Steric effects in the uncatalyzed and DMAP-catalyzed acylation of alcohols - Quantifying the window of opportunity in kinetic resolution experiments

Article abstract of DOI:10.1002/chem.200600280

The kinetics of the reaction of several alcohols (benzyl alcohol, ethanol, 1-phenylethanol, cyclohexanol, and 1-methyl-1-phenylethanol) with a selection of anhydrides (acetic anyhydride, propionic anhydride, isobutyric anhydride, isovaleric anhydride, and pivalic anhydride) as catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP)/triethyl amine have been studied in CH ₂Cl₂ at 20°C. In all cases the reaction kinetics can be described by rate laws containing a DMAP-catalyzed term and an uncatalyzed (back-ground) term. The rate constants for the background reaction respond sensi tively to changes in the steric demand of the alcohol and the anhydride substrates, making the reaction of cyclohexanol with acetic anhydride 526 times faster than the reaction with pivalic anhydride. Steric effects are even larger for the catalyzed reaction and the reactivity difference between acetic and pivalic anhydride exceeds a factor of 8000 for the reaction of cyclohexa nol. There is, however, no linear correlation between the steric effects on the catalyzed and the uncatalyzed part. As a consequence there are substrate combinations with dominating catalytic terms (such as the reaction of benzyl alcohol with isobutyric anhydride), while other substrate combinations (such as the reaction of cyclohexanol with pivalic anhydride) are characterized through a dominating background process. The implications of these findings for the kinetic resolution of alcohols are discussed.

Full text of DOI:10.1002/chem.200600280

FULL PAPER
DOI: 10.1002/chem.200600280
Steric Effects in the Uncatalyzed and DMAP-Catalyzed Acylation of
Alcohols—Quantifying the Window of Opportunity in
Kinetic Resolution Experiments**
Christian B. Fischer, Shangjie Xu, and Hendrik Zipse*[a]
Abstract: The kinetics of the reaction
of several alcohols (benzyl alcohol,
ethanol, 1-phenylethanol, cyclohexanol,
and 1-methyl-1-phenylethanol) with a
selection of anhydrides (acetic anyhy-
dride, propionic anhydride, isobutyric
anhydride, isovaleric anhydride, and
pivalic anhydride) as catalyzed by 4-
(N,N-dimethylamino)pyridine
(DMAP)/triethyl amine have been
studied in CH2Cl2 at 208C.In all cases
the reaction kinetics can be described
by rate laws containing a DMAP-cata-
lyzed term and an uncatalyzed (back-
ground) term.The rate constants for
the background reaction respond sensi-
tively to changes in the steric demand
of the alcohol and the anhydride sub-
strates, making the reaction of cyclo-
hexanol with acetic anhydride 526
times faster than the reaction with piv-
alic anhydride.Steric effects are even
larger for the catalyzed reaction and
the reactivity difference between acetic
and pivalic anhydride exceeds a factor
of 8000 for the reaction of cyclohexa-
nol.There is, however, no linear corre-
lation between the steric effects on the
catalyzed and the uncatalyzed part.As
a consequence there are substrate com-
binations with dominating catalytic
terms (such as the reaction of benzyl
alcohol with isobutyric anhydride),
while other substrate combinations
(such as the reaction of cyclohexanol
with pivalic anhydride) are character-
ized through a dominating background
process.The implications of these find-
ings for the kinetic resolution of alco-
hols are discussed.
Keywords: acylation
·
density
functional calculations · DMAP ·
kinetics · nucleophilic catalysis ·
substituent effects
Introduction
(N,N-dimethylamino)pyridine (1, DMAP), whose catalytic
potential is exploited widely in acyl- and other group-trans-
fer reactions.[11–22] In situ regeneration of these basic cata-
lysts is typically achieved through addition of a cheap auxili-
ary base, such as triethyl amine (2).The reaction works par-
ticularly well in apolar organic solvents[5a,g] and the overall
reaction can thus be described as shown in Scheme 1.
