Computational study of C-H insertion reactions with ethyl bromodiazoacetate

Article abstract of DOI:10.1002/ejoc.201000531

A computational study of C-H insertion reactions between ethyl bromodiazoacetate and three different; substrates is presented. The mechanism, of the C-H insertion, is shown tobe substrate dependent; the reaction follows either a concerted mechanism, or a two-step mechanism in which, complete hydride transfer precedes C-C bond, formation.

Full text of DOI:10.1002/ejoc.201000531

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000531
Computational Study of C–H Insertion Reactions with Ethyl
Bromodiazoacetate
Hanne Therese Bonge[a] and Tore Hansen*[a]
Keywords: Computational chemistry / Insertion / Reaction mechanisms / Carbenoids / Rhodium
A computational study of C–H insertion reactions between
ethyl bromodiazoacetate and three different substrates is
presented. The mechanism of the C–H insertion is shown to
be substrate dependent; the reaction follows either a con-
certed mechanism or a two-step mechanism in which com-
plete hydride transfer precedes C–C bond formation.
Table 1. Results from C–H insertion reactions with ethyl bromodi-
Introduction
azoacetate (1).[4]
Catalytic functionalisation of C–H bonds is an area of
immense interest and importance in organic synthesis.[1]
Among the protocols for C–H functionalisation, carbenoid
C–H insertions through RhII-catalysed reactions with diazo
compounds represent an attractive combination of selectiv-
ity and mild conditions.[1b,2] Whereas the field of intramo-
lecular carbenoid C–H insertions is well established,[2d] with
a range of diazoesters reacting well, the choice of diazo
compounds for use in intermolecular C–H insertions has
been limited to aryl- or vinyl-substituted diazoacetates.[1b,3]
We have, however, recently developed a procedure for RhII-
catalysed C–H insertion reactions with halodiazoacetates.[4]
Ethyl bromo-, chloro- and iododiazoacetates insert regiose-
lectively into C–H bonds in a variety of substrates with
yields up to 82%, and the reaction represents a new method
for selective introduction of halogens. Table 1 shows se-
lected examples of C–H insertion reactions with ethyl bro-
modiazoacetate (1).
bated, but a mechanism involving only the carbenoid and
the C–H bond is now preferred.[2e] Two extremes of this
mechanism have been suggested (Scheme 1): a concerted
process with C–H and C–C bond formation taking place
simultaneously (Path I), or a two-step pathway in which hy-
dride abstraction is followed by C–C bond formation
(Path II). It has been argued that because of the high level
of enantioselectivity observed in certain C–H insertions, the
reaction most likely follows a concerted, albeit asynchro-
nous pathway.[7] Thus, even though complete hydride trans-
fer has been reported for intramolecular C–H insertions
with certain systems, evident by formation of anomalous
The halodiazoacetates[5] are a novel class of diazo com-
pounds that can be used in C–H insertion reactions, and a
deeper understanding of their reactivity is of importance
from both a synthetic and a theoretical point of view. As a
follow-up to our recent computational study of cyclopro-
panation reactions with halodiazoacetates,[6] we will in this
paper present a computational study, at the B3LYP level
of theory, of C–H insertion reactions with representative
halodiazoacetate ethyl bromodiazoacetate (1).
RhII-catalysed C–H insertion reactions with diazo com-
pounds are assumed to follow a path in which the carbene
moiety of an intermediate metal carbenoid inserts into the
C–H bond. The mechanism of the insertion has been de-
[a] Department of Chemistry, University of Oslo,
Sem Sælands vei 26, 0315 Oslo, Norway
Fax: +47-2285-5441
E-mail: tore.hansen@kjemi.uio.no
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000531.
Scheme 1. Proposed mechanistic paths for RhII carbenoid C–H in-
sertions.
