooH
0 M+ Liq NH3 I. :ROH
\-\ \-\
Figure 1
4
-~
d
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 1\ R2 % yield
OCH3 OCH
3 H H 90*
OCH3
OCH3
H c2~ 90 1\ 13 OCH
3 OCH
3 H CH(CH
3)2 74
H H OCH
3 OCH
3 CH3 CH3
6
OCH3
OCH3
H C(CH3)3 8
* 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
l
L
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 ~co2H) ~S02NH2 ) ~CONH2 , (36) •
TABLE II
-K P a
Benzoic acid 4.5
Benzamide 15-16
Benzenesulfonamide 10
Ethanol 18
t-Butanol 19
Benzoic acid is highly acldic, so anionic form of carboxyl group
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. They found
the use of a weaker proton source (!_-butanol) preferentially led to re-
duction of the ring rather than the amide group.
Benzenesulfonamide is more acidic than benzamide, therefore it is
logical to predict that the ring rather than the sulfonamide group would
be reduced when either !_-butanol or ethanol is used as proton source.
However, it is well known that in the case of p-toluenesulfonamides,
6
the functional group is reduced to thiocresol (19) as shown in Figure 2.
Figure 2.
Rf!N-1~ -o _ Na./NH'. S \ J CH 11 \\ II ~ RoH 0
Kovacs et al (19) reported that during Birch reduction of the sub-
stituted tosylsulfonamide follows two paths. Cleavage of carbon-sulfur
(a) bond gives sulfur dioxide and toluene whereas cleavage of sulfur-
nitrogen bond (b) yields s ulfinic acid which undergoes further reduction
to both p-thiocresol and toluene, as depicted in Scheme II.
Scheme II. j G.. -. b !
b
7
r
The liquid ammonia cleavage of p-toluenesulfonamide gave 70-80%
of sulfite and 10-14% of thiocresol when 3.5 g atoms of sodium was
used (19) Table III.
TABlE III
Coll'q)ound g. a toms of sodium/mole
p-Toluenesulfonamide 3.5
p-Toluenesulfonamide 2.5
% sulfite Iodometric
70, 81
59, 65
% thiocresol
14, 10
traces
Later Closson and his coworkers (21) studied the similar reduction
of N-ethyl-N-phenyl-p-toluenesulfonamide in dimethoxyethane with sodium
naphthalenide. The stoichiometric data is provided in Table IV.
TABlE r1
The Products from the Cleavage of N-Ethyl-N-Phenyl-p-Toluenesulfon
amide with Sodium-Naphthalenide in Dimethoxyethane at 25° C*.
Exp. No. Molar ratio of arenide
to sulfonamide
1 9 2 7
* Reaction time = 12 hr
Toluene
85 78
** Yield based on sulfonamide
% yield **
Ethyl- Na2s
aniline
100 20
99 23
29 23
*** Calculated on the basis of sulfur content
8
Na S 0 *** 2 2 3
32 46
1
Closson ( 21) proposed a possible mechanism for N-ethyl-N-phenyl-
p-toluenesulfonamide cleavage by arene anion radical as depicted in
Scheme III.
SCHEME III.
'D i 'YYl et\-, 0 )( 'f e.tho..m e
e e SOi + C1o Hg•
e 2.. s 0 • :1-
'f. '
'Sodiww, No.phth~;lide
e 2.C1oHs
C. a:"-e11e AA'I i crY\ "1'-o.d i co. I )
(Qffll j de, CVYiiO')'))
?.---'>) S 02. + (I o H 8
9
It occurred to Dr. C.A. Matuszak and his coworkers to study arene
sulfonamide reduction by Birch method var~ing different experimental
parameters. They reported in 1965 ( 10) that benzenesulfonamide can
be reduced using ethanol or t-butyl alcohol as a proton source and found
that the Birch reduction preferentially reduced the sulfonamide group
rather than the arene ring. Thus reduction of sulfonamide does not
resemble the reduction pattern of aromatic amides or acids.
This thesis is a report on the study of the Birch reduction of
benzenesulfonamide and alkyl-substituted sulfonamides. This work was
carried out in order to elucidate the role of steric factors, to ex
amine the possibility of a large temperature effect (-33° vs ~75° C)
and to see the effect of no acidic hydrogen on the sulfonamide nitrogen.
With this objective the Birch reduction of benzenesulfonamide
N ,N-dimethylbenzenesulfonamide· and N ,N-diisobutylbenzenesulfonemi.de
were performed at -33°C and -75°C as well as 2,4,6-trimethylbenzene
suJ.foncunide (2-mesitylenesulfonanride) at -33°G.
10
Chapter II
DISCUSSION AND RESULTS
The present study involved the Birch reduction of benzenesulfonam1de,
N,N-dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide and
2-mesitylenesulfonamide.
It has been previously shown (10) that benzenesulfonamide gives
thiophenol and diphenyldisulfide upon Birch reduction. The sulfonamide
.group is easily reduced. Probably the electron deficient sulfur atom
in sulfonamide can accommodate an electron easily.
Diphenyldisulfide could have formed as shown in Figure 3 by dimer
ization of thiophenyl radicals possibJy formed during reduction or by
direct air oxidation of thiophenol during work-up.
Figure 3.
The reduction follows two competing pathways of reduction (19)
as shown in Scheme DJ. A higher yield of thiophenol would result when
pathway (b) is favored over pathway (a).
ll
Scheme IV.
a.. b
0 : 1? j /R 5--:-N · II : ........... R
. 0 :
No../NH?;, RoH
(a.. (j,)
R H
There were several experimental factors which effect the amount
of thiophenol isolated. ~nall amounts of thiophenol were being handled
in the work-up and millor losses affected the yield appreciably. The
b .p. of thiophenol is 168°C and some loss by evaporation probably oc-
curred during removal· of ether and ethanol using the rotatory evaporator
12
under vacuum with hot water for heating. Any unx'ellloved ether or ethanol
in the san:ple would increase the apparent yield of thiophenol. Mechanical
losses undoubtedly also occurred.
Birch Reduction of'Benzenesulfonamide:
Birch reduction of benzenesulfonamide yielded thiophenol and diphenyl~
disulfide. Benzene formation was assumed but no attempt 1<1as made to
isolate it , The reaction is shown in Figure 4,
o c. •C Li / li(jl NH3 -33 o-'t -'l5
Abso. EtoH /NH4-c.l CASSLI'YYiecl)
+
<(1}-s--6-Q Figure 4
~be reduction was carried out seventeen times under various ex-
perimental conditions, (See Table V.) The range of yields of thiophenol
ran from 10 to 28% (average 18%) but none of the experimental variations
c.aused a :!hange in the yield beyond experimental error. Thiophenol was
identifled by comparison of its ir spectrum with the ir spectrum of
authentic thiophenol .. A small amount of solid was also often present
13
! .
1--' -1="
--~'-
TABLE V
BIRCH P.EDUCTION OF BENZENESULFONAMIDE*
• Reduction
No. Reduction
·Temperature
Product **
% yield
1
2
3 4
5
6
NCJI'E: *
**
-75°C 22.3% (1.155 g)
-75°C 19.9%
-75°C 20.7%
-33°C 21.6%
-33°C 15. 2% some material was lost during work-up;
-33°C 21.0%
In each reduction 7.4 g (0.0471 mole) benzenesulfonawdde, 2.678 g (0.4 mole) lithium, 65 ml absolute ethanol and 21.4 g (0.4 mole) =nium chloride were used
In each case the isolated reduction product was a mixture of mostly thiophenol and small amount of diphenyldisulfide. The yield calculated as if all the product was thiophenol. Benzene is also assumed to fonn.