The base-catalyzed acylation of alcohols and amines through
reaction with anhydrides plays an important role in the pro-
tecting-group chemistry[1] and the kinetic resolution (KR) of
these substrates.[2] In both areas the use of sterically hin-
dered anhydrides enjoys widespread application, usually for
the sake of reduced reactivity (of the acylation product) or
enhanced selectivity (of the acylation process).This type of
acylation reaction can be catalyzed efficiently with basic cat-
alysts based on the pyridine[3–5] or imidazole[6–8] motif, but
tertiary alkyl amines[9] or phosphines[10] have also been used
successfully.In many cases the catalysts are derivatives of 4-
In a recent mechanistic study[23] of the DMAP-catalyzed
acetylation of cyclohexanol (R=cyclohexyl, R’=methyl) it
was shown that the catalyzed process depicted in Scheme 1
[a] Dr.C.B.Fischer, Dr.S.Xu, Prof.Dr.H.Zipse
Department Chemie und Biochemie, LMU München
Butenandtstrasse 5–13, 81377 München (Germany)
Fax : (+49)89-2180-77738
E-mail: zipse@cup.uni-muenchen.de
[**] DMAP=4-(N,N-dimethylamino)pyridine.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1.
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5779

is accompanied by a parallel, uncatalyzed pathway.This is
reflected in the rate Equation (1) through the presence of
two separate terms:
termination of rate constants k2 and k3 we have performed
kinetic measurements under pseudo-first-order conditions
with the alcohol as the minor component.Under these con-
ditions the rate equation can be simplified to Equation (2)
with the pseudo-first-order rate constant k1Y defined by
Equation (3).
r ¼ k2½RÀOHŠ½ðR0COÞ2OŠ þ k3½RÀOHŠ½ðR0COÞ2OŠ½DMAPŠ
ð1Þ
r ¼ k1Y ½RÀOHŠ
k1Y ¼ k2½ðR0COÞ2OŠ0 þ k3½ðR0COÞ2OŠ ½DMAPŠ
ð2Þ
ð3Þ
The uncatalyzed (background) process is characterized
through rate constant k2 and the catalyzed term through
rate constant k3.At millimolar concentrations of the DMAP
catalyst the rate of the catalyzed process was found to pro-
ceed approximately ten times faster than the background
process.Little is known about the influence of the steric
bulk of substituents R and R’ on the rate constants k2 and k3
(and thus on the ratio of the uncatalyzed and the catalyzed
processes).This information is, however, highly relevant for
the rationalization of results obtained in the kinetic resolu-
tion (KR) of alcohols.A recent review of the nonenzymatic
KR of alcohols arrives at the conclusion that secondary al-
cohols can be resolved effectively with carboxylic acid anhy-
drides of intermediate steric demand with the aid of a varie-
ty of chiral nucleophilic catalysts.[2] Thus, while very good
selectivities have been obtained with isobutyric anhydride
(R’=iPr) for a variety of secondary benzyl alcohols and cat-
alysts, few examples exist for other classes of alcohols (pri-
mary or tertiary) or anhydrides (e.g. R’=tBu).This may at
least partially be due to a larger sensitivity of the catalyzed
process to steric effects as compared to the uncatalyzed
process.To explore this point in a quantitative fashion we
have studied here the DMAP-catalyzed acylation of alco-
hols of different steric demand with anhydrides of equally
variable character.
0
0
The reactions have been followed through gas-chromato-
graphic determination of the alcohol concentration by using
n-nonane as internal standard.
The results for the acetylation of alcohols 3a–e with
acetic anhydride (4a) are given in Table 1.In line with the
Table 1.Rate constants k2 [mÀ1 sÀ1] and k3 [mÀ2 sÀ1] in the acylation of al-
cohols 3a–e with anhydrides 4a–e in CH2Cl2 at 208C.
[a]
[a]
Alcohol
Anhydride
k2 [mÀ1 sÀ1
]
k3 [mÀ2 sÀ1
]
3a
3b
3c
3d
3e
3d
3d
3d
3d
3a
3a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4e
4c
1.77ꢁ0.06”10À3
7.93ꢁ0.45”10À4
6.07ꢁ0.28”10À4
1.43ꢁ0.20”10À4
8.74ꢁ0.41”10À6
2.80ꢁ0.67”10À5
1.08ꢁ0.20”10À5
1.27ꢁ0.18”10À5
2.72ꢁ0.02”10À7
2.04ꢁ0.03”10À6
1.51ꢁ0.41”10À5
4.06ꢁ0.03”10+1
1.35ꢁ0.01”10+1
2.80ꢁ0.04
1.30ꢁ0.02
3.22ꢁ0.06”10À2
7.36ꢁ0.09”10À1
4.62ꢁ0.03”10À1
1.56ꢁ0.02”10À1
1.62ꢁ0.03”10À4
6.02ꢁ0.04”10À3
1.99ꢁ0.01”10+1
[a] Determined according to Equations (2) and (3).