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H. T. Bonge, T. Hansen
SHORT COMMUNICATION
Scheme 2. Formation of carbenoid 2. The energies are zero-point corrected sums of electronic and thermal energies at 25 °C, reported in
kcalmol–1.
products,[8] Path I is viewed as the mechanism operating in in carbenoid 2 to 0.26 in TS-3, and the Rh–Rh BO has
standard cases,[2e] a proposal that has been supported by increased from 0.46 to 0.60, approaching the value of 0.80
computational studies.[9]
in the free catalyst.
The transition state for this C–H insertion, TS-3, repre-
sents a predicted energy barrier of 22.9 kcalmol–1. The bar-
rier for insertion of the carbene moiety of carbenoid 2 into
a methane C–H bond is thus more than twice as high as
the barrier for nitrogen extrusion to form carbenoid 2, mak-
ing the C–H insertion step the rate-limiting step of the reac-
tion.[11] The 22.9 kcalmol–1 barrier is considerably higher
than the barriers reported for analogous C–H insertion
with diazomethane or methyl diazoacetate,[9a] a fact that
may be explained by a higher stability of carbenoid 2 com-
pared to the analogous non-halogenated carbenoids. For-
mation of the C–H insertion product (i.e., 4) is strongly
exothermic: the product is 57.7 kcalmol–1 more stable than
the starting materials [methane, 1 and Rh2(O2CH)4].
We then turned our attention to 1,4-cyclohexadiene
(Scheme 4). This activated[3a] substrate has been used exper-
imentally in C–H insertion reactions with 1,[4] giving good
yields (Table 1, Entry 2). With 1,4-cyclohexadiene as the
substrate, the mechanism for C–H insertion turned out to
be quite different from the mechanism found with methane.
Instead of concerted C–H and C–C bond formation, the
reaction follows a two-step pathway (Path II, Scheme 1); no
concerted pathway could be located. The first step is hy-
dride transfer from 1,4-cyclohexadiene to carbenoid 2 to
give complex 6. The transition state for hydride transfer,
TS-5, represents a barrier of 1.5 kcalmol–1 and is quite
early: the BO of the breaking 1,4-cyclohexadiene C–H bond
is 0.72, and that of the forming C–H bond is only 0.16. In
complex 6, the broken C–H bond has a BO of a mere 0.03,
meaning that complex 6 is a zwitterionic complex with the
hydride completely transferred from 1,4-cyclohexadiene.
This is reflected in the NBO charges. The cyclohexadiene
ring in complex 6 has a considerable positive charge of 0.59.
An increased BO (1.3) between the carbon atom where the
reaction takes place and its neighbouring carbon atoms im-
plies delocalisation of the charge. The Rh–C bond is weak-
ened compared to the Rh–C bond of carbenoid 2, with a
BO of 0.40, but no C–C bond formation is detectable (BO
0.09).
Results and Discussion
As in our previous computational study of halodiazo-
acetates,[6] we chose Rh2(O2CH)4 as a model catalyst in the
interest of computational facility. Rh2(O2CH)4-catalysed C–
H insertion reactions with ethyl bromodiazoacetate are in-
stigated by formation of RhII carbenoid 2, through a pre-
viously described path[6] of coordination of 1 to the catalyst
followed by nitrogen extrusion (Scheme 2). The carbenoid
then goes on to react with a C–H insertion substrate.
We first considered the reaction with the simple substrate
methane. Carbenoid C–H insertion reactions involving
methane have not been reported in the literature, but meth-
ane has been used as a model substrate in a computational
study of C–H insertions with diazomethane and methyl di-
azoacetate.[9a] Our findings with this rather unreactive sub-
strate mirrors the results from this study in that the inser-
tion follows a concerted pathway (Path I, Scheme 1); the
methane C–H bond breaks and new C–H and C–C bonds
form in a single event (Scheme 3).[10]
Scheme 3. Mechanism for C–H insertion reaction with methane.
The energies are zero-point corrected sums of electronic and ther-
mal energies at 25 °C, reported in kcalmol–1.
