Cationic intermediates in Friedel-Crafts acylation: Structural information from theory and experiment

Article abstract of DOI:10.1039/c0cc02286a

Experimentally-determined intramolecular and intermolecular deuterium kinetic isotope effects and computational studies imply three possible kinetic scenarios for the Friedel-Crafts acylation of xylene. The influence of the structural and energetic proper

Full text of DOI:10.1039/c0cc02286a

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Cationic intermediates in Friedel–Crafts acylation: structural information
from theory and experimentwz
Hui Zhu and Matthew P. Meyer*
Received 1st July 2010, Accepted 20th August 2010
DOI: 10.1039/c0cc02286a
Experimentally-determined intramolecular and intermolecular
deuterium kinetic isotope effects and computational studies
imply three possible kinetic scenarios for the Friedel–Crafts
acylation of xylene. The influence of the structural and energetic
properties of the p-complexes and r-complex upon the observed
isotope effects is explored.
groups of Brown and Olah. Hammett plots that explored the
phenylacylium substituent effects upon rate resulted in a slope
of r+ = 1.858.8 While this could be interpreted as evidence for
rate-limiting s-complex formation, it could also be the result
of substituent-dependent charge transfer in the p-complex.
Here we approach this problem by performing a suite of
inter- and intramolecular 2H kinetic isotope effect (KIE)
measurements upon the Friedel–Crafts acylation of xylene
with isobutyryl chloride catalyzed by aluminium chloride.
We discuss these results in the context of computed s-complex
and p-complex intermediate structures and estimates of
isotope effects derived from these structures.
Mechanisms that invoke p-complexes are very common. Much
less common are mechanistic characterisations of these and
other cationic intermediate species that serve as important
mediators of rate and product determination. While some
elegant work1,2 in this area has begun to clarify these
intermediates in terms of their energetic and structural
characteristics, their role in even the simplest of reactions
remains poorly understood. Studies on electrophilic aromatic
substitution were among the first to stimulate discussion of the
potential role of p-complexes.3
Intramolecular KIEs have proven useful in accessing
information regarding reaction steps that break the symmetry
between two groups that differ only in isotopic substitution,
even when the symmetry-breaking step follows the rate-
determining step.9 Here we have employed intramolecular
2H KIEs to probe the step responsible for breaking symmetry
between the equivalent methyl groups in p-xylene. Intra-
A vast literature is associated with mechanistic explorations
of electrophilic aromatic substitution reactions. Classic
mechanistic work on electrophilic aromatic substitution
reactions by Brown, Olah, and their coworkers has focused
primarily upon explaining relationships between reactivity and
selectivity with a view toward understanding the transition
states responsible for rate and product determination.4
Brown’s selectivity/reactivity relationship studies upon
acetylation suggested that reactivity and selectivity are
governed by a single step.5 By contrast, relative reactivity data
for Friedel–Crafts benzoylation implied that p-complex for-
mation is at least rate-determining.6 Together, these findings
raised the question of whether a p-complex could determine
product distribution in Friedel–Crafts acylation. Crystal
structures of Z1-p-complexes between bromine and the ortho
and para positions on toluene made the argument for product-
determination at the p-complex seem cogent.2 Furthermore,
excellent linear correlations between the absorbance wave-
length of p-complexes of bromine with various aromatic
compounds and the bromination rates of the aromatic
compounds have been observed.7 Together, these studies
suggested that Z1-p-complex formation might be at once rate-
and product-determining in electrophilic aromatic bromination.
If the same process were operative in Friedel–Crafts acylation,
it might explain the seemingly disparate data presented by the
2
molecular H KIEs in this system are reflected in the product
ratio of 20-d3-1 to 50-d3-1 resulting from the acylation of
d3-xylene. Quantitative estimates of the ratio of 20-d3-1 to
50-d3-1 were obtained using quantitative 2H NMR with 901
pulses separated by delay times of greater than 5 ꢀ T1 for the
peak of interest with the longest relaxation time. We utilized
13C–13C COSY obtained at natural abundance to assign 13C
NMR resonances. We then assigned 1H NMR resonances
(and thereby the corresponding 2H NMR resonances) using
an HMQC experiment. Both of the 2-dimensional NMR
experiments used for assignments were performed on a sample
utilized in KIE determinations to ensure against potential
concentration effects upon chemical shift. We found the
1
20-methyl group to have a H NMR resonance downfield of
that for the 50-methyl group. The intramolecular 2H KIE
resulting from three determinations is shown in Table 1. The
magnitude of the intramolecular 2H KIE translates into a
small but significant preference for deuterium residing at
the nascent 50-methyl position in the product-determining
transition state. This could imply product-determining
p-complex formation whereby the methyl groups on the
dimethylacylium electrophile come into incidence with the
50-methyl position on xylene. Alternatively, the intramolecular
2H KIE could reflect the influence of both hyperconjugative10
Dept. of Chemistry and Biochemistry, University of California,
Merced, USA. E-mail: mmeyer@ucmerced.edu;
Tel: +1 209-228-2982
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: NMR
integrations and details regarding the computation of KIEs, computed
structures. See DOI: 10.1039/c0cc02286a
2
Table 1 Values of intra- and intermolecular H KIEs
Rate constant ratio
Experimental value
0
2 -d /k5 -d
0
k
kd -1/kd
k1/kd -1
0.957 ꢁ 0.002
1.010 ꢁ 0.007
0.946 ꢁ 0.004
3
3
10-1
6
6
c
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Chem. Commun., 2011, 47, 409–411 409