I
--'·~--, __ ,_ L_ , --·--- --'"' ,
TABlE: V -Continued
BIRCH REDUCTION . OF BENZENESULFONAJVIIDE ***
Reduction Lithium Absolute Reaction Product ** -No. Ethanol Temperature % yield
7 2.768 g 65 ml -33°C 16.8% (0.4 role)
8 2.768 g 65 ml -33°C 15.0% (0.4 mole)
9 5-536 g '65 ml -33°C 15.2% (0.8 mole)
1-' \.YI
10 1.384 g 65 ml -33°C 10.1% (0.2 mole)
ll 11.072 g 105 ml -33°C 12.3% (1.6 mole)
12 5.536 g ,65 ml -33°C ll.O% (0.8 mole) 43.77 g (0.8 mole) some material was lost
ammonium chloride during work-up
13 5-536 g '65 ml -33°C 23.4% (0 .8 mole)
NOTE: ***In each reduction 7.4 g ~0.0471) benzenesulfonamide and 21.4 g (0.4 mole) ammonium chloride were used.
I
In reduction 7 and 8 specially dried ammonia was used (see for detail experimental reduction 7).
I-'
"'
Reduction No.
14 ****
15 ****
16
17
TABLE V - Continued ,
BIRCH REDUCTION OF BENZENESTJLFONAMIDE ***
Lithium
2.768 g (0.4 mole)
2.768 g (0.4 mole)
2.768 g (0.4 mole)
2. 768 g (0.4 mole)
Proton
SoUrce
65 ml absolute ethanol
'
65 ml ab~olute ethanol
20 ml t-butanol
5Q ml t-butanol
Reaction .Temperature
-33°C
-75°C
-33°C
-33°C Diff work-up see exp. reduc.
17
Product ** % Yield
28.2%
21.4%
14.0%
15.5% Thiophenol 2.34% Diphenyldisulfide
NOI'E: **** In reduction 14 and 15, different lithium metal was used (for detail, see experimental reduction 14).
and believed to be diphenyldisulfide. In one case (17th reduction)
the diphenyldisulfide was isolated and had the same melting point as
reported for diphenyldisulfide. The presence of small aiDJunts of diphenyl
disulfide did not alter the ir spectrum of thiophenol noticeably (see
figure 8 ) .
Reductions 1,2, and 3 were done at -75°C using dry ice and acetone
while 4,5,and 6 were performed at the b.p. of anmonia (-33°C). There
was no significant effect of temperature upon the yield.
In reductions 7 and 8, specially dried am:nonia, prepared by first
refluxing the liquid ammonia with lithium, was used to see if precluding
the possibility of water being a proton source could be important. No
significant effect on the yield of thiophenol occurred.
To examine the effect of moderate changes in the amount of lithium
used, exper·iments 9,10,ll,l2 and 13 wen~ perfor·med. In 9 and 13, double
the usual arnount of lithium was used. In 10, the amount was half, in -
11 the amount was four times and in 12, the amounts of both lithium a'1d
am:noniurn chloride were double. The yields of the products indicated that
within these limits, variations in the amounts of lithium have n:J large
effect. Since 6 equivalents of metal are theoretically needed to reduce
benzenesulfonamide to thiophenol via benzenesulfinic acid, the 4.25
equi v. used i11 experiment 10 does not seem enough to reduce all the
benzenesulfinic acid intermediate. However, since a major part of the
starting material was reduced via path (a) (Scheme IV) to benzene which
requires only 2 equivalents, there is theoretically more than enough.
In experiments 14 and 15,_ the lithium used had been in the department
17
for more than seven years and its origin was unknown. Ne:!m (10) u:sed
this lithium and he reported higher yields of thiophenol and diphenyl
disulfide than that found in the present investigation. But the present
investigation showed that the use of the same lithium had no large effect
upon the yields of thiophenol.
In reductions 16 and 17 !_-butanol was used instead of absolute
ethanol with no significant effect upon the yield of thiophenol.
Benzenesulfinic acid may be a possible initial product of benzenesul
fonamide reduction, but no attempts were made to isolate it.
Reduction of N,N-Dimetnylbenzenesulfonamide:
Reduction of N,N-d:!methylbenzenesulfonamide was performed eight
times (see Table V) under different experimental parameters using the
sa.'Jle procedure and work-up as with benzenesulfonamide (see Figure 5).
'Ihe yields of thiophenol were much higher ( 55-73% ,average 67%) , than
from ben~en~sulfonamide itself (10-28%, average 18%). 'l'hus the presence
of the two rr:ethyl groups on nitrogen seems to favor path (b) of Scheme
IV versus path (a), compared to unsubstituted benzenesulfonamide.
The experiments 1 and 2 were done at -33°C, the boiling point of
ammonia whereas 3 and 4 were done at -75°C, the dry ice and acetone
temperature. In experiments 5 and 6 (-33°C) and 7 and 8 (-75°C) specially
dried arrnnonia was used. 'Ihe exper:iinental variables examined did not
cause a change in thiophenol yield outside the exper:!mental error.
18
1--' \D
' --- i ' _j~-- --·"'"'--'--· L - ---~~,~~·~---.:..·--'--~--' _----'..-''---'-·--'---L..LJ-"--";"-----~-
TABlE VI
BIRCH REDUCTION OF N ,N-DTIVJETHYLBENZENES\JLFDNAMIDE * Reduction Reduction A111rnonia Product: % Yield
No.
l ** 2
3 4
5 *** 6
7 8
NOI'E:
Temperature, Calculated as all thiophenol
-33°C Approximately 55.4% Some loss during work-up
-33°C 600 ml of 61.0%
-75°C arihydrous liquid 73.0%
-75°C ammonia 73.16%
-33°C Approximately 69.0%
-33°C 600 rnl of 69.69%
-75°C specially dried 70.65%
-75°C liquid ammonia 68.34%
* In each case 8. 713 g ( 0. OIH mole) of N ,N-dimethylbenzenesulfonami.de, 2.768 g (0.4 mole) of lithium, 20 ml of absolute ethanol, and 21.4 g (0.4 mole) of ammonium chloride were used.
** In 1,2,3 and 4 reductions, 600 rnl of ammonia were used.
*** In 5,6, 7 and 8 reductions, 600 rnl of specially dried ammonia were used. For specially dried ammonia, see exper:!mental.
. ,
J-
Reduction. of N ,N-Diisobutylbenzenesulfonamide:
To examine the steric effect of bulky alkyl substituents on nitro
gen, six reductions of N,N-dilsobutylbenzenesulfonamide were performed .
(See Table VII).
The products were thiophenol and diphenyldisulfide as shown in Figure 4.
However, the finding that substantial amounts of starting material were
recovered indicates that isobutyl groups retarded the reduction. 1be
yield of thiophenol (36-53%, average 46% based on consumed starting mater
ial) is somewhat lower than from N ,N-dimethylbenzenesulfonamide ( 55-73%,
average 67%), but much higher than from benzenesulfonamide (10-28%,
average 18%) .
. Experiments 1 and 2 were run at - 33°C and 3 and 4 were run at -75°C.
The recovery .of the starting material was higher at -75°C ( V) 70%) than
at -33°C ( <11 30%).
In reductions 5 and 6 (-33°C) the amounts of lithium and alcohol
were doubled but did not appreciably increase the amount of reduction.
In these reductions excess lithium.probably reacted with alcohol. to
form hydrogen.
