MAGNETIC RESONANCE IN CHEMISTRY, VOL.

24, 651-655 (1986)

"N NMR: Iminothiol-Thioamide Tautomerism

of 2-Mercaptobenzazoles and l-Methyl-2-
mercaptoimidazole

R. S. Balestrero, D. M. Forkey* and J. G. Russell*

Department of Chemistry, California State University, Sacramento, California 95819, USA

lSN NMR spectra of a number of 2-mercaptoazoles were obtained and the position of the iminothiol-thio-
amide prototropic tautomeric equilibrium was determined. Because of the large chemical shift difference of
cu 100 ppm between the iminothiol and thioamide nitrogen atoms, the I5N chemical shifts of the S-methyl
and N-methyl analogs of each tautomer provided reasonable chemical shift models for the same nitrogen
atom in the tantomers. Only a small correction for an N-methyl effect was required.

INTRODUCTION the corrections for the effects of methyl substitution are

Iminol-amide and iminothiol-thioamide tautomeric
equilibria have been studied using a variety of
spectroscopic techniques, often with disappointing
results.' Included in these studies are 'H, I3C and 14N
NMR investigations of these tautomeric
In solution at room temperature, the tautomers
interconvert rapidly, with a resulting averaging of the
NMR chemical shifts and coupling constants. This is
exemplified by the iminothiol-thioamide tautomer-
ism, N-NH, shown below.
N NH
X = 0, S, NH, NCH3
= xNaN -k X N H a N H (1)
X N H = (8obs - aN)/( (2)
The 'H, 13C and nitrogen chemical shifts observed,
8&s, will be equal to the chemical shift values for each
tautomer, aN and &H, weighted by the molar fraction
of each tautomer, XN and X N H . The value of tiobsis
then given by Eqn (1) and the molar fraction of the
thioamide tautomer, XNH, is given by Eqn (2).
The use of Eqn (2) to obtain estimates of X N H
requires values for the chemical shifts for each
tautomer, aN and aNH, which are obtained from
suitable model compounds. The success of the method
requires a large difference between aN and 6 N H and
relatively close correspondence of the model chemical
shifts to those expected for the tautomers. Syntheti-
cally convenient tautomer model compounds are the
S-methyl and N-methyl derivatives of the iminothiol
and thioamide tautomers.
However, 'H chemical shifts are not useful, since
* Authors to whom correspondence should be addressed
usually similar to the magnitude of the chemical shift
differences of ca 1ppm for the tautomers.1,2,4-7With
I3C NMR the differences in tautomer chemical
shift^',^,"^ are 10 to 20ppm, but as the methyl cor-
rection may be larger than Sppm it is thus prudent
to interpret 13C chemical shifts only in a qualitative
fashion.
The nitrogen chemical shift difference between
amide and imino nitrogen atoms is large,' over
80ppm, and thus appears to be the most sensitive
method for studying iminothiol-thioamide or iminol-
amide tautomerism. This large nitrogen chemical shift
difference has been successfully exploited in 14NNMR
studies of tautomerism in hydroxypyridines2 and
mer~aptopyridines.~ Further, methylated analogs of
the tautomers were used as tautomer model
compounds, and the corrections for the effects of
methyl substitution were found to be small (1-2 ppm).
However, I4N is a spin 1 nucleus, which often yields
NMR spectra with large line widths. In contrast, 15N is
4
a spin nucleus and the NMR spectra exhibit the
expected narrow lines, as well as the large chemical
shift differences. The advantage of I5N is evident in
Fig. 1, which shows (a) the I4N and (b) the 15N NMR
spectra of 1-methyl-2-mercaptoimidazole(11). Thus,
we have employed 15N NMR to study the imino-
thiol-thioamide tautomerism of 2-mercaptobenzazoles
and 1-methyl-2-mercaptoimidazole.
RESULTS AND DISCUSSION
The 15N and 13C NMR spectra of several 2-mercapto-
benzazoles, 1-methyl-2-mercaptoimidazole and the
S-methyl and N-methyl derivatives of the iminothiol
and thioamide tautomers were determined, and the
"N chemical shifts and 13C chemical shifts of the ring
carbon bonded to sulfur (C-2) are collected in Table
1. The nitrogen chemical shifts were determined
experimentally with respect to external nitromethane

