Disparate behavior of carbonyl and thiocarbonyl compounds: Acyl chlorides vs thiocarbonyl chlorides and isocyanates vs isothiocyanates

Article abstract of DOI:10.1021/jo9004316

(Figure Presented) The reaction of benzoyl chloride with methanol catalyzed by pyridine is 9 times more rapid than is the same reaction with thiobenzoyl chloride. The difference in reactivity, as well as the dealkylation reactions that occur when the reaction of thiobenzoyl chloride is catalyzed by bases such as Et₃N, can be understood in terms of the charge distributions in the intermediate acylammonium ions. The reaction of PhNCO with ethanol occurs at a much higher rate (4.8 × 10⁴) than that of PhNCS, corresponding to a difference in activation free energies for the additions of 6 kcal/mol. Transition states for each of these reactions were located, and each involves two alcohol molecules in a hydrogen bonded six-membered ring arrangement. Information concerning differences in reactivity was derived from analysis of Hirshfeld atomic charge distributions and calculated hydrogenolysis reaction energies.

Full text of DOI:10.1021/jo9004316

Disparate Behavior of Carbonyl and Thiocarbonyl Compounds:
Acyl Chlorides vs Thiocarbonyl Chlorides and Isocyanates vs
Isothiocyanates
Kenneth B. Wiberg,* Yi-gui Wang, Scott J. Miller,* and Angela L. A. Puchlopek
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
William F. Bailey* and Justin D. Fair
Department of Chemistry, The UniVersity of Connecticut, Storrs, Connecticut 06269-3060
Kenneth.Wiberg@yale.edu; Scott.Miller@yale.edu; William.Bailey@uconn.edu
ReceiVed February 25, 2009
The reaction of benzoyl chloride with methanol catalyzed by pyridine is 9 times more rapid than is the
same reaction with thiobenzoyl chloride. The difference in reactivity, as well as the dealkylation reactions
that occur when the reaction of thiobenzoyl chloride is catalyzed by bases such as Et N, can be understood
3
in terms of the charge distributions in the intermediate acylammonium ions. The reaction of PhNCO
4
with ethanol occurs at a much higher rate (4.8 × 10 ) than that of PhNCS, corresponding to a difference
in activation free energies for the additions of 6 kcal/mol. Transition states for each of these reactions
were located, and each involves two alcohol molecules in a hydrogen bonded six-membered ring
arrangement. Information concerning differences in reactivity was derived from analysis of Hirshfeld
atomic charge distributions and calculated hydrogenolysis reaction energies.
Introduction
experimental and computational investigation of the contrasting
behavior of acyl chlorides and isocyanates vis- a` -vis their sulfur
analogs.
The chemistry of acyl chlorides and isocyanates often parallels
that of their sulfur analogs, thiocarbonyl chlorides and isothio-
1
cyanates. However, as detailed below, some significant dif-
Results and Discussion
ferences in the reactivity of carbonyl and thiocarbonyl com-
pounds have been noted in the literature. We have been
interested for some time in the effect that replacement of a CdO
bond by a CdS bond has on the chemistry of various functional
4
The literature indicates that benzoyl chloride is more reactive
5
toward methanol than is thiobenzoyl chloride. In this connec-
tion, the reactions of phenoxycarbonyl chloride and phenox-
ythiocarbonyl chloride with secondary alcohols in the presence
2
,3
groups.
Herein we report the results of a coordinated
3
of Et N has been examined and, whereas the carbonyl chloride
reacts normally to give the expected ester (eq 1), the thiocar-
bonyl chloride reaction occurs by nucleophilic substitution at
an ethyl group on N, leading to a thioamide as the product (eq
(
1) (a) Patai, S. Ed. The Chemistry of the Carbonyl Group; Interscience:
New York, 1966. (b) Mayer, R.; Scheithauer, S. In Methoden der Organischen
Chemie; Georg Thieme: New York, 1985; Vol. 5, pt. 2.
(
2) Hadad, C. M.; Rablen, P. R.; Wiberg, K. B. J. Org. Chem. 1998, 63,
668.
3) Sanchez-Rosello, M.; Puchlopek, A. L. A.; Morgan, A. J.; Miller, S. J. J.
Org. Chem. 2008, 73, 1774.
8
(
(4) Norris, J. F.; Young, H. H., Jr. J. Am. Chem. Soc. 1935, 57, 1420.