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and steric11 effects at the 20-methyl position such that the
substantial normal b-2H KIE due to hyperconjugation that
one might anticipate is compensated by the inverse steric
2H KIE. Finally, deprotonation which leads to rearomatization
might exhibit the observed intramolecular 2H KIE due to a
combination of steric and hyperconjugative influences.
A few previous studies have shown deprotonation to be at
least partially rate-limiting in Friedel–Crafts acylations.12 We
explored this possibility by measuring the 2H KIE at
the aromatic positions. Four replicates of competition
experiments (d6-1 vs. d10-1) were performed whereby the
extent of reaction (F) was measured for each isotopolog. The
KIE was computed using eqn (1). The average KIE with
associated error is reported in Table 1. While measurements
in similar Friedel–Crafts acylations typically yield a 2H KIE of
2 or greater, the value reported here is very near unity. Our
measurement seems to suggest that deprotonation is not
rate-limiting. As this is the last step in the consensus mechanism,
deprotonation can also be excluded as the product-determining
step.
Fig.
1
Optimized [M06-2X/6-31+G(d,p)] local minima corres-
ponding to the (A) Z6-p-complex, (B) Z1-p-complex, and the (C)
s-complex. Optimizations include a polarizable continuum model
for dichloromethane using the IEFPCM method.
expensive and often does not perform as well as most local
density functional methods in reproducing vibrational
frequencies. As a compromise, we have elected to use the
M06-2X functional which has been found to reproduce non-
bonding interactions well while not sacrificing fidelity in
estimates of vibrational frequencies.16 We found three unique
cationic structures both with and without the presence of a
polarizable continuum model for the dichloromethane solvent:
an Z6-p-complex, an Z1-p-complex, and a s-complex.17 While
kH lnð1 ꢂ FHÞ
structures computed in the presence of
a polarizable
KIE ¼
¼
ð1Þ
kD lnð1 ꢂ FDÞ
continuum model for dichloromethane solvent (Fig. 1) are
similar in kind to gas phase structures, they have quite
different structural properties (Fig. 2; Table 2).
Having narrowed putative rate-limiting steps down to
p-complex or s-complex formation, we sought to distinguish
between the two possibilities. To accomplish this, we
In systems where quantum mechanical tunneling is
unimportant, it is often assumed that the equilibrium isotope
effect (EIE) is an upper bound for the KIE.18 Here, we
compute intra- and intermolecular EIEs as an upper bound
estimate of the KIEs that one might expect for the funda-
mental steps leading to the three cationic intermediates
(Table 3). The first thing that can be gleaned from these
calculations is that gas phase and polarizable continuum
structures lead to drastically different predictions. All gas
2
performed four measurements of the intermolecular H KIEs
resulting from substitution at the methyl positions on xylene
(i.e. d6-1 vs. 1) using the same method used for the previous
intermolecular KIE experiment. We found that k1/kd -1
=
6
0.946 ꢁ 0.004 (Table 1). This value is close to the value
measured for the intramolecular KIE, which may suggest that
the rate-limiting and product-determining steps are the same.
At first glimpse, this overall inverse 2H KIE would seem to
preclude s-complex formation as the rate-limiting step based
on the assumption that electronic (hyperconjugative) effects
would outweigh steric effects upon the KIE. Computational
work discussed below, however, suggests that a number of
scenarios are commensurate with the experimental KIEs
reported in Table 1.
To gain insight regarding the nature of the putative s- and
p-complex(es), we attempted to optimize stationary points
upon the potential energy surface corresponding to these
structures. There are a number of challenges that make the
computational estimation of KIEs difficult in this system.
First, it is quite likely that saddle points upon the potential
energy surface that lead to the s- and p-complexes are a poor
representation of the transition state.13 This situation occurs
largely because the potential energy surface is almost certainly
quite flat in the vicinity of the p-complexes considered here. In
fact, it is often assumed that the formation of p-complexes is a
barrierless process.14
Fig. 2 Overlays of (A) Z6-p-complex, (B) Z1-p-complex, and (C)
s-complex structures computed in the gas phase and utilizing a
polarizable continuum solvent model.
Table 2 Structural and energetic properties of cationic intermediates
Distances to C(RO+)/A
a
Erel
10
20
30
40
50
60
Complex
sb