Reduction of 2-Mesitylenesulfonamide:
It is well known that benzoic acid (32) can be easily esterified
with alcohol in the presence of acid, whereas mesi toic acid ( 2, 4, 6-
trimethylbenzoic acid) does not undergo this type of esterification due
to the steric effect of the two ortho methyl groups. It interested us
to subject 2-mesitylenesulfonamide (2,4,6-trimethylbenzenesulfonamide)
20
___ l ,,. ___ . ____ !_ -~~-
I TABlE VII
BffiCH REDUCTION OF N1,N-DIISOBUTYI.BENZENESULFONAMIDE *
Reduction Lithium Absolute Reduction Ammonium Product * No. Ethanol Temperature Chloride % Yield
1 2.768 g 20 ml -33°C 21.4 g 32. 8% starting material (0.4 mole) (0.4 mole) (a) 27.8% Thiophenol
(b) 41.2% Thiophenol
2 2.768 g 20 ml -33°C 21.4 g 28. O% starting material (0.4 mole) (0.4 mole) (a) 26.0% Thiophenol
(b) 35.7% Thiophenol
3 2.768 g 30 ml -7~C 21.4 g 74.8% starting material
"' (0.4 mole) (0.4 mole) (a) 11.0% Thiophenol f-' (b) 41.9% Thiophenol
4 2.768 g 30 ml -75°C 21.4 g 67.6% starting material (0.4 mole) (0.4 mole) ·(a) 17.1% Thiophenol
(b) 53.0% Thiophenol
5 5.536 45 ml -33°C 42.8 g 24.2% starting material (0.8 mole) (0.8 mole) (a) 39.2% Thiophenol
(b) 52.0% Thiophenol
6 5-536 45 ml -33°C 42.8 g 24. 5% starting material (0.8 mole) (0.8 mole) (a) 39.0% Thiophenol
I (b) 51.5% Thiophenol
NO.I'E: * In each case, 12.688 g (0.0471 moleD of N,N-diisobutylbenzenesulfonamide was used. The % yield of thiophenol was calcu1Lated (a) in relation to all 12.688 g of starting material and (b) in relation to material consumed ( 12. 688 g minus the am:>unt recovered) •
I
to the Birch reduction in order to find out if .there is a similar retarding
steric effect of the ortho methyl groups on this reduction.
2-Mesitylenesulfonamide was subjected to four reductions (See
Table VIII) and yielded mesitylene, 2,4,6-trimethylthiophenol and mesityl-
disulfide as shown in Figure 5, The later two were formed in combined
yield (13-37%, average 27%) about the same or slightly more than from
benzenesulfonamide. The mesitylene was characterized by comparison
with ir spectrum and glc of known sample of mesitylene.
so2_NH2.
""'.:::::: CHJ L.i (li<f.NH3 "\c .::0. Aloso.J=toH / NH4-cl
CH3
r-----< c,\-13
··if ··~······ s ; ~---· -_···-;;.... ~ c
Figure 5.
22
·'·
cCC- _1, , '""-~~~- - __ j
;TABLE: VIII
' BIRCH REDUCTION ,OF 2-~'IESITl.wENESULFONJ\ll'liDE *
Reduction LithiUm Absolute A'llDlonimn T:iJll.e Interval Product No. Ethanol Chloride between reduc- % Yield
and tion and work-up Reaction Temperature
l 2.768 g 20 rrJ. 21.4 g about 4 hrs. 33.33% Mesitylene (0.4 mole) ~33°C (0.4 mcle) (some material used for IR)
20:27% 2,4,6-Trirnethyl-thiophenol
1\) 2 2.768 g 20 ml 21.4 g about 16 hrs. 21.27% Mesitylene w (0.4 mole) -33°C (0.4 mole) 2.13% 2,4,6-Trimethyl-
thiophenol ·21. O% Mesityldisulfide
3 2.768 g 20 ml 21.4 g about 16 hrs .-: 23. O% r1esitylene (0.4 mole) -33°C (0.4 mcle) (some material was lost
during work-up) 10.69% 2,4,6-Irimethyl-
thiophenol 20.00.% J'fJesityldisUlfide
4 2.768 g 20 ml 21.4 g about 4 hrs. 41.71% !1esitylene (0.4 mole) '-'33°C (0.4 mole) 28.30% 2,4,6-Trimethyl-
thiophenol
i
NOI'E: * In each reduction 9.385 g (0.0471 mel~) of 2-mesitylenesulfonamide and approximately 600 ml of dry liquid ammonia were used.
J -f
In reductions 1 and 4 the time interval between the reduction and
work-up was about 4 hours whereas in 2 and 3 it was 16 hours. The yield
of mesityldisulfide versus 2,4,6-trimethylthiophenol was greatly in
creased in reductions 2 and 3. This indicates that 2,4,6-trimethylthio
phenol air oxidized more easily than did thiophenol. This might be due
to increased stability of the thiol radical intermed:iate due to the electron
donating ability of methyl group as shown in Figure 5.
Thus di-ortho alkyl substitution in the arene ring did not slow
down the reduction or change the nature of the reduction products.
However, there could be differences in the ease of the reduction of 2-
mesitylenesulfonamide compared to benzenesulfonamide that these experiments
were not sensitive enough to detect.
24
SUMMARY AND CONCLUSION
1. Birch reduction of benzenesulfonarnide using lithium and absolute
ethanol or t-butanol yielded thiophenol (10-28%, avera§e 18.3%, 17
exper:illlents) and small amounts of diphenyldisulfide. Benzene is assumed
to also form. Variation in temperature (-33°C vs -75°C), variation in
the amounts of lithium from four times to half the usual amount and the
use of specially dried ammonia vs undried ammonia did not effect the
yield within experimental error.
2 . Reduction of N ,N-dimethylbenzenesulfonarnide also yielded thiophenol
plus small amounts of diphenyldisulfide but in much higher yield ( 55-73%,
average 67%, 8 experiments) than benzenesulfonarnide, The use of' -33°C
vs -75°C or specially dried aJm.onia vs undried ammonia did riot effect the
yield within experimental error.
3, The reduction of N,N-diisobutylbenzenesulfonarnide resulted in
recovery of starting material with more recovered using -75°C than
-33°C. This indicated that bulky alkyl substitution in sulfonamide
group did retard the reduction. The yield of' diphenyldisulfide and
thiophenol ( 36-53%, average 46%, 6 experiments) based on consumed
starting material, was not affected by temperature (-33°C vs -·75°C)
within experimental error but seems to be somewhat less than the yield
from N,N-dimethylbenzenesulfonarnide but substantially is larger than
from benzenesulfonarnide.
25
i I
'
4. 'lhe reduction of 2-mesitylenesulfonamide at -33°C gave 2,11,6-trimethyl
thiophenol (20-37%, average 27%, 4 experiments) and mesitylene (21-42%,
average 26%) leaving no starting material. Mesitylene was identified
by corrparison by :i.r and glc with known mesitylene. Thus di-ortho methyl
substitut.i.on did not cause an observable change in reduction within the
limits of the experiments perfonred. The 2,4,6-trimethylthiophenol
was more readily air oxidized to mesityldisulfide than was thiophenol
itself.
26
SUMMARY OF GENERAL EXPERIMENTAL PROCEDURES
In all of the reducUons the arru:nonia was distilled from the gas
cylinder and condensed into the reaction flask by a dry ice-acetone
condenser but was not dried \mless so indicated.
'!he lithium (Foot Mineral Co.) used was cut from llDiform thickness
lithium ribbon that was protected by petrolatum. '!he petrolatum was
removed by washing the lithium ribbon in a series of baths of low-boiling
petrolemn ether and cut into small pieces just before use.
A rotatory evaporator with partial vacuum from a water aspirator
··- and a hot v<ater bath for heating was used for evaporation of •5r·ganic
solvents and for concentration of solutions.
All melting points were determined with a 'Ihomas Hoover capillary
melting point apparatus and: are \lDcorrected. ·
Ir spectra were obtained utilizing a Perkin-Elmer Model 137 spectro
photometer.
Benzenesulfonanlide, N,N-dimethylbenzenesulfonamide and N,N-diiso
butylbenzenesulfonamide were prepared as indicated in experimental section
while 2-mesitylenesulfonamide was purchased from Aldrich Chemical.
Organic solvents used were, in general, not distilled prior to use.
Reductions were performed at either refluxing arru:nonia (-33°C) or at
about -75° C using dry ice-acetone bath and Wilds and Nelson's ( 3) pro
cedure of adding the alcohol last .
27
--~
EXPERIMENTAL
Preparation of Benzenesulfonamide:
To 800 ml of concentrated ammonium hydroxide, 314 g (2.00 mole)
of benzenesulfonylchloride was slowly added over a period of 20 minutes
wlth constant stirring. An additional 400 ml of concentrated ammonium
hydroxide was slowly added into the mixture and the mixture was allowed
· to stand for four hours. The excess ammonium hydroxide was decanted from
the sol:l.d benzenesulfonsmide which was then washed with three 200 ml
portions of distilled water. The benzenesulfonamide was recrystallized
from water, yielding 240 g (1.53 mole, 76% yield), melting point
1511·-155°C (lit. (10) rn.p. 155ac) and·had an ir spectrum identical to
a known sanple of' benzenesulf'onamide.