(5) Scheithauer, S.; Mayer, R. Chem. Ber. 1965, 98, 838.
1
0.1021/jo9004316 CCC: $40.75  2009 American Chemical Society
J. Org. Chem. 2009, 74, 3659–3664 3659
Published on Web 04/16/2009

Wiberg et al.
a
TABLE 1. B3LYP/6-311+G* Calculated Energies (Hartrees) of Acyl Derivatives
compound
E(0 K)
H(298 K)
G(298 K)
G(soln)
MeCOCl
MeCSCl
PhCOCl
PhCSCl
PhOCOCl
PhOCSCl
MeCONMe
MeCSNMe
PhCONMe
PhCSNMe
PhOCONMe
-613.52101
-936.46492
-805.29903
-1128.24334
-880.53796
-1203.48011
-327.55854
-650.50352
-519.33766
-842.28157
-594.58873
-917.52958
-174.51680
-460.30373
-613.46816
-936.41421
-805.18998
-1128.13648
-880.42400
-1203.36848
-327.37717
- 650.32399
-519.09984
-842.04607
-594.34658
-917.28992
-174.39007
-460.30137
-613.50163
-936.44872
-805.23157
-1128.17989
-880.46898
-1203.41442
-327.41997
-650.36697
-519.15040
-842.09709
-594.39728
-917.34168
-174.42379
-460.31875
-613.50716
-936.45184
-805.24152
-1128.18749
-880.48028
-1203.42384
-327.49747
-650.44125
-519.22427
-842.16925
-594.47138
-917.41290
-174.42601
-460.43280
+
3
+
3
+
3
+
3
+
3
+
PhOCSNMe
Me
3
3
N
-
Cl
a
The G(soln) values were derived from the solvation energies calculated using the PCM model with acetonitrile as the solvent; these were added to
the G(289K) values.
6
2
). It might be noted that the thioester is formed when a
reaction proceeded at a modest rate, and it was clearly slower
than the corresponding reaction of benzoyl chloride. In order
to have a more quantitative comparison, a competition experi-
pyridine base is used and dealkylation is not possible. The same
type of behavior has recently been documented in reactions of
phenoxycarbonyl chloride and phenoxythiocarbonyl chloride
ment was performed in which a CDCl solution containing one
3
3
with cyclohexanol.
molar equiv each of methanol, pyridine, benzoyl chloride and
1
thiobenzoyl chloride was followed by H NMR. The ratio of
products was determined by integration of the methyl singlets
of methyl benzoate (δ ) 3.85) and O-methyl thiobenzoate
1
0
(
δ ) 4.18) products. The average of three runs indicated that
benzoyl chloride was more reactive than thiobenzoyl chloride
by a factor of 9.0 ( 0.5 at 25 °C. In order to gain information
of potential significance to this rate difference, we carried out
a number of geometry optimizations for the relevant species
using the B3LP/6-311+G* theoretical model. The results are
summarized in Table 1.
In a related transformation, we have observed, as shown
below, that phenyl isocyanate reacts with cyclohexanol in the
presence of 20-mol% N-methylimidazole as the catalyst to give
an 85% yield of cyclohexyl phenylcarbamate in 24 h; (eq 3)
however, phenyl isothiocyanate gives no product under these
conditions (eq 4). There are other data that relate to this
The reactions of benzoyl and thiobenzoyl chlorides with
MeOH in the presence of an amine catalyst presumably involve
two steps: a relatively rapid reaction leading to an acylammo-
nium ion and a chloride ion followed by rate determining
7
,8
difference in reactivity.
1
1
reaction of a nucleophile to give the product. The energies
summarized in Table 1 allow the calculation of energy changes
for reactions of the acyl derivatives (the amine catalyst was
3
modeled as Me N in the calculations). The initial reaction will
be strongly disfavored in the gas phase because of the high
electrostatic energies of ions in the gas phase. This effect may
be minimized, but still provide the needed information, by
looking at the exchange reactions illustrated below since the
electrostatic energies will roughly cancel.
