Lessene et al.
JOCArticle
values of -2.3, -2.0, and -1.6 ppb/K, respectively, clearly
indicate a hydrogen-bonded conformation, which is stable
over the variable temperature NMR experiment, a situation
that is likely to be even more favored in CDCl3. We conclude,
therefore, that the CDCl3 NTDCS values for the NH proton
of -3.9, -5.0, and -5.4 ppb/K, respectively, align with
interpretation (ii) in Table 1, even though the last value lies
just outside the conventional range for this interpretation.54
All compounds exhibited an upfield shift in the resonance
of the NH proton in changing solvents from CDCl3 to
DMSO-d6, consistent with the situation in Figure 3a.
In summary, we conclude that class II compounds
adopt a hydrogen-bonded conformation in both CDCl3
and DMSO-d6. This conformation remains favored during
the variable-temperature experiment.
further upfield than those in the corresponding class II
compounds 2a-c, but not shifted upfield as much as those
in the corresponding respective model compounds 5b-d.
Using these NMR chemical shift data, we estimated the
respective proportion of the closed form to be 66%, 40%,
and 25%, respectively. The hydrogen-bonded form is, there-
fore, preferred in CDCl3 only for 4a where R2 is methyl,
and changing to isopropyl and then tert-butyl gives rise to
an increasing amount of the non-hydrogen-bonded form.
The CDCl3 NTDCS data is as follows: compound 4a dis-
played a large NTDCS (-8.8 ppb/K), 4b a moderate NTDCS
(-3.9 ppb/K), and 4c a very small (-1 ppb/K) NTDCS.
Considering the IR spectra, these values are consistent with
interpretations iv, i, and iii, respectively, in Table 1.
Class IV compounds can adopt a non-hydrogen-bonded
conformation in CDCl3, and it is expected that a strong
hydrogen-bond-disrupting solvent such as DMSO would
completely destabilize the hydrogen-bonded form, analo-
gous with the behavior observed for 3. This is confirmed
by the large DMSO-d6 NH NTDCS values of -4.7, -4.6,
and -5.2 ppb/K, respectively, for 4a, 4b, and 4c. The NH
resonance in all class IV compounds is shifted downfield in
DMSO-d6 compared with CDCl3, markedly so for 4c, less so
for 4b, and only marginally for 4a. This is consistent with
situations b and c in Figure 3, where in the case of 4a, the
situation depicted in Figure 3b is minor but in Figure 3c is
major (as 4a is mostly internally hydrogen-bonded in
chloroform). In contrast, for 4c, the situation depicted in
Figure 3b is major and in Figure 3c is minor (as 4c is mostly
not internally hydrogen bonded in chloroform), and so there
is a more marked downfield NH chemical shift observed in
DMSO-d6 relative to CDCl3. The situation for compound 4b
lies somewhere between those for 4a and 4c.
Class III. Compound 3 is closely related to 1 (class I) but
exhibits a distinctly different conformational behavior. At
room temperature, the IR spectrum of compound 3 shows a
strong, broad absorption band between 3200 and 3350 cm-1
,
indicative of hydrogen bonding, and of the closed form.
However, there is a small sharp NH band between 3400 and
3450 cm-1 indicating the presence of a non-hydrogen-bonded
conformation. In chloroform, the NH 1H NMR signal is far
downfield at 10.30 ppm but is still upfield from the correspond-
ing signal in 1, consistent with a mixture dominated by the
hydrogen-bonded form but containing a significant amount of
the non-hydrogen-bonded form. Using 1 and acetanilide as
models for hydrogen-bonded and non-hydrogen-bonded con-
formations, respectively, we can deduce from the chemical
shift value that the conformer population of 3 comprises 24%
of the non-hydrogen-bonded conformation and 76% of the
hydrogen-bonded conformation. The large NTDCS of -9.1
ppb/K is supportive of situation (iv) in Table 1.
The upfield shift observed for the chemical shift in DMSO-d6
at 300 K compared to CDCl3 is also indicative of a mixture
dominated by an internally hydrogen-bonded conformation in
CDCl3 (Figure 3a). In the more polar solvent, compound 3
adopts a non-hydrogen-bonded conformation: the DMSO-d6
NTDCS value of -4.5 ppb/K is diagnostic of a solvent-exposed
proton. As expected, the NH chemical shift of 9.93 ppm is very
close to the value for acetanilide in the same conditions (9.91
ppm). This downfield value is testament to the strong interac-
tion between the NH proton and DMSO for both compounds
and is only marginally upfield from the NH chemical shift of
the hydrogen-bonded form of 3 in CDCl3. In summary, class
III compounds prefer to adopt a hydrogen-bonded form at
room temperature in chloroform; however, they are readily
perturbed toward a non-hydrogen-bonded form in polar hy-
drogen-bond-accepting solvents.55
Class IV. The IR spectrum of compounds in this class
revealed an intriguing but consistent trend in conformational
behavior. As the N2 substituent becomes progressively bulk-
ier, from NHMe (4a) to NH-i-Pr (4b) to NH-t-Bu (4c), the
intensity of the IR absorption band corresponding to a
hydrogen-bonded NH becomes progressively smaller and
that for a non-hydrogen-bonded NH becomes progressively
larger to become the major feature for 4c. Consistent with
this trend, the chemical shift of the respective NH protons are
In conclusion, most of the benzoylureas preferentially
adopt hydrogen-bonded conformations in chloroform with
the exception of class IV compounds 4b and 4c, for which the
equilibrium is shifted toward the non-hydrogen-bonded
conformer at room temperature. In DMSO, compounds
from classes I and II retain a stable hydrogen-bonded con-
formation, but class III and IV compounds adopt the non-
hydrogen-bonded conformation.
Conformation in the Solid State. The inherent good crystal-
linity that we observed for class IV compounds naturally lent
them to X-ray crystallographic analysis. Shown in Figure 5a
is the solid-state structure of 4a, which crystallized from
acetonitrile in the twisted conformation. The spectroscopic
data for 4a had indicated that while it preferred to exist as the
closed form in CDCl3, the polar environment of DMSO
stabilized the twisted form, and it appears the crystal-pack-
ing stabilization has done so similarly. In the crystal lattice,
this compound formed loose dimers with favorable electro-
static interactions between the N2-H of one molecule with
the C1dO of another and the N2-H of the second molecule
with the C1dO of the first. The lack of propensity for this
compound to form tight dimers, even when crystallized,
was illustrated by the fact that the distance between the
respective N2 atom with its intermolecular O1 counterpart
was long, 3.16 A.56 Similar remarks apply to 4c, which also
˚
crystallized from acetonirile in the twisted conformation, as
shown in Figure 5c.
(54) Adrian, J. C.; Wilcox, C. S. J. Am. Chem. Soc. 1991, 113, 678–680.
(55) We have synthesized other class III compounds, and all behave
similarly (data not shown).
(56) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48–76.
J. Org. Chem. Vol. 74, No. 17, 2009 6517