REDUC'l'ION OF BE:NZmESULFONAMIDE:
Fi:rst Reduction of' Benzenesulfonamide (-75°C).
Benzenesulfonamide, 7.4 g (0.0471 mole) was added to 600 rru of dry
Hquid ammonia in a two liter, three-necked flask equipped with a mechan
ical stirrer, a dropping furmel and a dry ice condenser.
'lhen 2.768 g (0.400 mole) of lithium ribbon, after being cleaned
of 1.ts protective coating of petrolatum in a series of baths of low
boiling petroleum ether, was added in small pieces over a period of 15
minutes with stirring, to the mixture of benzenesulfonsmide and liquid
28
amnonia. While the solution was stirred, 65 ml of absolute ethanol was
added over a period of 30 minutes. The reaction was held at -75°C, the
temperature of dry ice and acetone. After the blue color of the rrd,xture
had disappeared, 21.4 g (0.4 mole) of amnonium chloride was added very
slowly to reduce the basicity, and the Jlli.xture was stirred an additional
hour. The amnonia was allowed to evaporate overnight at ambient temperature
and pressure.
The residual material was dissolved in 200 ml of ice cold distilled
water. After acidification with 10% hydrochloric acid to pH 1 to 2,
the solution was extracted with four 100 ml portions of ether. The com-
bined ether solution was dried over 3 g of anhydrous magnesium sulfate.
The ether and ethanol was removed by using a rotatory evaporator under
reduced pressure. The remaining light yellow liquid weighed 1.155 g
(22. 3% yield). The ir spectrum of the reduction product (Figure 6)
was identical to the spectrum of known thiophenol (Figure 7). The --- - - --- ---
ir spectrum of known thiophenol was not affected appreciably by the
addition of .small amounts of diphenyldisulfide (Figure 8).
Second Reduction of Benzenesulfonaw~de (-75°C).
Tne experimental conditions (equipment, quantities of reagents
and reaction temperature) were the same as the first reduction of ben-
zenesulfonsmide. The isolated light yellow liquid weighed l. 032 g
(19.9% yield) and its ir spectrum was the same as the .ir spectrum of
thiophenol.
29
I ,
I 4000 3000
.10
J.J J 20r• z· <( "' ~'i-· i [! """' 30 __ ,_,~ -, ::!:: • H .. L _
::> ~.40
2000
, --·--· ' - --'---- '- ---~ '· ·--·~--- .. L __ , ___ ,.. -~~-----'-,___.,___ -- __.____1____ _ ________ ~-_ ___ ,, ------- _, ~----~~-- _, -·'"----'--'-'-"--'--~"----~-- .. ·-·---
1500 . cM-l 1000 900 800 700 .0
.lO•
-= "0 ; •.L
~.50 .60f::i_ .70-
.30
'.40 -·50'
. '• ; i\ i -, --- ~- --rr ~~ T - -. ~-- .. __ __ _ _ • i
1 0=· " ' -~- ~ ~ 60 . ki~~9J!s_, ... 1 1 L ~- ~~ __ , ~ +- _ _ .. -~. . .: eg&JT ,, '-" · ~ · ,_, - 70 = ' " c <fi 1 ' " " • , i 'i " i 1 , ' i i ,
I - I
3
w 0
4
I ! II ' I 1 1 0 ' _j_"-[bY , H+!- • I I ·i=±±t-' -I I I - ., _______._,_.
: I ! I ! I I I I ~ I ·= 5 6 7 B 9 10 11 12 13 14 15
WAVELENGTH (MICRONS)
Ir Spectrum of Thiophenol from First Reduction Product of Benzenesulfonarnide (Neat)
Figure 6
I 4000 3000 2000
I' I _j
0.0
' In
.10~
-·'-J..._J_ I . ~~~~~~~~~~~~+ - J=i:cffcffl
1500
lu !I-I--·
il!
IJF ·1'-.. ·.'t} ~f:fi rl 1 '.'
X, ~c· •.
'-~--~--"· --·· .. J
CM·1 1000 -&rti::
+
i l I !
r::c.l
900 800
··I
700 I
. ±' c[c·'f't ..
.10 I
-~ . =~=t=t" + .. ·- e: "': - cc=Rcl=i= . · + · .. _ = .. o;c+• -i'it~:·ooc-lc 1 ft 1- 11 I · I
1 • ~~-~ '"'t.c.cLcL· • -• ·•-1-•- 1 ; I 1 I 1-\-- • I I i I I • I loll
11
1 00 • ~ -+- . i I '
-Lf.4'
00 _[I i I I I i I . '· II ! I 15 3
LV 1-'
4 5 6 7 8 9 10 11 W AVE~ENGTH (MICRONS)
Ir Spectrum of known Thiophenol (Neat) (Eastman Kodak)
' Ffca:ure 7
12 13 14
I
4000 3000
.10
;_u
~.20 <(
~.30 0 fj) 40R-ca· r <( H,
.50
.60 --
, ______ ---- ___ ____,______.., _______ ,, ___ ,_---'-..,.C .. _ -.LC...J•~·-"·''""---'-~- ····------
2000 1500 I cM-1 1000 900 800 ;700
.7 Q -::- r:-,.::··· _:;::_--'~ _ .--:.-. .•. -· __ ,- ·== ·1=1- =1-1=-" ,_ 1 1·- :.J=.:l=l :::r: ·:t::;:::t:.: ~ - ·-,:::c:-· - =t= - ;::;r___:;);::=-t- ·:::::r_:::.. ·· :--:·=r-. 8=E: .. : _-,-1 -l---- . -- ·~..:..:7::r: •.tJ: __ :-::.;-_.:::_
' I i ! I 1 I I I I I I ! I
10
a
'.30
10 "' ! i ,,, 1( • I I , •
00 I I I 00
3
w 1\)
4 5 6 7 8 9 10 11 12 WAVELENGTH (MICRONS)
Ir Spectrum of !mown mixture of Thiophenol and Diphenyldisulfide. (98% Thiophenbl and 2% Diphenyldisulfide) (Neat)
Figure 8
13 4 15
i l
Third Reduction of Benzenesulfonamide.
The factors were the same as the first reduction (-75°C). 'rhe
isolated yellow liquid weighed 1.07 g (20.7% yield). Their spectrum
was identical with the spectra of the first and second reduction product.
Fourth Reduction of Benzenesulfonamide.
The exper:ilnental conditions, equipment, quantities of reagents
and wor·k-up were the same as in the first reduction except that the
reaction temperature was -33°C.
The isolated light yellow liquid weighed 1.2 g (21.6% yield).
Fifth Reduction of Benzenesulfonamide.
The conditions were the same as the fourth reduction (-33°C). There
was an accidental loss of some compound during I'Otatory evaporation
to remove the ether. The isolated light yellow liquid weighed 0. 787 g
( 15. 2% yield) .
Sixth. Reduction of Benzenesulfonamide.
'l'he set-up, exper:ilnental conditions, ·quantities of reagents and
work-up were the same as the fourth reduction of benzenesulfonanrl.de
(-33°C). The isolated light yellow liquid weighed 1.09 g (2l.O%_yield).
Seventh Reduction of Benzenesulfonamide.
The procedure was the same as the first reduction except for the
arrnnonia used and the reaction temperature. The liquid ammonia was first
33
dried by being refluxed for two hours with 5 g of lithium in a two
liter, three-necked flask with stirring. It was then distilled into
another two-liter, three-necked flask for the reduction. 'Ihe reduction
reaction temperature was -33°C, the boiling point of arrnnonia. 'Ihe
light yellow liquid weighed 0.868 g (16.8% yield).
Eighth Reduction of Benzenesulfonamide.
'Ihe same experimental conditions, quantities of reagents and work-,
up were used as ih the.sevehth reduction (-33°C). TI1e isolated light
yellow liquid weighed 0.797 g (15.0% yield).
Nineth Reduction of Benzenesulfonamide.