We were interested in exploring the reasons for these
differences in reactivity, and we have made use of experimental
and computational tools to investigate the systems. There are
kinetic data reported for the reactions of benzoyl and thiobenzoyl
chlorides with methanol that indicate the former to be 12 times
4
,5
more reactive than the latter at 0 °C. In order to have a direct
comparison at 25 °C, thiobenzoyl chloride was prepared
However, to ensure that this approximation is reasonable, the
stabilization of the ions in acetonitrile solution (chosen because
9
following the procedure of Staudinger and Siegwart and its
reaction with methanol in pyridine solution was examined. The
12
it has a high dielectric constant) was calculated using the PCM
13
polarized continuum model. The gas phase free energies were
corrected for the solvation energies and the results are given in
the last column of Table 1. The calculated energy changes in
kcal/mol for the exchange reactions, including the effect of
solvent, are summarized in Table 2.
(
6) (a) Hsu, F.-L.; Zhang, X.; Hong, S.-S.; Berg, F. J.; Miller, D. D.
Heterocycles 1996, 39, 801. (b) Millan, D. S.; Prager, R. H. Tetrahedron Lett.
998, 39, 4387. (c) Millan, D. S.; Prager, R. H. Aust. J. Chem. 1999, 52, 841.
7) (a) Coseri, S. High Perform. Polym. 2007, 19, 520. The authors report
kinetic data for the reaction of PhNCO with ethanol obtained in dilute benzene
1
(
-1
-1
solutions. The rate constants (given as L mol min ) increase linearly with
ethanol concentration, suggesting a second order dependence on the alcohol
concentration. See, for example: (b) Caraculacu, A. A.; Agherghinei, I.; Baron,
P.; Timpu, D. ReV. Roum. Chim. 1996, 18, 725.
(
(
(10) Kata, S. Phosphorus, Sulfur, Silicon 1997, 120, 213.
(11) Fersht, A. R.; Jencks, W. P. J. Am. Chem. Soc. 1970, 92, 5432; 1970,
92, 5442.
8) Rao, C. N. R.; Venkataraghavan, R. Tetrahedron 1962, 18, 531.
9) Staudinger, H.; Siegwart, J. HelV. Chim. Acta 1920, 3, 824.
3
660 J. Org. Chem. Vol. 74, No. 10, 2009

BehaVior of Carbonyl and Thiocarbonyl Compounds
TABLE 2. Calculated Energy Changes (kcal/mol) for Exchange
Reactions (eq 5)
TABLE 3. Kinetic Data for the Reactions of PhNCO and PhNCS
with Ethanol
k, sec-
1
R
∆H(298)
∆G(298)
∆G(soln)
compound
medium
T, °C
-
-
-
-
5
5
5
6
Me
Ph
PhO
0.5
–0.2
–0.7
-0.1
-1.0
-0.7
-0.6
-0.6
-1.3
PhNCS
PhNCS
PhNCS
PhNCS
PhNCS
PhNCO
ethanol-benzene
ethanol-THF
ethanol
ethanol
ethanol
60.0
60.0
60.0
40.0
0.0
0.55 × 10
0.63 × 10
1.52 × 10
2.47 × 10
2.9 × 10
a
-8
-3
It can be seen that the energy changes are small, but they do
slightly favor the acylammonium ion over the thioacylammo-
nium ion. When R ) Ph, the computed ∆G values are too small
to explain the experimentally observed reactivity difference, but
it should be recognized that there are possible small errors in
the calculated values resulting from the theoretical level that
was used. It does not appear that the initial equilibrium can
fully account for the rate difference in the reactions of benzoyl
and thiobenzoyl chlorides with methanol.
It is not straightforward to carry out calculations for the
transition state for second step in the reaction since the species
involved are not well-defined, and nucleophilic attack might
involve the alkoxide ion that is in equilibrium with the alcohol
and the amine, or it may involve the alcohol itself, perhaps
hydrogen-bonded to the amine. In addition, the difference in
reaction rate for the formation of the esters is small. However,
there is another quantity that should be considered when
evaluating the reaction of an intermediate thioacylammonium
ion leading to dealkylation at nitrogen. To this end, atomic
ethanol
0.0
1.38 × 10
a
Extrapolated from the 60 and 40 °C rate constants.
There are some kinetic data available for the reactions of PhNCO
and PhNCS with ethanol. The rate of reaction between phenyl
isocyanate and ethanol was determined at 60 °C in dilute
7
benzene solutions. The rate constants were reported as second
order, but they increased linearly with ethanol concentration
suggesting a second order dependence on the ethanol concentra-
tion:
2
v ) k[PhNCO][EtOH]
The rate of reaction between phenyl isothiocyanate and
ethanol has been determined in pure ethanol solution at 43 and
53 °C: the pseudofirst order rate constant at 53 °C was 0.95 ×
-5
-1
8
10 sec . Second order behavior was noted when equal
concentrations of PhNCS and ethanol were used in benzene
8
solution: however, the concentration dependence was not
further investigated and, therefore, the order with respect to
ethanol is ambiguous. First order catalysis by triethylamine was
1
4
charges were calculated using the Hirshfeld model that we
have found to be particularly useful in comparing similar
compounds. These charges are illustrated in Figure 1.