0749-l581/86/080651-05$05 .OO Received 1 March 1985

01986 by John Wiley & Sons, Ltd. Accepted 20 June 1985
652 R. S. BALESTRERO, D. M. FORKEY AND J. G. RUSSELL

2 0 0 Hz
H Table 1. "N and =C chemical shifts" of some 2-mercapto-
benzimidazoles 2-mercaptoimidazoles and their
methyl derivatives in DMSO solution
Compound hN(ppm1 ~~~c~c.,~(~~ml
a) 2-Mercaptobenzoxazole(1) 157.0 180.3
3-Methyl-2(3H)-benzoxazolethione (2) 149.8 179.5
2-Methylthiobenzoxazole (3) 237.1 165.3
2-Mercaptobenzothiazole (4) 183.4 162.1
3-Methyl-2(3H)-benzothiazolethione (5) 174.9 183.7
2-Methylthiobenzothiazole(6) 296.3 167.8
2-Mercaptobenzimidazole (7) 154.9 168.2
1-Methyl-2-mercaptobenzimidazole ( 8 ) 147.2 (N-1) 168.7
153.2 (N-3)
1-Methyl-2-methylthiobenzimidazole(9) 139.2 (N-1) 152.6
237.2 (N-3)
1,3-Dimethyl-l,3-di hydro-3H- 144.7 169.1
benzimidazole-2-thione (10)
1-Methyl-2-mercaptoimidazole (11) 161.6 (N-1) 161.0
166.8 (N-3)
(DCCI,) 162.2 (N-1) 160.2
169.5 "-3)
1,3-Dimethyl-l ,&dihydro3H- 159.7 161.9
imidazole-2-thione (12)
(DCCI31 159.8 162.6
1-Methyl-2-methylthioimidazole(13) 161.5 (N-1) 141.7
262.6 (N-3)
Figure 1. Nitrogen NMR spectra of DMSO solutions of (DCCI,) 159.5 "-1) 142.9
1-methyl-2-mercaptoimidazole (11): (a) 5.742 MHz I4N
258.3 (N-3)
spectrum of 11 (5000 transients); (b) 8;059 MHz I5N spectrum
of 11 (50000 transients) determined with continuous 'H Thioacetanilide (14) 171.7 199.3
broad-band decoupling and no added Cr(acac), in order to (DCCI,) 170.2 (E) 204.0 ( E )
show the relative NOE of the NH and NCH, nitrogen 168.5 (Z) 200.5 (Z)
resonances, with the spectrum phased upright; (c) I5N N-Methylthioacetanilide (15) 164.6 199.8
spectrum of 11 determined as in (b), but after the addition of (DCCI,) 164.8 201.0
DO
, and NH-ND exchange. a 6,5N relative to external liquid ammonia and 613c relative to in-
ternal TMS.
and then corrected to be reported with respect to
external liquid arnrn~nia.','~ Magnetic susceptibility A comparison of the 15N chemical shifts of the
corrections were neglected for both the external unmethylated parent 2-mercaptoazoles 1, 4 and 11
reference',l0 and any added Cr(acac), relaxation with the chemical shifts of methylated tautomer
agent" as these effects are generally small (less than derivatives shows the parent chemical shifts to be
1PPmb similar to those for the N-methylthioamides 2, 5 and
The assignment of the nitrogen resonances was 12, respectively. This similarity results in the
unambiguous, with the exception of 1-methyl-2-mer- qualitative conclusion that the thioamide tautomer is
captobenzimidazole (8) and 1-methyl-2-mercaptoimid- the predominant tautomer. A similar conclusion is
azole (11). Each exhibited two lines separated by reached on comparing the 13C chemical shifts for C-2
5-6ppm, with one resonance due to an N-methyl of the 2-mercaptoazoles 1, 4 and 11 to the C-2
nitrogen atom and the other to an NH nitrogen atom. chemical shifts of the S- and N-methyl tautomer
With continuous broad-band proton decoupling, the model compounds. The I3C chemical shifts of the
N-methyl resonance showed a much smaller nuclear parent compounds closely match those of the
Overhauser effect than the NH nitrogen atom which N-methylthioamide tautomer, suggesting a pre-
allowed assignment of the lower field, more intense, dominance of this tautomer. These results are in
resonance to the NH nitrogen atom. This assignment agreement with previous qualitative 13C NMR studies
was confirmed by addition of several drops of of 2-mercaptoazoles 44 and ll.5
deuterium oxide to the sample tube, which resulted in However, it is possible to examine iminothiol-
NH-ND exchange and the disappearance of the thioamide tautomerism in a quantitative manner using
low-field resonance. The 15N NMR spectrum of 15N chemical shifts to obtain the molar fraction of the
mercaptoimidazole 11 is shown in Fig. lb, and the thioamide tautomer according to Eqn (2). The
effect of deuterium oxide addition is seen in Fig. lc. 2-mercaptoazoles are rapidly equilibrating between
A comparison of iminothiol nitrogen chemical shifts two tautomers, exemplified by 2-mercaptobenzoxazole
with the corresponding thioamide nitrogen chemical (la and lb), which yield a single nitrogen resonance
shifts shows the iminothiol nitrogen to be shifted to
low field by a considerable amount. The iminothiol
nitrogen resonates approximately 90, 100 and 120 ppm
to low field of the thioamide nitrogen atoms in
methylbenzoxazoles 2 and 3, methylimidazoles l2 and
13 and methylbenzothiazoles 5 and 6 , respectively.
a;-
with a chemical shift given by Eqn (1).