'Ihe factors were the same as the fourth reduction (-33°C) except
that double the aT!JOunt (5.536 g, 0.8 mole) of lithium was used. 'Ihe
isolated light yellow crude liquid 0.789 g (15.2% yield).
Tenth Reduction of Benzenesulfonamide.
Here the procedure, the reagents and the reaction were the same
as the fourth reduction (-33°C) except that one half the amount (1.384
g, 0.2 mole) of lithium was used. 'Ihe extracted li@1t yellow crude
liquid weighed 0.526 g (10.1% yield).
Eleventh Reduction of Benzenesulfonamide.
'Ihe parameters were the same as the fourth reduction (-33°C) except
that four times the amount (11.07 g, 1.6 moles) of lithium and 105 ml
34
of absolute ethanol were used. The isolated light yellow liquid weighed
0.636 g (12.3% yield).
Twelfth Reduction of Benzenesulfonamide.
Everything was the same as in the fourth reduction (-33°C) except
that double the amount ( 5 . 536 g, 0. 8 mole) of lithium and 4 3. 77 g ( 0. 85
mole) of ammonium chloride were used, yielding 0.568 g (11.0% yield)
light yellow liquid product; the ir spectrum was identical to the ir
spectrum of the previous reduction products.
Thirteenth Reduction of Benzenesulfonamide.
The factors·(-75°C) were the same as in the first reduction except
that double the amount (5.536 g, 0.8 mole) of lithium was used, yielding
1.212 g (23.4% yleld) of light yellow liquid.
-- -- --
Fourteenth Reduction of Benzenesulfon8inide. ··
In this reduction the major change was that the 2. 768 g ( 0. 40 mole)
of lithium used was in large pieces which had been in the department for
years and whose origin is unlmown and which Neim (10) used. It was
cleaned using low boiling petroleum ether, flattened, and cut into small
pieces. The amounts of benzenesulfonamide, absolute ethanol and arrmonium
chloride, the reaction temperature (-33°C) and the isolation procedure
were the same as the fourth reduction. The light yellow liquid weighed
1.46 g (28.2% yield).
35
.,
Fifteenth Reduction of Benzenesulfonamide.
Everything was the same as the fourteenth reduction except that
the reaction temperature was -·75°C. The light yellow liquid weighed
1.11 g (21.4% yield).
Sixteenth Reduction of Benzenesulfoncurrl.de.
The set-up, work-up, quantities of reagents and experimental con
ditions were the same as the fourth reduction (-33°C) except that 40 rol
of t-butanol was used instead of absolute ethanol. The isolated liquid
weighed 0.726 g (14.0% yield). The product's ir spectrum was not sig
nificantly different from the ir spectrum of the products of the previous
reductions.
Seventeenth Reduction of Benzenesulfonamide.
Ir1 this_re(j_uctlon the major ch§Ilge .was the work-up. 'I'he quantities
of reagents, reaction temperature and procedure were the same as in the six
teenth reduction ( -33°C).
The residual material was dissolved in 200 ml of ice cold distilled
water and acidified with 10% hydrochloric acid to pH l to 2; the solution
was extracted wlth four 100 ml portions of ether. The ether extract
was again extracted with four 100 ml portions of 10% sodium hydroxide.
The ether solution was dried over 3 g of anhydrous magnesium sulfate
and was concentrated using the rotatory evaporator. The remaining di
phenyldisulfide weighed 0.12 g (2. 34% yield), m.p. 66-68°C [lit. (3'7)
m.p. 68°C].
36
The above basic solution was acidified with .10% hydrochloric acid
to pH 1 to 2 and was extracted with four lOO rnl portions of ether. The
ether solutions were combined and dried over anhydrous magnesium sulfate.
The ether and ethanol were removed using a vacuum rotatory evaporator.
The remaining light yellow liquid weighed 0 .804 g (15. 5% yield), n~5
l. 5260, [lit. (37), n65 l. 5893] and was identified from its ir spectrum
as thiophenol by comparison with ir spectrum of an authentic sample.
The refractive index is lower than the literature value. This is probably
due to presence of some diphenyldisulfide and/or solvent.
37
. i j
'
Preparation of N,N-Dimethylbenzenesulfonamide:
One hundred grams ( 2. 5 mole) of sodium hydroxide was dissolved in
200 ml of distilled water, and the solution was allowed to cool. Then
100 g (1.1 mole) of dimethylamine hydrochloride was slowly added followed
by 200 ml of ether. The solution was constantly stirred by a magnetic
stirrer for 30 minutes, while 80 g (0.46 mole) of benzenesulfonylchloride
was slowly added. The ether layer was decanted and evaporated at room
temperature yielding 85 g (0.40 mole~ 80% yield) of solid N,N-dimethyl
benzenesulfonamide white needle crystals, m.p. 47-48°C [lit. (ll) m.p. 48°C].
REDUCTION OF N ,N-DIMETHYLBENZENESULFONAMIDE.
First Reduction of N,N-Dimethylbenzenesulfonamide (-33°C).
In a three-necked, round-bottomed, two liter flask, equipped with
a mechanical stirrer and dry ice condenser, was placed 8. 7155 g ( 0. 04'(1
mole) of N,N-dimethylbenzenesulfonamide and approximately 600 ml of
anhydrous liquid ammonia.
Then 2.768 g (0.4 mole) of lithium ribbon was cleaned of its pro~
tective coating of petrolatum in a series of baths of low boiling petro-
leum ether and was added in small pieces over a ·period of 15 minutes
with stirring at -33°C (boiling point of amnonta). While the soluUon
was sti.rred, 20 ml of absolute ethanol was added over a period of 30 minutes.
After the blue color of the mixture had disappeared, 21.4 g (0.4 mole)
of amrr.on:tum chloride was added very slowly to reduce the basicity. and
the mixture was stirred an additional hour. The amnon:ta was allowed
to evaporate overnight at ambient temperature and pressure •
38
i
I
The residual material was dissolved in 200 ml of ice cold distilled
·water. After acidification with 10% hydrochloric acid to pH 1 to 2,
the solution was extracted with four 100 ml portions of ether. The.
combined ether extracts were dried over 3 g of anhydrous magnesium sulfate
and the ether and ethanol were removed using a rotatory evaporator under
vacuum. The remaining light yellow liquid weighed 2. 87 g (55. 4% yield) •
Second Reduction of N,N-Dimethylbenzenesulfonamide,
The experimental conditions, equipment, quantities of reagents,
reaction temperature (-33°C) and work-up were the same· as in the first
reduction of N,N-dimethylbenzenesulfonamide. The extracted light yellow
liquid weighed 3.16 g (61.0% yield).
Third Reduction of N~-Dimethylbenzenesulfonamide.
The factors were the same as in the first reduction of N,N-dimethyl-
benzenesulfonamide except that the reaction temperature was -75°C.
Reaction work-up yielded 3.79 g (73.0% yield) of light yellow liquid
whose ir spectrum was identical to the spectrum of the product of the
first reduction.
Fourth Reduction of N,N-Dimeth.ylbenzenesulfonamide,
'Ihis reduction was the same as the third (-75°C), yielding 3. 79 g
(73.16% yield) of product.
39
Fifth Reduction of N,N-Dimethylbenzenesulfonamide.
The parameters were the same as the first reduction of N,N-dimethyl
benzenesulfonamide (-33°C). The major change being that the arrmonia was
dried prior to use in the reduction by refluxing with 5 g of lithium
for an hour in a two liter, three-necked flask with stirring. It was
then distilled into another two liter, three-necked, round-bottorr.ed
flask for the reduction. The isolated light yellow liquid weighed
3.73 g (69.0% yield).
Sixth Redu~tion of N,N-Dimethylbenzenesulfonamide.
The parameters were the same as the fifth reduction (-33°C), yielding
3.61 g (69.69% yield) of light yellow liquid.
Seventh Reduction of N 1N--Dimethylbenzenesulfonamide.
The set-up, work-up and quantities of reagents were the same as the-- - --
fifth reduction except that the reaction temperature was -75°C. The
isolated light yellow liquid weighed 3.66 g (70.65% yield).
