Unusually low barrier to carbamate C-N rotation

Article abstract of DOI:10.1021/jo025554u

The barrier for rotation about an N-alkylcarbamate C(carbonyl)-N bond is around 16 kcal/mol. In the case of an N-phenylcarbamate, the rotational barrier is lowered to 12.5 kcal/mol, but with N-(2-pyrimidyl)carbamates the barriers are so low (<9 kcal/mol)

Full text of DOI:10.1021/jo025554u

J . Org. Chem. 2002, 67, 3949-3952
3949
Un u su a lly Low Ba r r ier to Ca r ba m a te C-N
Rota tion
Martin J . Deetz, Christopher C. Forbes, Marco J onas,
J eremiah P. Malerich, Bradley D. Smith,* and
Olaf Wiest
F igu r e 1. Secondary carbamate rotamers.
Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46656
smith.115@nd.edu
Received J anuary 24, 2002
Abstr a ct: The barrier for rotation about an N-alkylcar-
bamate C(carbonyl)-N bond is around 16 kcal/mol. In the
case of an N-phenylcarbamate, the rotational barrier is
lowered to 12.5 kcal/mol, but with N-(2-pyrimidyl)carbam-
ates the barriers are so low (<9 kcal/mol) that the syn and
anti rotamers cannot be observed as separate signals by 500
MHz NMR spectroscopy at 183 K. X-ray and computational
data show that the N-(2-pyrimidyl) carbamates have C(car-
bonyl)-N bonds that are on average 0.03 Å longer than for
related N-phenylcarbamates. The computational results
trace the origin of the effect to increased single bond
character for the C(carbonyl)-N bond due to the increased
electron-withdrawing ability of the pyrimidyl ring.
F igu r e 2. Association of 1 with the syn rotamer of 2 favored
over association with the anti rotamer leading to an increased
syn:anti ratio.
we have prepared and characterized the secondary car-
bamates 4-6 and the tertiary carbamates 7-9. Unex-
Hindered rotation about the amide C-N single bond
is one of the most extensively studied phenomena in
conformational stereochemistry.1 Carbamates are also
known to exist as syn and anti rotamers (Figure 1)
although far fewer systems have been investigated.2
From the experimental data, it appears that the typical
isomerization barrier for carbamates (∼16 kcal/mol) is
1-4 kcal lower than that for structurally related amides.
Typically, secondary carbamates and amides strongly
prefer an anti conformation; however, hydrogen bonding
templates can be used to alter the equilibrium.3,4 For
example, we recently reported that the presence of
donor-acceptor-donor (DAD) template 1 increases the
syn/anti ratio for N-(2-pyridyl)carbamate 2 and N-(2-
thiazyl)carbamate 3 in CDCl3 by selectively forming
hydrogen-bonded complexes with the syn rotamer as
shown in Figure 2.4
An exception to the normal conformational preference
of secondary amides is a report by Beijer and co-workers,
who showed that the amide group in a secondary 2-(acyl-
amino)pyrimidine prefers a syn conformation.5 This
unusual result has prompted us to examine some analo-
gous N-(2-pyrimidyl)carbamate derivatives. Specifically,
pectedly, we find that we are unable to measure the syn/
anti equilibrium for the pyrimidyl carbamates using low-
temperature, high-field NMR spectroscopy because the
C-N rotational barriers are very low. We provide struc-
tural data and computational analyses to help rationalize
our results.
Secon d a r y N-(2-P yr im id yl)ca r ba m a tes. Separate
samples of N-(2-pyrimidyl)carbamates 4-6 in CDCl3
solution were examined by NMR spectroscopy. Usually,
the rate of conformational exchange for carbamate rota-
mers is sufficiently slow at low temperature that separate
signals can be observed by 1H NMR. However, in the
cases of 4-6, only one set of signals is observed upon
cooling the samples to 213 K. Even the addition of 10
mol equiv of template 1 does not induce the appearance
of a second set of signals, which is contrary to the prev-
iously studied cases of pyridyl analogue 2 and thiazyl 3.4
In an effort to explain these unexpected results, we
considered the following questions: (i) Do these secondary
* Corresponding author. Phone: 574 631 8632. Fax: 574 631 6652.
(1) (a) Oki, M. Applications of Dynamic NMR Spectroscopy to
Organic Chemistry; VCH: Deerfield Beach, FL, 1985; Chapter 2. (b)
Stewart, W. E.; Siddall, T. H. Chem. Rev. 1970, 70, 517-551. (c)
Scherer, G.; Kramer, M. L.; Schutkowski, M.; Reimer, U.; Fischer, G.
