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"N NMR: Iminothiol-Thioamide Tautomerism of 2-Mercaptobenzazoles and L-Methyl-2-Mercaptoimidazole
"N NMR: Iminothiol-Thioamide Tautomerism of 2-Mercaptobenzazoles and L-Methyl-2-Mercaptoimidazole
"N NMR: Iminothiol-Thioamide Tautomerism of 2-Mercaptobenzazoles and L-Methyl-2-Mercaptoimidazole
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.
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 653
fraction, X,, of the thioamide tautomer, 7c, is given by NMR is the method of choice in studies of prototropic
Eqn (4). tautomerism involving imino-amino nitrogen atoms.
EXPERIMENTAL
The NH nitrogen atom of 7a is an azole NH-type
nitrogen atom and is taken as the N-methyl of 9, Spectra
139.2ppm, corrected by +5.6ppm7 which is the
'DMSO N-methyl correction' previously determined Frequency sweep CW 'H NMR spectra were
for a z ~ l e s The
. ~ imino nitrogen atom chemical shift, determined at 60MHZ with a Perkin-Elmer R-20 or
6b, for the 7b tautomer was the 237.2ppm chemical at 100MHz with a Varian HA-100 NMR spectrom-
shift of the imino nitrogen atom of 9. Finally, the eter. The 13CNMR spectra were recorded at
thioamide nitrogen shift, a,, is given by the 144.7 ppm 20MHz using a Varian FT-80A NMR spectrometer.
nitrogen chemical shift of 10 corrected by the The 13Cspectra were determined at a spectral width of
+7.1 pprn thioamide 'DMSO N-methyl correction,' 4 kHz with a 16K data table, applying a 45" pulse with
and 6obs is the 154.9 pprn observed for 7. a repetition rate of 2 s and continuous broad-band 'H
The equilibrium thioamide tautomer molar fraction decoupling.
estimates obtained from the 15N chemical shifts are The 15N NMR spectra were determined at
collected in Table 2. With the exception of 8.059 MHz with the Varian FT-8OA instrument, using
2-mercaptobenzimidazole (7), all the compounds in solutions of 750mg of compound dissolved in 2ml of
DMSO solution are seen to exist exclusively as the
DCC1, or DMSO-d6. The 15N spectra of the NH
thioamide tautomer. After this paper had been compounds were recorded under the following
submitted, a report15 appeared on the tautomerism of conditions: 4 kHz spectral width, 8K data table, 15" or
2-mercaptoimidazole using a similar 15N NMR 30" pulse angle, I s pulse repetition rate and
technique. This recent result of 0.99 molar fraction
continuous 'H broad-band decoupling. In order to
thioamide tautomer for 2-mercaptoimidazole is obtain the chemical shift of the N-methyl or imino
consistent with these results. A possible contribution nitrogen atoms, 30mg of Cr(acac), were added to the
to this extreme bias towards the thioamide tautomer is sample and the spectrum was determined with a 4 kHz
that DMSO is a good hydrogen bond acceptor and spectral width, 4K data table with 4K of zeros, 15" or
might be expected to favor this tautomer through the 30" pulse angle, 0.5 s acquisition time and 2.5 s pulse
DMSO-HN hydrogen bond. Hydrogen bonding delay. The broad-band 'H decoupler was on only
involving an NH is expected to lower the tautomer during the acquisition time to ensure maximum
energy more than that involving an SH. However, suppression of the NOE. In all cases it was necessary
2-mercaptoimidazole (11) in DCCl, solution is to accumulate 30 000-100 000 transients in order to
essentially present completely as the thioamide obtain s ectra with an acceptable signal-to-noise ratio.
tautomer , suggesting that hydrogen bond formation is The 5' N chemical shifts were determined with
a minor consideration and the equilibrium is respect to external nitromethane contained in a 2 mm
dominated by energy lowering resulting from the capillary tube held concentrically in the sample tube.
thioamide functional group. Further, neither the The nitrogen chemical shifts referenced to nitro-
nature of the heteroatom in the benzazole ring nor the methane, 8cH3N02,were then converted into a
benzo ring fusion have a detectable effect on the chemical shift relative to li uid ammonia, 6 N H 3 , using
position of the iminothiol-thioamide equilibrium. the following expression:,,la
The sole exception to the complete dominance of
the thioamide tautomer is 2-mercaptobenzimidazole
(7), which has a 0.92 molar fraction of thioamide &H3 =~ + 380.2
C H ~ N O ~ P P ~
tautomer. While the determination of a 0.08 molar
fraction of iminothiol tautomer is pushing the limit of No effort was made to correct the chemical shifts for
uncertainty, it may well be the result of the statistical solution magnetic susceptibility differencesg or mag-
advantage of two equivalent tautomers 7a and 7b and netic susceptibility changes" resulting from the
hydrogen bonding of the azole NH of the iminothiol Cr(acac), .
tautomer.
We have shown that the S- and N-methyl
derivatives provide reasonable 15N chemical shift Materials
models of their respective SH or NH tautomers. After
application of a relatively small correction for the The mercaptoazoles 1,4, 7 and 11and thioacetanilide
effect of methylation, it is clear that a maximum of were obtained from commercial sources and used
only 0.02-0.04 molar fraction of iminothiol tautomer, without further purification. The N - and S-meth 1
with the exception of 7, may be present in the derivatives 2,16 3,16 5,17 6,18S,19 9;' 10,lg l2;l 13"
2-mercaptoazole iminothiol-thioamide equilibrium and 1523 were synthesized according to published
mixture. The establishment of this upper limit on the procedures. The structures and purities of the
molar fraction of iminothiol tautomer is not possible compounds were verified by their 'H and 13C NMR
from 'H or 13C chemical shifts, suggesting that 15N spectra.
'*N NMR. TAUTOMERISM OF 2-MERCAPTOBENZAZOLES AND I-METHYL-2-MERCAPTOIMIDAZOLE 655
REFERENCES