expectation of increasing steric demand on going from pri-
mary to secondary and tertiary alcohols, a general decrease
in the rates of the uncatalyzed as well as the catalyzed proc-
ess can be observed.This is particularly easy to see for the
three benzyl alcohols 3a, c, and d, whose background rate
constants k2 differ by a factor of 200.The rate constants k3
describing the catalyzed process vary by a factor 1260 for
the same substrates, indicating that steric effects are signifi-
cantly larger in the catalyzed
Results
In all cases studied here, the reaction has been performed
by using dichloromethane as the solvent and catalyzed by
the DMAP/NEt3 combination.Alcohols 3a–e and anhy-
drides 4a–e were selected as substrates.
process.With the rate constants
k2 and k3 in hand the ratio of
the catalyzed and the uncata-
lyzed (background) process can
be expressed quantitatively
through Equation (4).
rðcat:Þ=rðuncat:Þ ¼ k3½DMAPŠ0=k2
ð4Þ
ce ¼ k3 ꢀ 10À3=k2
ð5Þ
The rate law described in Equation (1) has been assumed
to be valid for all the systems studied here.The linear de-
pendence of the rate of reaction, r, on the catalyst concen-
tration has been confirmed for all cases.To simplify the de-
This ratio depends linearly on the catalyst concentration.
Choosing a millimolar concentration for DMAP typical for
catalytic transformations the catalytic efficiency (ce) can be
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Acylation of Alcohols
FULL PAPER
expressed according to Equation (5).It should be kept in
mind, however, that the choice of this catalyst concentration
is still arbitrary and that different reaction conditions will
also result in different catalytic efficiencies.
The ce data for the acetylation of alcohols 3a–e compiled
in Table 2 indeed show that the higher sensitivity of the cat-
All kinetic rate constants determined here must be ex-
pected to depend on the reaction conditions and the choice
of solvent.One particularly important point concerns the
auxiliary base NEt3, for which the concentration was found
to have no influence on the reaction rate in earlier measure-
ments on the DMAP-catalyzed reaction of 3d with 4a.[23]
These measurements have now
been repeated for the reaction
of 3d with 4c at a variety of dif-
ferent DMAP concentrations.
At low DMAP concentrations
there is essentially no influence
of the NEt3 concentration on
the reaction rate, while at the
highest DMAP concentration
Table 2.Catalytic efficiency ( ce) of DMAP/NEt3 at [DMAP]0 =1”10À3 molLÀ1 in reactions of various alcohols
and anhydrides as defined by Equation (5).
À
CH3 (4a)
22.9
1318
2.9
17.0
4.6
9.1
26.3
42.7
12.3
0.6
3.7
À
CH2CH3 (4b)
À
CH
ACHTREUNG
studied
here
(1.25”
À
ACHTREUNG
10À3 molLÀ1) the reaction rate
is reduced by 10% on increas-
ing the NEt3 concentration
from 0.06 to 0.12 molLÀ1 (three
À
C
ACHTREUNG
alyzed process to steric effects degrades the catalytic effi-
ciency with increasing steric bulk of the alcohol substrate.
This is somewhat unfortunate as the acetylation rate of terti-
ary alcohol 3e is rather small in absolute terms and thus
most deserving of catalytic enhancement.Preliminary ex-
periments with tert-butanol as a sterically even more de-
manding substrate indicate that the reaction rates will be
smaller by at least a factor of three relative to those for 3e.
These experiments have therefore not been continued.
Increasing the steric bulk of the anhydrides along the
series 4a–e also leads to a reduction of the rate constants
for the uncatalyzed and the DMAP-catalyzed process, here
determined for the acylation of cyclohexanol (3d).The
background rate constant k2 varies by a factor of 526 for
this substrate, while variations of rate constant k3 are again
larger with a range of 8025.This indicates that the catalyzed
process is again more sensitive to steric bulk than the unca-
talyzed process.However, the catalytic efficiency does not
decrease steadily in this series, but shows a maximum for
the anhydrides of intermediate size 4b and c (ce=42.7) and
eventually degrades completely for pivalic anhydride 4e
(Table 2).Anhydrides 4b and c thus provide the largest “ki-
netic distance” between the uncatalyzed and the catalyzed
process at a given catalyst concentration.
The additivity of steric effects in the alcohol and anhy-
dride substrates was explored through further measurements
including the reaction of benzyl alcohol 3a with anhydrides
4c and e.Based on the results obtained for the reaction of
alcohols 3a and d with acetic anhydride (4a), a ce value
>100 would be expected for the reaction of 3a with 4c.The
catalytic efficiency values calculated from the k2 and k3 rate
constants indeed show the effects to be more than additive,
predicting a ce value >1300 for the combination 3a/4c!