J . Am. Chem. Soc. 1998, 120, 5568-5574.
(2) (a) Rablen, P. R. J . Org. Chem. 2000, 65, 7930-3937. (b) Lectka,
T.; Cox, C. J . Org. Chem. 1998, 63, 2426-2427. (c) Kost, D.; Kornberg,
N. Tetrahedron Lett. 1978, 35, 3275-3276.
(3) Marcovici-Mizrahi, D.; Gottlieb, H. E.; Marks, V.; Nudelman, A.
J . Org. Chem. 1996, 61, 8402-8406. Deetz, M. J .; Fahey, J .; Smith, B.
D. J . Phys. Org Chem. 2001, 14, 463-467.
(4) Moraczewski, A. L.; Banaszynski, L. A.; From, A. M.; White, C.
A.; Smith, B. D. J . Org. Chem. 1998, 63, 7258-7262. Deetz, M. J .;
J onas, M.; Malerich, J .; Smith, B. D. Supramol. Chem., in press.
(5) Beijer, F. H.; Sijbesma, R. P.; Vekemans, J . A. J . M.; Meijer, E.
W.; Kooijman, H.; Spek, A. L. J . Org. Chem. 1996, 61, 6371-6380.
10.1021/jo025554u CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

3950 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
significantly. Experimentally, template 1 has a surpris-
ingly weak affinity for carbamate 4 (K1:4 ) 8 M-1 in CDCl3
at -20 °C, which is significantly lower than the value of
400 M-1 previously measured for the association between
1 and 23,12). Although a thermochemical analysis of the
binding energies by computation is not useful because
the expected binding energy is smaller than the expected
basis set superposition error, the computed structures of
the hydrogen-bonded complexes (Figure 4) can be used
to rationalize this weak affinity. The computed structures
show that the intermolecular hydrogen bonds do not have
an optimal alignment. In the case of the 1‚syn-4 complex,
the planes of the molecules have a 27.1° angle to each
other, whereas for 1‚anti-4, steric repulsion leads to an
increase of this angle to 43.7°.
Experimental evidence that the carbamate C(carbon-
yl)-N bond in 4 (see Figure 5 for bond-labeling scheme)
is unusually long comes from its X-ray crystal structure
(Figure 3). Unlike the literature structure of ethyl
N-phenylcarbamate, where the C(aryl)-N bond
(1.405(6) Å) is significantly longer than the C(carbo-
nyl)-N bond (1.352(8) Å),13 the C(aryl)-N bond (1.381-
(4) Å) in 4 is essentially the same length as the C(car-
bonyl)-N bond (1.377(4) Å). This is also the case for
another N-(2-pyrimidinyl)carbamate described in the
literature.14
F igu r e 3. X-ray structure of carbamate 4 showing the atom-
numbering scheme and important intermolecular interactions.
Each hydrogen-bonded antiparallel dimer is connected via
bifurcated CH-X interactions.
Ter tia r y N-Ar yl-N-m eth ylca r ba m a tes. To further
test this hypothesis of an unusually low C-N rotational
barrier, we prepared and analyzed the tertiary N-aryl-
N-methylcarbamates 7-9. We observed that cooling
pyrimidyl carbamates exist in an unusual tautomeric
1
form? No tautomeric forms were observed by H NMR
in agreement with the known preference for 2-(acyl-
amino)pyridines to exist solely as their acylamino tau-
(9) Even 13C NMR does not give a clear picture. Probably the most
diagnostic signal is the chemical shift for the tert-butyl quaternary
carbon, which in the case of 2 in the presence of 1 mol equiv of template
1 at 253 K is 81.2 ppm for the anti rotamer and 84.0 ppm for the syn
rotamer.4 In the case of 4 under the same conditions, the quaternary
tert-butyl carbon signal occurs at 81.9 ppm. This could be interpreted
as a rapidly equilibrating mixture that is 75% anti rotamer but the
uncertainty is high. We also considered if adventitious water in the
1
tomers.6 In addition, a low-temperature H NMR study
of carbamate 4 in the more polar solvent acetone-d6
showed no additional peaks upon cooling to 183 K. (ii)
Do these pyrimidyl carbamates exist as predominantly one
rotamer? In the solid state, carbamate 4 adopts an anti
conformation although the structure is somewhat dis-
torted.7 It packs as an array of hydrogen bonded anti-
parallel dimers (Figure 3), but it does not strongly
dimerize in solution (Kdimer ) 8 M-1 in CDCl3 at 20 °C).8
The inability to obtain dynamic NMR data makes it
difficult to unambiguously measure the isomerization
equilibrium in solution.9,10 However, theoretical insight
was gained by performing a series of hybrid DFT calcula-
tions.11 The syn and anti isomers of 4 were found to be
very close in energy. The calculated energy and free
energy differences are 0.4 and -0.1 kcal/mol, within the
error limits that can reasonably be expected for the
calculation of rotamers at this level of theory. (iii) Can
the rotational barrier for 4 be so low as to not produce
separate rotamer signals in the NMR? The calculated
transition structure for the syn/anti interconversion in
4 is only 8.4 kcal/mol higher in energy than anti-4. This
suggests that the barrier to rotation is unusually low and
that the presence of template does not increase it
NMR solvent selectively stabilizes anti-4 by forming
a chelated
complex. Experimentally, we find that the presence or absence of water
in the CDCl3 has no apparent effect on the low-temperature 1H NMR
spectrum of 4. In addition, calculation of some bridged structures did
not yield a stable doubly hydrogen bonded species.