Eighth Reduction of N ,N-Dimethylbenzenesulfonanrl.de.
The factors were the same as the seventh reduction (-75°C). The
isolated lig.ht yellow liquid weighed 3.54 g (68.34% yield).
40
Preparation of N,N-Diisobutylbenzenesulfonamide:
To a solution of 40 g of sodium hydroxide in 300 ml of distilled
water, 100 g (0.7 mole) of diisobutylamine was slowly added followed
by adQition of 85 g (0.49 mole) of benzenesulfonylchloride. While the
solution was stirred with a magnetic stirrer for 15 minutes, 200 ml of
ether was added. The ether portion was decanted and evaporated at am
bient temperature and pressure .. The N,N-diisobutylbenzenesulfonamide was
recrystallized in low boiling petroleum ether giving 95 g (0.35 mole,
70% yield), m.p. 54-55°0 {lit. (8) m.p. 55°C).
REDUCTION OF N,N-DIISOBUTYLBENZENESULFONAMIDE.
First Attempt of R~duction of N,N~Diisobutylbenzenesulfonamide.
To a three-necked, round-"bottom flask equipped with a dry ice
condenser ~"ld mechanical stirrer was added 12.6888 g (O,Oij7l mole) of
N,N-diisobutylbenzenesulfonamide and approximately 600 ml of .anhydrous - - --
liquid ammonia.
Then 2.768 g (0.4 mole) of lithium ribbon (after being cleaned of
its protective coating of petrolatum in a series of baths of low boiling
petroleum ether) was added in small pieces to the reaction Jrj_xture over
a period of 15 minutes with stirring at the boiling polnt of a'lllllonia
(-33°C). While the solution was being stirred, 20 ml of absolute ethanol
was added over a period. of 30 minutes . After the 15lue color of the
mixture had disappeared, 21. lj g ( 0. 4 mole) of ammonium chloride was
added very slowly to reduce basicity and the mixture was stirred an
additional hour. The ammo11ia M>s allowed to evaporate overnight at
41
ambient teJlllerature and pressure.
The residual material was dissolved in 200 ml of ice cold distilled
water. After acidification with 10% hydrochloric acid to pH 1 to 2,
the solution was extracted with four 100 ml portions of ether. Then the
combined ether extracts were extracted with four 100 ml portions of
10% sodium hydroxide. The ether was dried with 3 g of anhydrous mag-
nesium sulfate and was allowed to evaporate at ambient temperature and
pressure. The remaining solid material weighed 4.16 g ( 32.8% recovery) .
After recrystallization in petroleum ether it had m.p. 54-55°C and was
identified as starting material, N ,N-diisobutylbenzenesulfonamide, from
its ir spectrum.
The basic portion.was acidified with 10% hydrochloric acid to pH
l to 2 . The solution was extracted with four 100 ml portions of ether.
The cornbined ether extracts were dried with 3 g of anhydrous magnesium.
su~fate, and the ether solution was concentrated by distillation under -- ----- -- -- ----
vacuum to- :remove -etner-and tEe ethanoL 'ihe r6naining pale yellow
liquid weighed 1.44 .g (27.8% y~eld). It was identified as thiophenol
from the ir spectrum which was identical to the ir spectrum of known
thiophenol.
Second Reduction of N,N-Diisobutylbenzenesulfonamide.
The experimental conditions, equipment, .quantities of reagents,,
reaction temperature (-33°C), and work-up were the same as in the first
reduction of N,N-diisobutylbenzenesulfonamide. The extracted solid
material weighed 3.61 g (28.5% recovery). It was identified as the
42
l !
starting material, N ,N-diisobutylbenzenesulfonamide. The extracted light
yellow liquid weighed 1.39 g (26.83% yield) and was identified as thio-
phenol from its ir spectrum, which was identical to the spectrum of
known thiophenol.
Third Reduction of N,N-Diisobutylbenzenesulfonamide.
The set-up, quantities of reagents and work-up were the same as the
first reduction except that 30 ml of absolute ethanol was used and the
reaction temperature was -75°C. The isolated solid material weighed
9.49 g (74.8% recovery) and the liquid 0.54 g (10.9% yield),
The solid material was identified as starting material (m.p. 53-55°C),
N,N-diisobutylbenzenesulfonamide,from its ir spectrum. The light yellow
liquid was identified as thiophenol from its ir spectrum which was identical
to the ir spectrum of known thiophenol.
-Fourth- Reduction-er-N ,N-'Diisobutyltrenzenesulfonamide ;- -
The factors were the same as in the third reaction (-75°C). The
isolated solid rraterial weighed 8.58 g (67.62% recovery) and liquid
0. 89 g (17 .18% yield) . The solid material was identified as starting
material (m.p. 53-55°Ch N,N-diisobutylbenzenesulfonamid~ w~th small
amounts of diphenyldisulfide from ir spectrum. The light yellow liquid
was identified as thiophenol from its ir spectrum which was identical to
the spectrum of known thiophenol.
Fifth Reduction of N,N-Diisobutylbenzenesulfonamide.
'Ihe experimental apparatus, conditions and reaction temperature
were the same as in the first reduction of N ,N-diisobutylbenzenesulfonamide
(-33°C) except that double the amount (5.536 g, 0.8 mole) of lithium
ribbon was used followed by 45 ml of absolute ethanol and 42.8 g (0.8 mole)
of arrnmnium chloride , 'Ihe isolated solid and liquid material weighed
3.07 g (24.2% recovery) and 2.04 g (39.0% yield) respectively.
The solid material was identified as the starting material (m.p.
52-55°C),N,N-diisobutylbenzenesulfonamide,with small amounts of di
phenyldisulfide from iT spectrum.
The liquid was identified as thiophenol from its ir spectrum which
was identical to the spectrum of known thiopheno1.
Sixth Reduction of N ,N-Diisobutylbenzenesulfonamide.
'Ihe factors were the same as the fifth reduction (-33°C) of N,N-
- diisooutylbehzenesulTonalnide. The -isolated solid-and-liqUid material weigheo
3.108 g (24.,5% recovery) and 2,02 g (39.0% yield) respectively.
The solid material was identified as the starting material (m.p.
53-55°C),N,N-diisobutylbenzenesulfonamide,with small amounts of di-
phenylsulfide from ir spectrum. 'Ihe light yellow liquid was identified
as thiophenol from its ir spect1~ which was identical with the ir spectrum
of known thiophenol.
44
REDUCTION OF 2-MESITYLENESULFONAMIDE.
First Reduction of 2..;.Mesi tylenesulforuimide. ( 2 , 4 , 6..;.Tr:i.Jilethylberizene
sulfonamide) :
2-Mesitylenesulfonamide (Aldrich Chemical Co.)(9.3856 g, 0.0471 mole)
was added to 600 ml of dry liquid ammonia in a two liter, three-necked
flask equipped with a mechanical stirrer, a dropping funnel and a dry
ice condenser.
Then 2.768 g (0.4 mole) of lithium ribbon, after being cleaned of
its protective coating of petrolatum in a series of baths of low boiling
petroleum ether, was added in small pieces over a period of 15 minutes
with stirring to the mixture at the boiling point of ammonia (-33°C). ·
While the solution was stirred,· 20 ml absolute ethanol was added over
a period of 20 minutes. After the blue color of the mixture had dis-
appeared, 21.4 g (0.4 mole) of anmonium chloride was added very slowly
to reduce the basicity, and the mixture was stirred an additional hour.
Then the anmonia was allowed to evaporate over a warm water bath for four
hours.