However, even for the rather reactive benzyl alcohol 3a the
ce values eventually degrade on enlarging the steric bulk of
the anhydride as was shown for reaction with 4e.
to six equivalents relative to alcohol 3d, Figure 1).This ob-
servation indicates that the uncatalyzed background reaction
is essentially insensitive to the NEt3 concentration, while the
Figure 1.Dependence of the pseudo-first-order rate constant k1Y on the
concentration of DMAP (1).The auxiliary base, NEt (2), is used in 3, 4,
3
or 6 equivalents relative to the minor reaction component cyclohexanol
(3d).
catalyzed process responds to the NEt3 concentration in an
inverse fashion.This latter observation may most easily be
rationalized with a larger sensitivity of the catalyzed process
to solvent polarity, higher polarity being detrimental to the
overall reaction rate.[24]
To explore possible reasons for the largely variable acyla-
tion rates compiled in Table 1, we have determined the en-
thalpies of reaction for the transformations shown in
Scheme 2.In the absence of sufficiently detailed experimen-
tal data, the gas-phase reaction enthalpies at 298.15 K have
been calculated with two different theoretical methods
(Table 3).The G3 (MP2)B3 compound method used here
R
has been found to reproduce thermochemical values of neu-
tral organic molecules with an average absolute deviation of
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5781

H.Zipse et al.
5.03), we can expect the reac-
tion exothermicity to be largely
similar under experimental con-
ditions.Under the assumption
that these reaction energies are
representative for the rate-lim-
iting step, the source of the
largely different reaction rates
must be found in the different
intrinsic reaction barriers.
Discussion
The large dependence of reac-
tion rates on the steric bulk of
anhydrides found here is by no
means the first quantitative as-
sessment of these effects.[28]
Previous examples include the
acylation of 3-nitrophenol in
CCl4 at 258C catalyzed by vari-
ous bases.[29] Relative rates for
the anhydrides 4a, b, c, and e
have been determined for 3-pi-
Scheme 2.
Table 3.Gas-phase reaction enthalpies at 2981.5 K [kJmol À1] for the re-
action of cyclohexanol (3d) with anhydrides 4a–4e as calculated at the
B3LYP/6-311+G
theory.
coline (krel =29.5:14.8:11.9:1.0) and for 4-picoline (krel =
12.9:8.1:5.2:1.0) as the catalysts. The spontaneous hydrolysis
of this series of anhydrides in dilute aqueous solution has
been studied previously and relative rates of reaction of
33.3:17.3:10.7:1 have been determined at 258C.[30] While the
rate variations in k2 and k3 found here for cyclohexanol
follow the same relative order, the absolute range of reactiv-
ities is significantly larger (Table 1).However, one point ob-
served in all studies is the large rate decrease on passing
from isobutyric anhydride 4c to pivalic anhydride 4e.For
cyclohexanol (3d) the rate decrease in k2 and k3 amounts to
a factor of 40 and 2852, respectively!
G
C
Reactants
Products
DHrxn (B3LYP)[a]
A
3d+4a
3d+4b
3d+4c
3d+4d
3d+4e
5a+6a
5b+6b
5c+6c
5d+6d
5e+6e
À61.2
À59.0
À58.3
À59.0
À59.4
[a] Calculated at the B3LYP/6-311+G
theory.[b] Calculated at the G3 (MP2)B3 level of theory.
A
AHCTREUNG
The fact that the background and the catalyzed reaction
respond differently to steric effects has some implications
for the kinetic resolution of alcohols, which can most easily
be discussed with respect to the general reaction scheme
shown in Scheme 3.Here a racemic mixture of alcohols
2.2 kJmolÀ1, while the B3LYP hybrid functional in combina-
tion with large basis sets reproduces the same thermochemi-
cal data with an average absolute deviation of
11.5 kJmolÀ1.[25–27]
À
À
Both methods predict largely similar enthalpies of reac-
tion for the acylation reactions described in Table 3, making
the predictions quite reliable.Both methods also agree on
the fact that the enthalpies of reaction are more or less inde-
pendent of the choice of anhydride, the reaction enthalpy
for the most reactive anhydride (4a) being only 5 kJmolÀ1
larger than that for the least reactive anhydride 4e (À63.1
versus À58.2 kJmolÀ1).These theoretical estimates differ
from the corresponding reaction under experimental condi-
tions in that the neutral carboxylic acids are generated as
products.Deprotonation of the latter through reaction with
NEt3 will make the reaction more exothermic under our ex-
perimental conditions.As the acidities of the acids generat-
ed from the most reactive anhydride 4a and the least reac-
tive anhydride 4e are hardly different in water (4.75 versus
R(R) OH and R(S) OH react with the anhyride (R’CO)2O as
Scheme 3.