(10) We acquired IR spectra of dilute samples of 2, 4, and tert-butyl
N-(phenyl)carbamate, 10, in CH2Cl2, and in each case a single NH
stretching vibration was observed. Specifically, the NH stretching
frequencies for 2, 4, and 10 (5 mM in CH2Cl2) are 3417, 3422, and
3431 cm-1, respectively. It is known experimentally that the NH
stretching vibration for an anti amide is about 40 wavenumbers higher
than the syn form,5 and we have confirmed this large difference with
DFT calculations. However, in the case of the syn and anti isomers of
secondary carbamates, our calculations indicate that the difference in
NH stretching frequencies is so small (∼5 wavenumbers) that the
experimentally observed values cannot be unambiguously assigned to
a specific structure. Other major IR absorbances not obscured by the
solvent are the following: 2, 1731, 1578, 1514, 1153 cm-1; 4, 1754,
1576, 1504, 1147 cm-1; 10, 1728, 1605, 1595, 1522, 1161 cm-1. The
carbonyl stretching frequency order of 4 (1754 cm-1) > 2 (1731 cm-1) >
10 (1728 cm-1) agrees with the resonance effect described in Figure 7.
(11) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen, W.;
Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.; Pople,
J . A. Gaussian 98, revision A.9; Gaussian, Inc.: Pittsburgh, PA, 1998.
(12) Typically, the association constants for hydrogen-bonded ADA‚
DAD complexes are around 102 M-1: Prins, L. J .; Reinhoudt, D. N.;
Timmerman, P. Angew. Chem., Int. Ed. 2001, 40, 2382-2426.
(13) Ganis, P.; Avitabile, G.; Migdal, S.; Goodman, M. J . Am. Chem.
Soc. 1971, 93, 3328-3331.
(6) Katritzky, A. R.; Ghiviriga, I. J . Chem. Soc., Perkin Trans. 2
1995, 1651-1653.
(7) To minimize electrostatic repulsion between the carbonyl oxygen,
O(1), and the ring nitrogen, N(2), the molecule adopts some unusual
bond and torsional angles (see Figure 3 for atom numbering). In
particular, the bond angle C(5)-N(3)-C(4) is increased to 127.7°. The
torsional angles O(1)-C(5)-N(3)-C(4) ) 15.16° and C(5)-N(3)-C(4)-
N(2) ) 10.25° demonstrate how the carbamate group is skewed from
planarity.
(8) Association constants were determined using the NMR titration
and dilution methods described in the following: Kelly, T. R.; Kim,
M. H. J . Am. Chem. Soc. 1994, 116, 7072-7080.

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3951
F igu r e 4. Top and side views of the B3LYP/6-31+G*-calculated structures of the syn-4‚1 (left) and anti-4‚1 (right) complexes.
F igu r e 5.
F igu r e 6.