When the ammonia evaporated, the residual material was dissolved
in 200. ml of ice cold distilled water. After acidification with 10%
hydrochloric acid to pH 1 to 2, the solution was extracted with four
100 ml portions of ether. The combined ether extracts were extracted with
four 100 ml portions of 10% sodium hydroxide. Thus an ether solution
(A) and a basic solution (B) were obtained. The ether portion (A) was
dried over 3 g of anhydrous magnesium sulfate. The ether and ethanol
were removed using a vacuum rotatory .evaporator. The remaining light
45
J --
yellow liquid weighed 1.88 g (33.33% yield), ~5 1.5135, [lit.(37), ~5
l. 5155]. This was identified as mesitylene by corrlJarison with known
mesitylene by glc and ir (Figure 9 and 10). The g_lc analysis was done
by comparison of retention time of the reduction product with known
samples of mesitylene. The analysis wa'3 performed on Carle Instrument
Model 6500, 5 ft. x 1/8 .inch columns, l38°C. On a Polar Colurrm (8%
CaT'bowax 15liO on 90-100 mesh anala'om ABC) the retention time was 1.5
minutes. On a nonj:Jolar column (8% di-n-nonyl phthalate on 90-100 mesh
anakron ABC) the retention time was 0. 5 minutes.
The basic portion (B) was acidined with 10% hydrochloric acid
to pH l to 2 and extracted with four 100 ml portions of ether. The
combined ether extract was dried over 3 g of anhydrou'3 magnesiurr1 sulfate.
'I'he ether and ethanol were removed using a rotatory evaporator;· The
rer:].aining crt.::.de matsr:tal was mostly liquid with a s;naJ.l arrnunt of solid,
wej£Shed 1.5 g (2ci .27%yie1d), n~5 1.565~, and was assLl!lled to be mostly .
2,4,6-trimethylthiophenol (major product) and small amount of mesityl
d~sulfide. (For ir spectrum see Figure 11).
Second Reduction of 2-Mesitylenesulfonamide.
The experimental conditions (equipment, quantities of reagents
and reaction temperature (-33°C) were the same as the first reduction
of' 2..:.mesitylenesulfo[lamide, except that after the reaction, the ammonia
was allowed to evaporate overnight (approximately 15 hours) at ambient
terr~erature and pressure.
'l'he residual material was dissolved in 200. ml ice cold distilled
46
I 4000 3000
~,,,1
00 . ~,,~1'
--·-1
,--~,
r"'" .10[ifl:q~m i--L-·
'+
'J tt t:!: . l: = J 1 I __._L_.j_ ••
.J.20H-i- ; ·i t.:l @t:U:tJ:t:t 7 :!=!=, : ~ l:£i :tl ""' lt++' -~n:J -m
2000 ' ''
lr-HH -r't'l
.•... :.
~t-
·ii!ft~~· U!1'
-~. :t·
'"" 8?=tt- ·:t- ~:-r-I ~~ t=t=~ ~.30f+t-~g··~lf ww --~--·--~--·-
) rTf ~ ~-~ 1-H·rf , -n 40 ,,. , .. , · n · rill r : ':± ±l ~ .. t::+~ ::[. 50 ·. ~r t:i R= • ~'::!:±:""'f=E· :·±ti·7·t 60 '~+;-~~- 't:p~ - ·-~
)o~~fl 1C: '~~~i~,fao I I I! 'I I :I I I :I I I I
0 ' ! I ' I'" 1. ~
-}-rr--r
-'-+-;.=t
nxtJJ
r
__,.. 00 ULL_j__l II
3 4 5 6
1500
n
-f.-Ul.
;---~ c:r •.
111--::. :I= I
CM·1
LLt' t--1--1~~' r-L ..
["'.-"
tt_ ,-n-i r
'-~l=r! I! I I I , n ' . 1+++-fl·:iS-!__,.
"
[:£ ~ :.!
9~ .. ·~r.~ ..
b-:t~ -~-:t-·
II I I I I! iIi I! i
!fTTT[
1000
-LY+
-~·Hi
'--~-T ·, _ __,__,_"_
7 8 9 10 WAVEL.ENGTH (MICRONS)
900 800
1-
+-t-' it-EEIHH,"
11
-~1-:..i l_V
:1 I i'Tl
.i \tic[ I ft=fi=f-
~n~~ j! r.~.!=!::-
'"'-BI~miMfit¥ n -+ .. ··t·
·H• ~1-:::l .i
c!.cj 'I ''·t-! .. co :t.:r. -::::r=l=l--·~='F£b I j·H·! tt --~-~~::t::~::£_; t- j: fl· _::f::EF::Et::::t:c
I II
12 [_L
13
Ir Spectrum of lm~ Mesi tylene (Eastman Kodak) (Neat)
-1=" Figure 9 -'I
_[
II
700 I i i
..J l++t±
=t±+~1 tw_::o: ~_1.0 IJ.UJoo
14 15
! 4000 3000
.10
u ~.20 ;(
2000 1500
--~--'--' . :"'-- - ---'~---"-·--~---· -"--- ----- - "-~-- -----. -------- __ ., _______ _
·cM-1 1000 900 800 700 0.0
.10
.20
fl i~f+lf1l~TI ctfff'tffff+r+fj-fffff-t¥FlJ4Ij1ffltlffRifH'fffFFFFFft1frtfl4'ffffilf/fffffffimtfFffffWtH1Tftf¥tt-'=fH=r_ttfff'T!il WWl. 3 0 ~.30 _____ II.,m o f __ 1111 _.II II I I I _ I. t _ I. I J~J Ci 1J1J .lLLL
) l) 40 -t+t+ 1\ r-t i-ti , ,-1-+t+ •lj- - I --- -+I -- - - - - t-H · +-· -t-+ -• >+ t-f-j- 4Q :a· -n_'';'-+--:f-J':_r_tH- - , - 1'-' . __j '--- ---- --- -H+_ --_~--+'-t_· ,.,. =-+ :p 1 ctlt :J , -- t= ", - +tf - +> ""' t::..Q - _ · '•·-+H+ . --H- 50
• .., ~t-+=1=$ :-' : -- H ~ti:: • ' 60 . . • -·=! • . -+ +:tct.- •t+= A()
:7og~-~:~g~~~~~:,~=t=~-~ >- .J .:: ___ ~. -~
- " -- - -~~: -~-
I I I I I ,\ I I I '
10 ,1 ' ' !I 'I li_+ • I ! I ~ *
' ~ ,__. - :r, I I I I' I' t I I I I I I I I I I 00 I 1!-' II 11 11 11 ~~~~~~~~~· 00
3 4 5 6 7 8 9 10 11 12 13 14 15
..
-"'" 00
W AVHENGTH (N\ICRONS) I
Ir Spectrum of Mesitylene from First Reduction Product
of 2-M<:isitylenesulfonamide (Neat)
Figure 10
i 4000 3000
.10
J..J
{20 <{ ~.30· ) :2.40 <{.50
.6olf.
2000 1500
- --•--'---' '- ~~ ·-·'--'~---- - "~~----·"-"'""-''
I (ll/\-1 1000 900 800 700
.10
0
30
40 50 60 70 .70~~ .____,._.- _-;-:-:r_~ ~·~·...:"'1:: ..... +=---~·_,_··---= --.-:..T;:;~:::t.- >= ,_r-··:~·:::r:> ~:J;:::f:::-·:. .. ,· · .. :::1~-Tnz-·~..":l-- ···::: -~-- ~:- -~ = ...:;.;. ):_..' ___,__ -"-ct.-
i! i Ill hi I i II ii Ill I 1. I i I i II
1 0 1 · . I I I I 0,,...., I I . I I 1 I I I ' 1 I· 1 1 • . r •. , ~ II l++ . -r .- ::.-H- • 0 - .
CO I I I I i II
3
.I= \!)
4 5 6 7 8 9 10 11 12 W A YELENGTH (MICRONS)
Ir Spectrum of 2,4,6-Trimethylthiophenol from First Reduction Product
of 2-l"!~sitylenesulfonamide (Neat)
Figw:>e 11
13 14 HTI=
15
water and extracted with four 100 ml portions of ether. The combined
ether extracts were extracted with four 100 ml portions of 10% NaOH.
Thus an ether portion (A) and a basic portion (B) were obtained. The
ether portion (A) was dried over 3 g anhydrous magnesium sulfate. The
ether and ethanol were removed using a rotatory evaporator. The light
yellow residual material (mostly solid) weighed 4. 22 g (59. 67% yield
calculated as if all mesityldisulfide; 76% yield calculated as if all
mesitylene). This was washed with low boiling petroleum ether and
filtered. The mesityldisulfide was recrystallized from petroleum ether
and weighed 1.5 g (21.0% yield) m.p. 124-l25°C [lit, (8) m.p. l25°C].