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Acylation of Alcohols
FULL PAPER
trogen atmosphere; acetic anhydride (4a, Ac2O) was refluxed with
coarse Mg filings at 80–908C for five days and then distilled.
the resolving reagent under the influence of a chiral catalyst,
cat.*. In favorable cases the rate constants k3(R) and k3(S)
for conversion of the alcohols are significantly different, re-
sulting in the preferred conversion of one of the alcohols.
The selectivity of the catalyst is defined by the ratio of the
two rate constants s=k3(R)/k3(S).Kagan et al.have shown
in very elegant studies that the s-factor can be determined
indirectly without the necessity of measuring individual rate
constants.[31] In practice, however, the catalyzed processes
are accompanied by uncatalyzed (and unselective) back-
ground processes characterized through the rate constant
Kinetic measurements: Reaction solutions were prepared through mixing
stock solutions of DMAP with a calibrated solution containing cyclohex-
anol, anhydride, and triethylamine.Reactions have been performed
under a nitrogen atmosphere at 208C.All kinetic measurements have
been performed by using gas chromatography (FISONS 8130, column:
SE30) with n-nonane as the internal standard.Rate measurements have
been performed by following the disappearance of the minor reaction
component under pseudo-first-order conditions.In order to maintain
first-order conditions throughout all measurements, the conversion of the
minor component was limited to below 80% in all cases.
Theoretical calculations: All structures have been optimized at the Beck-
e3LYP/6-31G(d) level of theory.The conformational space of each
system has been explored with the MM3 force field as implemented in
the Tinker program suite.[33] The energetically most favorable structures
have then been reoptimized at the Becke3LYP/6-31G(d) level of theory.
The nature of all stationary points has been verified through calculation
of the vibrational frequency spectrum.Thermochemical corrections to
calculate enthalpies at 298.15 K have been obtained by using the rigid
rotor/harmonic oscillator model and the force constants calculated at
Becke3LYP/6-31G(d) level.Single point calculations have subsequently
kback
.
For cases in which the kinetic resolution experiment can
be performed with high selectivity, the uncatalyzed back-
ground process is obviously of little significance.However,
there may be two rather different reasons for an unsuccess-
ful KR experiment: (1) The difference in k3(R) and k3(S) is
simply too small to provide a kinetic advantage of one proc-
ess over the other or (2) the background process is so fast
that it competes efficiently with the faster of the two cata-
lyzed processes.It is only in this latter case that the rate
constants reported in Table 1 provide a guideline for a rea-
sonable choice of reaction partners and reaction conditions.
Under the condition that the chiral nucleophilic catalysts
used in kinetic resolution experiments are not significantly
faster than DMAP (1),[32] the window of opportunity for the
kinetic resolution of a given set of reactants can be approxi-
mated by the ce values in Table 2.The best chances for suc-
cessful kinetic resolution experiments with secondary alco-
hols thus exist for the reaction with (iPrCO)2O.With respect
to the alcohol substrates it appears that primary alcohols
enjoy a particularly large window of opportunity, while the
very low absolute reactivity of tertiary alcohols in combina-
tion with the small ce values poses a severe challenge to suc-
cessful kinetic resolution processes.The definition of ce in
Equations (4) and (5) also shows that the window of oppor-
tunity depends on the catalyst concentration as one of the
key experimental variables.The variation of the absolute
catalyst concentration is thus of critical importance in reac-
tions with overly large background rates.How the window
of opportunity, defined through the catalyst concentration
and the ratio of the catalyzed and uncatalyzed rate con-
stants, is used depends, of course, ultimately on the ratio of
k3(R) and k3(S).
been performed at the Becke3LYP/6-311+G(d,p) level of theory.Combi-
T
nation of the single point energies with thermochemical corrections cal-
culated at Becke3LYP/6-31G(d) level yields the “H298” values cited in the
text.Based on the Becke3LYP/6-31G(d) structures relative enthalpies at
298.15 K have also been determined by using the G3(MP2)B3 compound
C
method.[20, 21] All calculations have been performed by using Gaussian 03,
[34]
Rev.B0. 3.
Acknowledgements
This work has been supported financially by the Deutsche Forschungsge-
meinschaft (DFG Zi 436/10-1).We also thank Prof.Wolfgang Steglich
and Prof.Herbert Mayr for helpful comments and inspiring discussions.
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2
under
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Published online: May 23, 2006
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