Ta ble 1. Exp er im en ta l a n d Ca lcu la ted C(ca r bon yl)-N
Ta ble 2. Ca lcu la ted Bon d Len gth s (Å) a n d P a r tia l
Rota tion a l Ba r r ier s (k ca l/m ol)
Ch a r ges on th e Ca r bon yl Oxygen for syn - a n d
∆Gq
<9
∆Gq
comp
a n ti-Ca r ba m a te Rota m er s
carbamate
exp
5.7c
carbamate
rotamer
charge
(carbonyl oxygen)
7
8
9
10.2a
12.3b
10.2c
13.4c
C(aryl)-N
C(carbonyl)-N
syn-7
anti-7
syn-8
anti-8
syn-9
anti-9
1.401
1.407
1.421
1.422
1.433
1.430
1.402
1.399
1.388
1.388
1.380
1.384
-0.582
-0.576
-0.595
-0.595
-0.624
-0.611
203 K. 250 K. c 298 K.
a
b
samples of pyridyl carbamate 8 and phenyl analogue 9
resulted in splitting of the spectra into two sets of signals
(ratio of 29:71 for 8 at 183 K and 41:59 for 9 at 218 K);15
however, the 500 MHz 1H NMR spectra of the pyrimidyl
analogue 7 remained sharp even at 183 K in THF-d8.
Coalescence of the tert-butyl signals occurred at 203 K
for 8 in THF-d8 and at 250 K for 9 in CDCl3. These values
correspond to ∆Gq of 10.2 and 12.3 kcal/mol, respectively.
In the case of 7 we estimate from the experimental data
that the rotational barrier is <9 kcal/mol (see Experi-
mental Section).
Å. This trend is also seen in the partial charges on the
carbonyl oxygen, also listed in Table 2. The effect is
explained in part by the resonance contributor shown in
Figure 6. The N-aryl ring withdraws π-electron density
which shortens the carbamate C(aryl)-N bond and thus
there is less π-electron density available for resonance
delocalization with the carbamate carbonyl.10 Electron-
withdrawing ability is enhanced in the case of pyrimidyl
analogues 4 and 7 because of the presence of the aryl
ring nitrogens. This barrier-lowering effect also occurs
with N-aryl amide systems, although in this case it is
experimentally harder to characterize because N-aryl
amide rotational equilibria are usually strongly biased
We also studied the rotational energetics for 7-9 using
computational methods. In each case, the syn and anti
rotamers were found to be essentially identical in energy.
As shown in Table 1, the calculated free energy barriers
for rotation around the respective C(carbonyl)-N bonds
are very close to the experimentally observed values.
Inspection of the calculated rotamer structures provides
further insight into the geometric and electronic origin
of these very low barriers. As already seen in the X-ray
structure of 4, the calculated C(aryl)-N and C(carbon-
yl)-N bond lengths in 7 are almost identical (Table 2).
However, in case of the N-phenyl analogue 9, the
C(aryl)-N and C(carbonyl)-N bond lengths differ by 0.05
toward one isomer.5,16
The barrier for rotation about an N-alkylcarbamate
C(carbonyl)-N bond is usually around 16 kcal/mol.2 In
the case of an N-phenylcarbamate, such as 9, the
rotational barrier is lowered to 12.5 kcal/mol, but in the
case of N-(2-pyrimidyl)carbamates, such as 4 and 7, the
barrier is around 5-8 kcal/mol. This effect is attributed
primarily to increased contribution by the resonance
(16) For conformational studies of N-methyl-N-phenyl amide deriva-
tives, which are known to rotate the amide C-NdO plane out of
conjugation with the phenyl ring, see: Azumaya, I.; Kagechika, H.;
Yamaguchi, K.; Shudo, K. Tetrahedron 1995, 51, 5277-5290. Saito,
S.; Toriumi, Y.; Tomioka, N.; Itai, A. J . Org. Chem. 1995, 60, 4715-
4720. Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J . Am.
Chem. Soc. 1992, 114, 10649-10650.
(14) Muller, J .-C.; Ramuz, H.; Daly, J .; Schonholzer, P. Helv. Chim.
Acta 1982, 1454-1466.
(15) Attempts to assign the resolved low-temperature signals to syn
or anti rotamers by NOE were unsuccessful. For example, irradiation
of the N-methyl signals produced no enhancement of either of the tert-
butyl signals.

3952 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
(125.7 MHz, 295 K, CDCl3) δ 28.4, 34.5, 81.3, 119.4, 119.6, 137.1,
147.5, 154.6, 155.2; MS (FAB+) 209 [M + H]+.
structure shown in Figure 6. To put these values into
perspective, the barriers for rotation around the C2-C3
single bond in 1,3-butadiene and the C1-C2 single bond
in acrolein are about 4 and 6 kcal/mol, respectively.17
ter t-Bu tyl N-m eth yl-N-(p h en yl)ca r ba m a te (9): 90% yield;
1H NMR (500 MHz, 295 K, CDCl3) δ 1.45 (s, 9H) 3.25 (s, 3H)
7.2 (m, 5H); 13C NMR (125.7 MHz, 295 K, CDCl3) δ 28.4, 37.5,
80.4, 125.5, 125.6, 128.7, 143.9, 154.9; MS (FAB+) 208 [M + H]+.