8
also observed and a study of substituent effects led to F ) 1.70.
To determine the relative rates of reaction of the two
isocyanates under the same conditions, and to study the kinetic
order in ethanol, the following studies were carried out. The
rate of reaction of phenyl isothiocyanate with pure ethanol was
determined at 40.0 °C and at 60.0 °C, and the rate was also
determined using a 1:1 mixture of ethanol and benzene as well
as a 1:1 mixture ethanol and THF at 60.0 °C. Additionally, the
rate of reaction of PhNCO with pure ethanol was determined
at 0.0 °C. The pseudofirst order rate constants, summarized in
Table 3, include the extrapolated rate of reaction of PhNCS
with pure ethanol at 0.0 °C. These data indicate that the reaction
of PhNCO with ethanol is ∼48 000 times more rapid than the
analogous reaction with PhNCS. This corresponds to a differ-
FIGURE 1. Hirshfeld charges for the initial product of the reaction of
acyl and thioacyl chlorides with trimethylamine.
q
ence in activation free energy (∆∆G ) for the addition of ethanol
The replacement of O by S leads to significant changes in
charge populations due to the difference in electronegativity of
these atoms, and these are especially large at the carbonyl and
thiocarbonyl carbons. The reaction of that carbon with a
nucleophile would be expected to be more rapid with the more
electrophilic (positively charged) carbon. With the reduced
carbon charge (and presumably lower reactivity) in the thio-
to PhNCO and PhNCS of about 6 kcal/mol.
If the reaction of PhNCS were second order in ethanol in
pure ethanol solution, in the absence of a solvent effect, the
rate of reaction would decrease by a factor of 4 in the 1:1 mixed
solvents. Since the rate of reaction was similar in the two quite
different mixed solvents, the solvent effect appears to be
relatively small. The decrease in rate by a factor of 2.4 to 2.8
suggests that much of the reagent is hydrogen bonded to ethanol
(that would lead to a rate factor of 2 rather than four) and that
the reaction involves both free and hydrogen-bonded PhNCS
in pure ethanol. Evidence for hydrogen bonding between PhNCS
carbonyl derivative it is not surprising that a nucleophile could
+
react with the positively charged carbon at the NMe
3
group
(
+0.200) relative to SdC (+0.150) leading to dealkylation as
observed in such reactions.
8
The reactions of PhNCO and PhNCS are potentially of greater
interest because of the apparently larger difference in reactivity.
and ethanol has been noted in a previous study.
In an effort to understand the sizable difference in reactivity
of PhNCO and PhNCS with ethanol, we explored the reactions
computationally. The results of these studies are summarized
in Table 4. Methanol rather than ethanol was used as the reactant
in these computations so as to avoid conformational problems
associated with the intermediate species.
(12) In the polarized continuum model, all solvents with a dielectric constant
of 20 or greater will give approximately the same solvent effect.
(
13) (a) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys. 2002,
1
9
17, 43. (b) Cammi, R.; Mennucci, B.; Tomasi, J. J. Phys. Chem. A 1999, 103,
100.
(
14) (a) Hirshfeld, F. L. Theor. Chim. Acta 1977, 44, 129. (b) Nalewajski,
In examining these energies, it is useful to again use exchange
reactions. The relevant reactions are illustrated below. The
R. F.; Parr, R. G. Proc. Natl. Acad. Sci. 2000, 97, 8879. (c) Parr, R. G.; Ayers,
P. W.; Nalewajski, R. F. J. Phys. Chem. A, 2005, 109, 3957.
J. Org. Chem. Vol. 74, No. 10, 2009 3661

Wiberg et al.