la
=K >

lb
H
s
 ”N NMR. TAUTOMERISM OF 2-MERCAPTOBENZAZOLES AND 1-METHYL-2-MERCAPTOIMIDAZOLE
Application of Eqn (2) to obtain values of the
thioarnide molar fraction, X N H , requires nitrogen
chemical shifts, (SN and aNH,for the iminothiol and
thioarnide tautomer. Using the nitrogen chemical
shifts of the S - and N-methyl tautomer analogs as 6,
and for the tautomers requires a correction for
the effect of methyl substitution. The 15N spectra of
the NH parent compounds and the N - and S-methyl
model compounds were determined in DMSO
solutions and, for one compound set (11-13), also in
DCCI, solution. Thus, a methylation correction must
be determined for both solutions.
The N-methyl correction was taken as the
difference in the I5N chemical shift between
thioacetanilide (14) and N-methylthioacetanilide (15).
In DCCI3 solution, 14 shows two NH resonances, one
at 170.2ppm with a relative intensity of 1 and the
second at 168.5ppm with a relative intensity of 5,
which arise from the E- and 2-stereoisomers,
respectively. This assignment was based on the I3C
spectrum of 14, which gave two overlapping spectra
from the E- and 2-isomers. The thioacetyl methyl
resonance, 6 35.4ppm, for the Z-isomer was three
times the intensity of that for the E-isomer, which was
at 6 30.1 ppm. The higher field position of the
thioacetyl methyl resonance of the E-isomer results
from steric interaction with the ortho-hydrogen
atom.” This result is in agreement with the bias
towards the 2-isomer derived from the ‘H spectrum13
of 14. In the case of N-methylthioacetanilide ( E ) , the
‘H NMR results indicate that the Z-isomer is the only
isomer present’, in DCCl, solution, and only one 15N
resonance at 164.8ppm is observed. Hence the
‘DCCI, N-methyl correction’ is 3.7 ppm, the
difference between the chemical shifts of 168.5 ppm
for the 2-isomer of 14 and 164.8 pprn of 15.
In DMSO solution both 14 and the N-methyl
derivative 15 give one I5N resonance at 171.7 and
164.6ppm, respectively. Both 14 and 15 show
evidence of only one isomer in their DMSO solution
13C spectra. From the correspondence of the 13C
spectra in DCC13 solution to the DMSO solution
spectra of 14 and 15, it can be concluded that both 14
and 15 exist as the 2-isomer. The 2-isomer of 14 in
DCCI, solution has the thioacetyl methyl resonance at
35.4 ppm and the thiocarbonyl carbon at 200.5 ppm;
these are at 35.3 and 199.3ppm, respectively, in
DMSO solution. Similarly, for 15 the thioacetyl
methyl resonance at 33.8 ppm and thiocarbonyl
carbon at 201.0 ppm in DCC1, solution appear at 33.5
and 199.8ppm, respectively, in DMSO solution.
The DMSO solution correction to the nitrogen
chemical shift of the N-methyl for the thioamide
tautomer, the ‘DMSO N-methyl correction,’ was the
7.1 ppm chemical shift difference between thio-
acetanilide, 171.7 ppm, and N-methylthioacetanilide,
164.6ppm. Thus, a 7.1 ppm correction must be added
to the chemical shift of the N-methylthioamide to
yield a value of 6 N H for the DMSO solutions. This
correction is consistent with the 5.2 ppm chemical shift
difference between the nitrogen atoms of N,N,N’-tri-
methyl~rea’~ in DMSO solution, where the NH
nitrogen atom resonates to lower field. Similarly, the
NH atom of pyrrole resonates 5.6ppm to low field of
653
Table 2. Molar fraction of thioamide tautomer determined
from 61.5~
Molar fraction,
thioarnide
Compound Solvent tautorner
2-Mercaptobenzoxazole (1) DMSO 1 .oo
2-Mercaptobenzothiazole (4) DMSO 0.99
2-Mercaptobenzimidazole (7) DMSO 0.92
I-Methyl-2-mercaptobenzimidazole ( 8 ) DMSO 0.98
I-Methyl-2-mercaptoimidazole(11) DMSO 1 .oo
DCCI, 0.98
the nitrogen resonance of N-methylpyrrole in DMSO
solution^.^