The above petroleum ether filtrate was concentrated using a rota-
tory evaporator. The residual crude liquid was decanted and weighed
l. 2 g (.21. 27% yield) . Its ir spectrum was the same as the ir spectrum
of the product of the first reduction and appears to be mostly mesitylene
and a small amount of mesityldisulfide. -- -- -
The basic portion (B) was acidified with -10% hydrochloric aCid and
extracted with four 100 ml portions of ether. The combined ether solution
was dried over 3 g of anhydrous magnesium sulfate. The ether and ethanol
were removed using a rotatory evaporator. The light yellow liquid
weighed 0.158 g (2.13% yield) and was considered to be 2,4,6-trimethyl-
thiopehnol. Its ir spectrum was consistent with that assignment and
it easily air oxidized to material with the same m.p. as that reported
for mesityldisulfide (8).
50
·'·
Third Reduction of 2-Mesitylenesulfonamide.
The conditions were the same as the second reduction including
evaporation of armnonia over 15 hours. The residual material was dis-
solved in 200 rnl ice cold distilled water . After acidification, the
solution was extracted with four 100 rnl portions of ether. The com
bined ether extracts were extracted with four 100 rnl portions of 10%
NaOH. Thus an ether portion (!\) and a basic portion (B) were obtained.
The ether portion (A) was dried over 3 g of anhydrous magpesium
sulfate. The ether and ethanol were removed using the rotatory evap-,
orator. The residual crude material (A) was a mixture of liquid and
solid and weighed 4.766 g (67.22% yield, calculated as if all mesityl
disulfide; 78% yield calculated as if all mesitylene). The liquid was
decanted from the solid. The solid was washed with small amount of
low boiling petroleum ether to give 1.47 g (20% yield) of mesity1disulfide,
m.p. 124-125°C [lit. (8) m.p. 125°C). The liquid weighed 1.1 g (23%
yield) and was identified from its ir spectrum as mesitylene.
The basic portion (B) was acidified and extracted with four 100 ral
portions of ether. The combined ether solution was dried over 3 g of
anhydrous magpesium sulfate. The ether and ethanol were removed using
the rotatory evaporator. The light yellow liquid weighed 0.79 g (10.69%
yield) and assumed to be a mixture of 2,4 ,6-trimethylthiophenol· with':.
trace amounts of mesityldisulfide.
Fourth Reduction of 2-Mesitylenesulfonamide.
Everything was the same as in the first reduction of 2-mesitylene-
51
sulfonamide (-33°C) including evaporation of ammonia over a period of
4 hours. The residual material was dissolved in 200 ml ice cold dis
tilled water. After acidification with 10% HCl, the solution was ex
tracted with four 100 ml portions of ether. The combined ehter extracts
were extracted with four 100 ml portions of 10% NaOH. Thus an ether
portion (A) and a basic portion (B) were obtained.
After removal of ether and alcohol from ether portion (A) , 'there
was obtained 2.36 g (41.71% yield) of a ligpt yellow liquid, n65 1.5020.
This was identified as mesitylene with trace amounts of mesityldisulfide
by comparison of ir spectrum with the ir spectrum of !mown mesitylene.
The basic portion (B) was acidified and extracted with four 100 ml
portions of ether. The combined ether extracts were dried over anhydrous
magnesium sulfate. The ether and alcohol were removed using the rotatory
evaporator. The ligpt.yellow liquid weigped 2.09 g (28.30% yield) and
was assumed to be 2,4 ,6-trimethylthiophenol with small amount of rnesityl
disulfide. The ir spectrum was the same as the first reduction product •
52
l ---
'f 1.
>( 2.
L 3.
'{ 4.
V5.
i . 6.
;(7.
8.
'! 9.
10.
111.
·:/12.
/13.
)(1.4.
\15.
(16.
/17.
,./ 18.
BIBLIOGRAPHY
G.B. Wooster, U.S. Patent 2,182,242 (1938). ~· Amer. Chern. Soc., 59' 596 (1937).
A.J. Birch,~· Chern. Soc., 430 (1944).
A.L. Wilqs and N.A. Nelson, ~· Amer. Chern. Soc., 75, 5366 (1953).
A.J. Birch, Nature, 158, 585 (1946).
A.J. Birch, Quart. Revs.,~, 69 (1950).
M.E. Kuehne and B.F. Lanbert, ~· Amer. Chern. Soc., 81, 4278 (1959).
A.J. Birch and J. Cymerman-Grais, ~·Austral. Chern.,~ 512 (1955).
Chern. Abst. 56:3392 f and 4284 h.
A.J. Birch, ~· Chern. Soc., 809 (1945).
'l'. P. F. Niern, Masters Thesis, Birch Reduction of Bcnzcnesulfonamide and Benzenepl)osphonic Acid, University of the Pacific, l9ti5.
Z.S. Ariyan and C.A. W:lles, ;!_. Chern. ~oc., 1961, 11510. - --- -
A.J. Birch and H. Smith, Quart. Rev., 12, 17 (1958).
W. Huckel, B. Graf and D. rlhmker; 1\nr!_. 614, 47 (1958).
P.T. Cottrell and C.A. Mann, ~· Amer. Chern. Soc., 93, 3579 (1971).
A.P. Krapcho and A.A. Bothner, ~· Amer. Chern. Soc., 81, 3658 (1959).
A.J. Birch and D. Nasipuri, Tetrahedron,§_,_ 148 (1959).
J .F. Easthan and D.R. Larldn, ~· JlJner. Chern. Soc_., 81_, 3652 (1959).
H.L. Dryden, Jr., G.M. Webber, R.R. Burtner and J .A. Cella, ~· Or_g_. Chem. , 26, 3237 ( 1961) .
>:19. J. Kovacs and U .R. Ghatak, ~· Org. Chell!., 31, 119 (1966).
20. V. DuVigneaud and O.K. Berhens, ~· Bio. Chern., ll7, 27 (1937).
21. W.D. Closson, Sungchul Jj_ and S. Schulenberg, ~· Amer. Chern. Soc., 92_, 650 (1970).
53
22. H. Smith, Organic React:ton ill Liquid .Ammoma,. John WHey and Sons, Inc., New York, NY, 1963, p. 253.
(23. A. Koch,:!_. Chern. Soc., 408 (1949).
><24. A. C. Cope and E.C. Herrick, :!_. Arner. Chern. Soc., 72, 983 (1950).
7-25. K. Kumler and C. Strait, :!_. Arner. Chern. Soc., 65, 2349 (1943).
)<:'26. H.E. Z:i_mmennan, Tetrahedron, 16, 169 (1961).
27. Luther Dickson, Masters Thesis, A Study of the Birch Reduction of m-Methoxybenzamide, University of the Pacific,(l968).
28. H.O. House, Modem Synthetic Reaction, Benjamin, Inc., New York, Chapt. 3,(1965).
29. R.L. Shriller, R.C. Fuson, and D.Y. Curtin, The Systematic Identification of Organic Compounds. John WHey and Sons, New York, NY. 1965.
r- 30. A.J. Birch and R.J. Harrison, :!_. Chern. Soc., §., 519 (1955).
31. R.F. Morrison, and R.N, Boyd, Organic Chemistry, John Wiley and &~ns, Inc., New York, NY. 1957, p. 590.
·( 32. A.J. Birch, :!_. Roy. Inst. Chern., 81, 100 (1957).
33. F.J. Y.ak:is, Steroid Reactions, ed. by C. Dierassi, Holden-Day, Inc. 1963, p. 267.
\·34. L. Homer and H. NeUlnan, Chern. Ber., 98, 3462 (1965).
35. A.H. Qazi, Masters Thesis, Birch Reduction of Benzamide, Umversity of the Pacific, 1965. ·
36. Handbook of Physics and Chemistry, The Chemical RUbber Company, 51st edition, 1970-71. New York, NY.
54
..