TABLE 4. B3LYP/6-311+G* Calculated Energies (Hartrees) of
Isocyanates, Isothiocyanates, and their Reaction Products
compound
PhNCO
PhNCS
PhNC(dO)OMe
PhNC(dS)OMe
E(0 K)
H(298 K)
G(298 K)
G(solv)
-399.83490 -399.72337 -399.76393 -399.77294
-722.79444 -722.68500 -722.72720 -722.73536
-515.06059 -514.90458 -514.95148 -515.04127
-838.02061 -837.86728 -837.91235 -838.99880
PhNHC(dO)OMe -515.62480 -515.45348 -515.50091 -515.51722
PhNHC()S)OMe -838.56853 -838.39935 -838.44783 -838.46290
MeOH
MeO
-115.75387 -115.69845 -115.72548 -115.73624
-115.14208 -115.10331 -115.1237 -115.24380
-
reaction shown in eq 6 is concerned with the exchange of
methoxide ion; eq 7 shows the exchange of methanol. The
calculated energies (kcal/mol) for these exchange reactions are
given in Table 5.
TABLE 5. Energies (kcal/mol)of Exchange Reactions 6 and 7
reaction
∆H
∆G
∆G(soln)
1
2
0.7
-9.9
-1.5
-10.3
-3.1
-10.5
The computed energy change for reaction 6 demonstrates that
methoxide ion has a small preference for addition to PhNCO
vis- a` -vis PhNCS. However, the results for reaction 7 show that
methanol has a large preference for addition to PhNCO vs
PhNCS. In addition, there is only a small solvent effect on these
reactions. The calculated ∆G for exchange of methanol (reaction
FIGURE 3
TABLE 6. B3LYP/6-31+G* Calculated Energy Changes in
kcal/mol for Conversion of Reactants to Products for the Reactions
of PhNCO and PhNCS with 2 Equiv of Methanol
q
q
q
q
2
, Table 5) is, as might be expected, somewhat larger than the
reactant
∆E (0 K)
∆H (298 K)
∆G (298 K)
∆G (soln)
q
experimental ∆∆G (6 kcal/mol) for additions of ethanol to
PhNCO and PhNCS. These results beg the question: why is
there such a large change on going from methoxide ion to
methanol? A clue is provided by the Hirshfeld charges for these
compounds illustrated in Figure 2.
PhNCO
PhNCS
5.7
15.1
5.1
29.5
38.8
39.3
46.6
14.4
of course, refers to the thermodynamics of the reactions.
However, given the large differences in rates that have been
found in the reactions of PhNCO and PhNCS with ethanol, it
is likely that the kinetics of the reactions will be related to the
overall thermodynamic changes.
Since it has been found that the addition of an alcohol to
PhNCO and PhNCS is second order in the alcohol, it is
reasonable to propose that one alcohol forms a hydrogen bond
with the nitrogen of the reactant, and the second alcohol is
involved with nucleophilic attack on the carbon. Transition states
were located for this type of reaction using methanol as the
reactant in which the two methanol molecules are bridged via
a hydrogen bond, leading to a six-membered ring transition state
(
Figure 3). The calculated energy changes are given in Table 6
and they include the effect of methanol as the solvent.
In reviewing the results summarized in Table 6, it should be
noted that there is a small change in energy on going from E(0
FIGURE 2. Hirshfeld charges for isocyanate and isothiocyanate
derivatives in exchange reactions 6 and 7.
q
The product of addition of methoxide to PhNCS leads to a
considerably larger negative charge at sulfur than is found at
the carbonyl oxygen for addition of methoxide to PhNCO
K) to ∆H (298 K) due to differences in zero-point energies and
thermal excitation of low frequency vibrations. The large
q
q
difference between the ∆H (298 K) and ∆G (298 K) values is
mainly due to the unfavorable entropy change on going from
three molecules to one in the gas phase as the reaction proceeds.
(
Figure 2, top row). Clearly, sulfur is better able to bear a
negative charge than is oxygen (cf. the greater acidity of H
as compared to H O). This benefit is lost in the neutral products
2
S
q
2
The further change on going to ∆G (soln) is a result of the
generated by addition of methanol (Figure 2, bottom row), and
now the difference in exchange reactions increases. All of this,
difference in solvation energies between reactants and products.
What is not included in this analysis is the significant change
3
662 J. Org. Chem. Vol. 74, No. 10, 2009

BehaVior of Carbonyl and Thiocarbonyl Compounds
in reaction entropy on going from the gas phase to solution
resulting from translation being converted to diffusion. There
is no simple way of calculating this change, and it will lead to
distributions, albeit within quite different intermediates en route
to quite different transition states, as consistent with the observed
reactivity trends. In the chemistry of the acyl/thiocarbonyl
chlorides, the corresponding acyl/thioacyl ammonium ions
possess substantial differences in positive charge at the reacting
carbon center, suggesting substantial Coulombic differentials
in the transition states leading to products; the more positively
charged acylammonium ion reacts more rapidly with electron-
rich nucleophiles than the corresponding thioacylammonium ion.