X-r a y Cr ysta llogr a p h y. Single crystals of 4 were obtained
by recrystallization from dichloromethane/hexanes. Crystal-
lographic summary:18 monoclinic, C2/c; Z ) 8 in a cell of
dimensions a ) 19.109(3) Å, b ) 8.888(2) Å, c ) 13.961(3) Å, â
) 112.572(13)°, V ) 2189.5(8) Å3; Fcalc ) 1.184 Mg M-3; F(000)
) 832. The structure was refined on F2 to a Rw ) 0.1168, with
a conventional R ) 0.0423 (1469 reflections with I > 2σ(I)) and
a goodness of fit ) 1.016 for 180 refined parameters.
Exp er im en ta l Section
ter t-Bu tyl N-(2-P yr im id yl)ca r ba m a te (4). 2-Aminopyri-
midine (0.49 g, 5.0 mmol) was dissolved in tert-butyl alcohol (10
mL) containing di-tert-butyl carbonate (1.20 g, 5.5 mmol). The
reaction was stirred at room temperature for 48 h under an
atmosphere of argon. The solvent was removed in vacuo and the
residue dissolved in ethyl acetate. The organic layer washed
three times with brine and dried with MgSO4, and the solvent
was removed leaving a white solid (0.50 g, 51% yield): mp 147-
Com p u ta tion a l Stu d ies. All computations were performed
using the GAUSSIAN98 series of programs.11 All geometries
were fully optimized and subjected to harmonic frequency
analysis at the B3LYP/6-31+G* level of theory. Bond distances
are given in Å, and energies are zero-point corrected and are
given in kcal/mol. Gibbs free energies were calculated from the
harmonic frequency analysis from 298 K and 1 atm. Partial
charges were calculated using the ChelpG model.
1
148 °C; H NMR (500 MHz, 295 K, 10 mM in CDCl3) δ 8.59 (d,
2H, J ) 4.5 Hz), 7.77 (bs, 1H), 6.96 (t, 1H, J ) 4.5 Hz), 1.55 (s,
9H) ppm. 13C NMR (125.7 MHz, 295 K, CDCl3) δ 158.4, 158.0,
115.4, 81.5, 28.1 ppm. HRMS (FAB+) calcd for [M + H]+
196.1086, found 196.1079. Anal. Calcd for C9H13N3O2: C, 55.37;
H, 6.71. Found: C, 55.19; H, 6.52.
ter t-Bu tyl N-(5-Nitr o-2-pyr im idyl)car bam ate (5). 2-Amino-
5-nitropyrimidine (0.075 g, 0.52 mmol) was dissolved in tert-
BuOH (3 mL). Di-tert-butyl dicarbonate (0.133 g, 0.57 mmol) was
added along with 4-(dimethylamino)pyridine (∼2 mg, catalytic).
The mixture was heated to reflux for 15 h under an atmosphere
of argon. The solvent was removed and the residue dissolved in
EtOAc and washed twice with water. The combined organic
layers were dried over MgSO4. The material was chromato-
graphed on silica (19:1 CH2Cl2/MeOH, Rf ) 0.2), leaving a white
solid (2.2 mg, 2% yield): 1H NMR (300 MHz, 295 K, CDCl3) δ
9.19 (s, 2H), 8.00 (bs, 1H), 1.62 (s, 9H); 13C NMR (75 MHz, 295
K, CDCl3) δ 160.1, 154.9, 149.2, 137.9, 83.4, 28.1; MS (FAB+)
m/e 241 [M + H]+.
ter t-Bu tyl N-(4,6-Dim eth oxy-2-p yr im id yl)ca r ba m a te (6).
2-Amino-4,6-dimethoxypyrimidine (0.50 g, 3.2 mmol) was dis-
solved in tert-BuOH (10 mL). Di-tert-butyl dicarbonate (0.80 g,
3.5 mmol) was added, and the mixture was heated to reflux for
15 h under an atmosphere of argon. The solvent was removed
and the residue dissolved in EtOAc and washed three times with
water. The combined organic layers were dried over MgSO4. The
solvent was removed under vacuum leaving a white solid (0.3
g, 35% yield): 1H NMR (300 MHz, 295 K, CDCl3) δ 5.32 (s, 1H),
5.15 (bs, 1H), 3.70 (s, 6H), 1.40 (s, 9H); 13C NMR (75 MHz, 295
K, CDCl3) δ 172.1, 162.2, 146.4, 84.7, 79.1, 53.2, 27.0; MS (FAB+)
m/e 256 [M + H]+.