1.741 2.521 3.578 4.036 3.715 2.677 3.2
2.964 3.210 4.101 4.674 4.539 3.727 1.2
3.438 3.513 3.355 3.152 3.129 3.245 0.0
1.613 2.528 3.667 4.110 3.723 2.588 5.3
3.155 3.407 4.284 4.838 4.679 3.877 0.1
3.529 3.590 3.494 3.372 3.355 3.407 0.0
Z1-pb
Z6-pb
sc
Z1-pc
Z6-pc
Another challenge to optimizing stationary points upon the
Friedel–Crafts acylation potential energy surface is that most
commonly used density functionals are incapable of accurately
reproducing correlation-mediated attractive and repulsive
dispersion forces.15 On the other hand, MP2 theory is capable
of reproducing these interactions but is more computationally
a
b
Energy relative to that of the s-complex in kcal molꢂ1
.
Structures
c
optimized in the gas phase. Structures optimized in the presence of a
polarizable continuum; relative energies do not include solute cavitation,
solute–solvent dispersion, or solute–solvent repulsion contributions.
c
410 Chem. Commun., 2011, 47, 409–411
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Table 3 Equilibrium isotope effects corresponding to the KIEs
shown in Table 1 as computed from optimized cationic complexes
structure of the s-complex (7). One would expect the b-2H
KIE resulting from hyperconjugation to dominate the inter-
molecular KIE if s-complex formation were rate-limiting.
However, it appears that steric interactions that develop at
both the nascent 20- and 50-methyl positions override this
sa
Z1-pa
Z6-pa
sb
Z1-pb
Z6-pb
0
0
k2 -d /k5 -d
1.003
0.894
1.035
0.944
0.999
0.948
0.945
0.930
1.023
0.950
0.930
0.950
3
k1/kd3 -1
2
6
effect, yielding an overall inverse H KIE.
a
b
Structures optimized in the gas phase. Structures optimized in the
presence of a polarizable continuum.
In summary, the results presented here represent a cogent
mechanistic argument for rate- and product-limiting
s-complex formation in the Friedel–Crafts acylation of
xylene. Computed structures of cationic intermediates yield
insight into the energetics that control reactivity and selectivity
in the Friedel–Crafts acylation. Finally, the substantial role of
steric interactions in determining the direction and magnitude
of the KIEs measured here has been highlighted and are in
phase structures yield intramolecular EIEs that are either near
unity or favor deuterium in the 20-methyl position, which is
contrary to our intramolecular KIE measurements. The
computed intramolecular EIE for the Z1-p-complex is also
contrary in direction and smaller in magnitude than our
measured intramolecular KIE. This leaves fundamental
reaction steps resulting in the s-complex or Z6-p-complex in
consideration as product-determining steps.
2
accordance with steric H KIEs measured in other systems.19
This work has implications upon future reaction development
as inroads to asymmetric Friedel–Crafts reactions are made.20
We thank the Petroleum Research Fund (#48064-G4) for
financial support and the National Science Foundation for
computational resources through TeraGrid access provided
by PSC.
The intermolecular KIE determined from the competitive
reaction of 1 and d6-1 is 0.946. If one considers that the EIE is
an upper bound to the KIE, then s-complex formation is the
most likely candidate as the rate-limiting step. If one assumes a
direct progression from the Z1-p-complex to the s-complex
along the reaction pathway, then it is reasonable to expect the
transition state that separates these two intermediates to yield
a KIE between the computed EIEs corresponding to these
structures. Furthermore, if we consider the energetic
properties of the Z1-p-complex to the s-complexes (Table 2),
the higher relative energy of the s-complex implies that the
transition state leading to this complex is rate-limiting. The
relative energies in Table 2 do not take vibrational entropy
into consideration; however, it is reasonable to expect entropy
terms to be larger for the p-complexes, resulting in an even
lower free energy for these structures. These considerations,
taken in the context of the intermolecular competitive
(d6-1/d10-1) KIE, which eliminates deprotonation as the rate-
limiting step, further implicate s-complex formation as being
product-determining. It is satisfying, then, that the intra-
molecular EIE approximation (0.945) for the s-complex is in
excess of but quite close to the measured intramolecular KIE
(0.957). This result is surprising in view of what might
intuitively be expected. Scheme 1 illustrates one resonance
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Scheme 1 Consensus mechanism for the Friedel–Crafts acylation of
xylene including putative representations of the p-complex.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 409–411 411