The nitrogen chemical shifts of the S-methyl model
compounds will be applied uncorrected as the
nitrogen chemical shift of the corresponding imino-
thiol tautomer. The S-methyl is removed from the
pertinent nitrogen atom, and consequently the effect
is expected to be small, less than 1~ p m , and
’ ~ ~may be
neglected. The large difference between 6 , and
results in a correction term uncertainty of 1ppm,
giving a relatively small uncertainty of less than 2% in
the molar fraction estimate obtained from Eqn (2).
With consideration of the ‘DMSO N-methyl
correction,’ Eqn (23 was applied to the DMSO
solution chemical shifts of 2-mercaptoazoles 1, 4, 8
and 11 to yield estimates of the molar fraction of
thioamide tautomer, which are collected in Table 2.
The nitrogen chemical shifts of N-methylthioamides 2,
5, 10 and 12 were corrected by the +7.1 ppm ‘DMSO
N-methyl correction’ to provide the respective values
for BNH. The iminothiol tautomer chemical shifts, dN,
were taken as equal to the imino nitrogen chemical
shifts of the methylthioazoles 3, 6, 9 and 13.
Similarly, the effect of a non-hydrogen-bonding
solvent on the equilibrium can be observed from the
DCC13 solution spectrum of mercaptoimidazole 11.
The ‘DCC1, N-methyl correction’ of +3.7 ppm was
applied to the DCCl, solution nitrogen chemical shift
of 12 and the DCC13 solution uncorrected imino
nitrogen chemical shift of 13 were used as iSNH and
(SN, respectively, in Eqn (2). Unfortunately, 11 was
the only mercaptoazole which was sufficiently soluble
in DCC1, to permit the determination of an 15N
spectrum.
In the case of 2-mercaptobenzimidazole (7) there
are three rapidly equilibrating tautomers for which the
observed 15N chemical shift, gobs,is the molar fraction
weighted average given by Eqn (3), where Xec are the
molar fractions of 7a-c and ,,si are the chemical
7a lb lc
shifts of the same nitrogen atom in each of the
tautomers 7a-c. Since the sum of the molar fractions
equals one and Xa and X, are equal, the molar
654 R. S. BALESTRERO, D. M. FORKEY AND J. G . RUSSELL
fraction, X,, of the thioamide tautomer, 7c, is given by
Eqn (4).
The NH nitrogen atom of 7a is an azole NH-type
nitrogen atom and is taken as the N-methyl of 9,
139.2ppm, corrected by +5.6ppm7 which is the
'DMSO N-methyl correction' previously determined
for a z ~ l e s The
. ~ imino nitrogen atom chemical shift,
6b, for the 7b tautomer was the 237.2ppm chemical
shift of the imino nitrogen atom of 9. Finally, the
thioamide nitrogen shift, a,, is given by the 144.7 ppm
nitrogen chemical shift of 10 corrected by the
+7.1 pprn thioamide 'DMSO N-methyl correction,'
and 6obs is the 154.9 pprn observed for 7.
The equilibrium thioamide tautomer molar fraction
estimates obtained from the 15N chemical shifts are
collected in Table 2. With the exception of
2-mercaptobenzimidazole (7), all the compounds in
DMSO solution are seen to exist exclusively as the
thioamide tautomer. After this paper had been
submitted, a report15 appeared on the tautomerism of
2-mercaptoimidazole using a similar 15N NMR
technique. This recent result of 0.99 molar fraction
thioamide tautomer for 2-mercaptoimidazole is
consistent with these results. A possible contribution
to this extreme bias towards the thioamide tautomer is
that DMSO is a good hydrogen bond acceptor and
might be expected to favor this tautomer through the
DMSO-HN hydrogen bond. Hydrogen bonding
involving an NH is expected to lower the tautomer
energy more than that involving an SH. However,
2-mercaptoimidazole (11) in DCCl, solution is
essentially present completely as the thioamide
tautomer , suggesting that hydrogen bond formation is
a minor consideration and the equilibrium is