The experiments and calculations involving the reactions of
isocyanates and isothiocyanates reveal a more complicated story.
In the reactions of these compounds with alcohols, a second
order dependence of the rate of reaction in alcohol concentration
unveils a substantial role for hydrogen bonding throughout the
reaction coordinate for these processes. In the rate-determining
transition states, it may be that the internal charge distributions
start to reflect those observed in the products as multivalent
hydrogen bond-stabilized ensembles are no longer present. In
this limit, the internal charge distributions emerge as rather
different in comparing the carbonyl- and thiocarbonyl-containing
products. For the isocyanate-derived product, the internal
Coulombic stabilization substantially exceeds that available in
the corresponding thiocarbamate product. To the extent that
these effects are mirrored in the final, rate-determining transition
state, Coulombic effects once again, appear to account for the
phenomenological rate differentials rather well.
q
exaggerated values of ∆G (soln) This effect will approximately
cancel in comparing the energy changes for the two reactions
q
in Table 6. The difference in the computed ∆∆G values of 7
kcal/mol, favoring more rapid addition of methanol to PhNCO
vis- a` -vis PhNCS, is in very good agreement with the experi-
mentally determined difference in activation free energy (6 kcal/
mol) derived from kinetic data for the addition of ethanol to
PhNCO and PhNCS (Table 3).
How can one account for the considerable difference in
reactivity of an alcohol with PhNCO and PhNCS? A suggestion
may be found in the Hirshfeld charges illustrated in Figure 2:
the calculations indicate that the O-C-O charges in the PhNCO
product are significantly larger than are the O-C-S charges
in the PhNCS product because of the greater electronegativity
of O vs S. In an earlier study of substituent effects on a carbonyl
group, it was found that internal Columbic attraction was
2,15
important in stabilizing the compounds.
This is, for example,
a reason why methyl fluoride has a larger bond dissociation
energy than methyl chloride despite its lower covalent bond
order. Therefore, we suggest that the greater stability of methyl
phenylcarbamate relative to phenyl isocyanate (in comparison
to their sulfur analogs) is due to the increased internal Cou-
lombic attraction.
One might wonder if the difference in charge distribution is
sufficient to give the calculated energy difference. It is possible
to provide evidence in favor of this proposal by examining the
hydrogenolysis reactions shown below. The energies were
calculated at the B3LYP/6-31+G* level and the details are given
in the Supporting Information.
Experimental Section
Kinetic Experiments. The reaction of phenyl isothiocyanate with
ethanol was studied by preparing a 1.0 M solution of the reagent
plus tetradecane as an internal standard in 40 mL of the solvent
(
ethanol, 1:1 ethanol-benzene or 1:1 ethanol-THF). The solvent
was prewarmed to the reaction temperature before the addition of
the isothiocyanate. The reaction solutions were kept at 60 ( 0.1 or
4
0.0 ( 0.1 °C; 1.2 mL samples were removed at appropriate times
and were cooled to -25 °C prior to GC analysis.
The reaction of phenyl isocyanate with ethanol was studied by
weighing an appropriate amount of the reactant along with undecane
as an internal standard, and cooling the solutions to 0 °C. Ethanol
(
20 mL) was similarly cooled, and at the initial time it was added
There are differences between the calculated quantities ∆E,
H, and ∆G because of differences in vibrational frequencies
to the reactant, maintaining it at 0 °C. At 1 min intervals, 0.25 mL
samples were removed and added to 1 mL of THF in a GC vial
that had been cooled to 0 °C. It was quickly shaken to mix the
contents, immediately placed in Dry-Ice, and stored at -75 °C until
GC analysis using a FID detector. In both cases, the isocyanate or
isothiocyanate was well separated from the reaction product. The
rate of appearance of the product corresponded to the rate of
appearance of the reactant.
∆
between reactants and products. However, in each case, the
reaction of the carbonyl compound is endothermic and that of
the thiocarbonyl compound is exothermic. The difference in
calculated energies is about 8.5 kcal/mol in all cases. Clearly,
there is an energetic preference for the carbonyl group to be
attached to oxygen, whereas there is a disadvantage for a
thiocarbonyl group to be attached to oxygen.