Dyn a m ic NMR Stu d ies. Variable-temperature NMR spectra
were acquired using a 500 MHz instrument. Probe temperatures
((0.5 K) were measured with a calibrated, digital thermocouple.
The rotational barriers at coalescence were determined by
treating the dynamic 1H NMR spectra as an exchange between
two unequally populated sites.19 Values for ∆p (the rotamer
population difference) and ∆ν (the limiting chemical shift
difference) were obtained from spectra acquired at temperatures
well below coalescence. Coalescence temperatures (Tc) were
determined for the tert-butyl signals for 8 and 9. For compound
8 in THF-d8, Tc ) 203 K, ∆p ) 0.42, and ∆ν ) 30 Hz, which
leads to kc ) 43 s-1 and ∆Gq of 10.2 kcal/mol. For compound 9
in CDCl3, Tc ) 250 K, ∆p ) 0.18, and ∆ν ) 53 Hz, which leads
to kc ) 90 s-1 and ∆Gq of 12.3 kcal/mol. Coalescence could not
be observed for compound 7 in THF-d8, at 183 K. This means
that kc > 80 s-1 at 183 K or ∆Gq < 9 kcal/mol.
NMR Titr a tion s.8 The chemical shift for the NH signal in 4
(10 mM) was monitored as a function of increasing amounts of
1 and the resulting curve fitted to a 1:1 binding model. The
homodimerization of 4 was determined by the dilution method.8
Ack n ow led gm en t. This work was supported by the
National Science Foundation and the University of
Notre Dame (George M. Wolf Fellowship for M.J .D.). We
are grateful to Dr. M. Shang for solving the X-ray
structure of 4, and we thank the OIT at the University
of Notre Dame for the generous allocation of computa-
tional resources. We appreciate the helpful comments
provided by an anonymous reviewer.
Gen er a l Syn th esis P r oced u r e for Ter tia r y N-Meth yl-
ca r ba m a tes. The appropriate secondary carbamate4 in DMF
(∼50 mg/mL) was treated with 1.5 mol equiv of NaH (60%
dispersion in mineral oil) and 5 mol equiv of methyl iodide. The
reaction was stirred for 30 min, quenched with water, and
extracted with CH2Cl2. The organic phase was dried and then
evaporated. The residue was purified by chromatography (silica
gel) using 80:20 CH2Cl2/hexanes as the eluent.
Su p p or tin g In for m a tion Ava ila ble: X-ray data in CIF
format and the coordinates, energies, zero point energies, and
Gibbs free energies of all calculated structures that are
discussed. This material is available free of charge via the
Internet at http://pubs.acs.org.
ter t-Bu tyl N-m eth yl-N-(2-p yr im id yl)ca r ba m a te (7): 40%
1
yield; H NMR (500 MHz, 295 K, CDCl3) δ 1.56 (s, 9H) 3.46 (s,
3H) 7.08 (t, J ) 4.5 Hz, 1H) 8.71 (d, J ) 4.5 Hz); 13C NMR (125.7
MHz, 295 K, CDCl3) δ 28.2, 35.2, 81.8, 116.4, 153.6, 157.9, 160.9;
MS (FAB+) m/e 210 [M + H]+.
J O025554U
ter t-Bu tyl N-m eth yl-N-(2-p yr id yl)ca r ba m a te (8): 40%
yield; 1H NMR (500 MHz, 295 K, THF-d6) δ 1.51 (s, 9H) 3.37 (s,
3H) 6.95 (dd, J ) 7.5, 4.5 Hz, 1H) 7.60 (td, J ) 8.0, 2.0 Hz,) 7.80
(d, J ) 8.5 Hz, 1H, py) 8.29 (dd, J ) 4.8, 1.8 Hz, 1H); 13C NMR
(18) The X-ray data have been deposited with the Cambridge
Crystallographic Data Centre. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ,
U.K. Fax: (+44)1223-336-033. E-mail: deposit@ccdc.cam.ac.uk.
(19) (a) Martin, M. L.; Delpuech, J . J .; Martin, G. J . Practical NMR
Spectroscopy; Heyden: London, 1980; Chapter 8. (b) Shanan-Atidi, H.;
Br-Eli, K. H. J . Phys. Chem. 1970, 74, 961-968.
(17) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994.