dominated by energy lowering resulting from the
thioamide functional group. Further, neither the
nature of the heteroatom in the benzazole ring nor the
benzo ring fusion have a detectable effect on the
position of the iminothiol-thioamide equilibrium.
The sole exception to the complete dominance of
the thioamide tautomer is 2-mercaptobenzimidazole
(7), which has a 0.92 molar fraction of thioamide
tautomer. While the determination of a 0.08 molar
fraction of iminothiol tautomer is pushing the limit of
uncertainty, it may well be the result of the statistical
advantage of two equivalent tautomers 7a and 7b and
hydrogen bonding of the azole NH of the iminothiol
tautomer.
We have shown that the S- and N-methyl
derivatives provide reasonable 15N chemical shift
models of their respective SH or NH tautomers. After
application of a relatively small correction for the
effect of methylation, it is clear that a maximum of
only 0.02-0.04 molar fraction of iminothiol tautomer,
with the exception of 7, may be present in the
2-mercaptoazole iminothiol-thioamide equilibrium
mixture. The establishment of this upper limit on the
molar fraction of iminothiol tautomer is not possible
from 'H or 13C chemical shifts, suggesting that 15N
NMR is the method of choice in studies of prototropic
tautomerism involving imino-amino nitrogen atoms.
EXPERIMENTAL
Spectra
Frequency sweep CW 'H NMR spectra were
determined at 60MHZ with a Perkin-Elmer R-20 or
at 100MHz with a Varian HA-100 NMR spectrom-
eter. The 13CNMR spectra were recorded at
20MHz using a Varian FT-80A NMR spectrometer.
The 13Cspectra were determined at a spectral width of
4 kHz with a 16K data table, applying a 45" pulse with
a repetition rate of 2 s and continuous broad-band 'H
decoupling.
The 15N NMR spectra were determined at
8.059 MHz with the Varian FT-8OA instrument, using
solutions of 750mg of compound dissolved in 2ml of
DCC1, or DMSO-d6. The 15N spectra of the NH
compounds were recorded under the following
conditions: 4 kHz spectral width, 8K data table, 15" or
30" pulse angle, I s pulse repetition rate and
continuous 'H broad-band decoupling. In order to
obtain the chemical shift of the N-methyl or imino
nitrogen atoms, 30mg of Cr(acac), were added to the
sample and the spectrum was determined with a 4 kHz
spectral width, 4K data table with 4K of zeros, 15" or
30" pulse angle, 0.5 s acquisition time and 2.5 s pulse
delay. The broad-band 'H decoupler was on only
during the acquisition time to ensure maximum
suppression of the NOE. In all cases it was necessary
to accumulate 30 000-100 000 transients in order to
obtain s ectra with an acceptable signal-to-noise ratio.
The 5' N chemical shifts were determined with
respect to external nitromethane contained in a 2 mm
capillary tube held concentrically in the sample tube.
The nitrogen chemical shifts referenced to nitro-
methane, 8cH3N02,were then converted into a
chemical shift relative to li uid ammonia, 6 N H 3 , using
the following expression:,,la
&H3 =~ + 380.2
C H ~ N O ~ P P ~
No effort was made to correct the chemical shifts for
solution magnetic susceptibility differencesg or mag-
netic susceptibility changes" resulting from the
Cr(acac), .
Materials
The mercaptoazoles 1,4, 7 and 11and thioacetanilide
were obtained from commercial sources and used
without further purification. The N - and S-meth 1
derivatives 2,16 3,16 5,17 6,18S,19 9;' 10,lg l2;l 13"
and 1523 were synthesized according to published
procedures. The structures and purities of the
compounds were verified by their 'H and 13C NMR
spectra.
 '*N NMR. TAUTOMERISM OF 2-MERCAPTOBENZAZOLES AND I-METHYL-2-MERCAPTOIMIDAZOLE
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