Relative Rates of Reaction of Benzoyl and Thiobenzoyl
Chlorides with Methanol. A solution consisting of one mmol each
of benzoyl chloride, thiobenzoyl chloride, pyridine and methanol
9
1
Summary
in 5 mL of CDCl was monitored at 25 °C by H NMR over a
3
period of 90 min. The product ratio was determined by integration
In conclusion, we have performed experiments and calcula-
tions to explore the marked difference in reactivity between acyl
chlorides and thiocarbonyl chlorides on the one hand, and
between isocyanates and isothiocyanates on the other. The
general reactivity trends are similar in these two compound
classes (O-substituted compounds react more rapidly with
alcohols than their S-homologues). In both cases, the experi-
mental and computational data point to differential charge
of the CH singlets for methyl benzoate at δ ) 3.85 and O-methyl
3
10
thiobenzoate at δ ) 4.18. The product ratio (methyl benzoate/
O-methyl thiobenzoate) from three replicate runs was 9.0 ( 0.5.
Reaction of Cyclohexanol with Phenyl Isocyanate. To a
solution of cyclohexanol (15.0 µL, 0.142 mmol) in dichloromethane
(1.4 mL) was added N-methylimidazole (2.3 µL, 0.028 mmol) and
phenyl isocyanate (31.0 µL, 0.284 mmol). The orange solution was
allowed to stir at room temperature for 24 h and then the excess
isocyanate was quenched with diethylamine. The product ratio was
1
determined by H NMR integration of the carbinol C-H proton
(
15) (a) Wiberg, K. B.; Hadad, C. M.; Rablen, P. R.; Cioslowski, J. J. Am.
for cyclohexanol at δ ) 3.58 and cyclohexyl phenylcarbamate C-H
at δ ) 4.76 (1:17.2 or 94% conv.). The orange solution was
Chem. Soc. 1992, 114, 8644. (b) Wiberg, K. B.; Rablen, P. R. J. Am. Chem.
Soc. 1995, 117, 2201.
J. Org. Chem. Vol. 74, No. 10, 2009 3663

Wiberg et al.
concentrated and purified by silica gel flash chromatography to yield
Supporting Information Available: Calculated energies for
the formation of transition states for the reactions of PhNCO
and PhNCS with methanol and for the hydrogenolysis reactions
of methyl N-phenylcarbamate and methyl N-phenylthiocarbam-
ate. Calculated structural data in Cartesian coordinates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2
8
6.5 mg (85%) of cyclohexyl phenylcarbamate, mp 80 °C (lit
16
2-82.5 °C ).
Reaction of Cyclohexanol with Phenyl Isothiocyanate. To a
solution of cyclohexanol (15.0 µL, 0.142 mmol) in dichloromethane
(
1.4 mL), was added N-methylimidazole (2.3 µL, 0.028 mmol) and
phenyl isothiocyanate (33.9 µL, 0.284 mmol). The solution was
allowed to stir at room temperature for 24 h and then the excess
isocyanate was quenched with diethylamine. No product formation
JO9004316
1
was observed by H NMR and TLC analysis.
Calculations. All of the ab initio calculations were carried out
1
7
(17) Frisch, M. J. ; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kundin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala,
P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortis, J. V.; Cui, Q.; Baboul,
A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian DeVelopment
Version E; Gaussian, Inc.: Wallingford, CT, 2006.
using a development version of Gaussian. The Hirshfeld charges
1
8
were obtained using a local program that makes use of the wave
function file derived from Gaussian.
Acknowledgment. Research at Yale was carried out with
support from the National Science Foundation (KBW, CHE-
445847) and the NIH (S.J.M. and A.L.A.P., NIGMS068649);
the work at UCONN was supported by a grant from Procter &
Gamble Pharmaceuticals, Mason, Ohio. We thank Prof. Paul
Carlier (VA Tech) for a helpful suggestion.
0
(
16) (a) Ungnade, H. E.; Nightingale, D. V. J. Am. Chem. Soc. 1944, 66,
1
218. (b) Leardini, R.; Zanardi, G. Synthesis 1982, 3, 225.
(18) Program written by P. R. Rablen, Ph.D. thesis, 1994.
3
664 J. Org. Chem. Vol. 74, No. 10, 2009