The Wiberg bond orders (BOs) of the forming C–C and
C–H bonds in TS-3 are 0.52 and 0.54, respectively, which
implies that C–C and C–H bond formation happen in a
quite synchronous manner. The BO of the reacting methane
C–H bond is 0.31, and the methane CH3 moiety has a NBO
charge of +0.20, signifying that the methane C–H bond is
The second step of the C–H insertion, leading to product
breaking. The dissociation of the carbene moiety from the 8 with a relative energy of –58.8 kcalmol–1, is the C–C bond
catalyst has started; the Rh–C BO has decreased from 0.73 formation. In the transition state for this step, TS-7, the
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Computational Study of C–H Insertion Reactions
Scheme 4. Mechanism for C–H insertion reaction with 1,4-cyclohexadiene.[12] The energies are zero-point corrected sums of electronic
and thermal energies at 25 °C, reported in kcalmol–1.
dissociation of the carbene moiety has proceeded rather far,
This reaction is, to the best of our knowledge, the first
as illustrated by the Rh–C and Rh–Rh BOs of 0.19 and reported example of an intermolecular RhII-catalysed C–H
0.63. The forming C–C bond has a BO of 0.25. The insertion reaction in which complete hydride transfer pre-
1.7 kcalmol–1 barrier for C–C bond formation is about the cedes C–C bond formation. The barriers for hydride trans-
same height as the barrier for hydride transfer, and the rate- fer (TS-5) and for C–C formation in the zwitterionic com-
determining step for the overall reaction is nitrogen ex- plex (TS-7) are both low, but significant.[13] Davies et al.
trusion to form carbenoid 2 (Scheme 2), with a barrier of studied C–H insertions with 1,4-cyclohexadiene with
8.0 kcalmol–1. Figure 1 shows the energy profile of the reac- methyl diazoacetate or methyl phenyldiazoacetate as the re-
tion; Figure 2 shows the structures of transition states TS- acting diazo compounds and report concerted mechanisms
5 and TS-7 and zwitterionic intermediate 6.
for both reactions.[9c] In the reaction with methyl phenyl-
diazoacetate, a zwitterionic complex similar to 6 was lo-
cated, but the authors argue that this complex is merely an
artefact of the optimisation algorithm.
THF is another good substrate for C–H insertion reac-
tion with 1 (Table 1, Entry 3). Like 1,4-cyclohexadiene,
THF is a compound with a good ability to stabilise a posi-
tive charge on carbon atom in a C–H insertion reaction,
and once again we found a two-step mechanism for the C–
H insertion with carbenoid 2. In this reaction, two dia-
stereomeric products can be formed, each diastereomer
with its own path leading to it (Scheme 5).
The transition states for hydride transfer, TS-9a and
TS9-b, are both as early as the analogous transition state
for the reaction with 1,4-cyclohexadiene (TS-5), and the rel-
evant BOs in TS-11a and TS-11b are also highly similar to
those in TS-7. As in the reaction with 1,4-cyclohexadiene,
nitrogen extrusion is the rate-determining step of the overall
reaction, and C–C bond formation is the rate-determining
step of the insertion: TS-9a and TS-9b represent small en-
ergy barriers of 0.2 and 0.9 kcalmol–1, respectively, whereas
TS-11a and TS-11b represent barriers of 3.4 and
1.9 kcalmol–1.
Figure 1. Energy profile of Rh2(O2CH)4-catalysed C–H insertion
reaction between 1 and 1,4-cyclohexadiene. The energies are zero-
point corrected sums of electronic and thermal energies at 25 °C,
reported in kcalmol–1.
The described C–H insertion reactions and the pre-
viously reported cyclopropanation reaction with 1[6] are all
carbenoid reactions that proceed through intermediate car-
benoid 2. Though there are similarities between the reac-
tions, there are also notable differences. One difference be-
tween the studied C–H insertion reactions and the cyclo-
propanation is the heights of the energy barriers repre-
Figure 2. Important structures in the C–H insertion reaction be-
tween 1 and 1,4-cyclohexadiene.
When Gibbs free energies are considered, zwitterionic sented by the transition states. Even though the barriers
complex 6 is more stable than carbenoid 2 by 9.7 kcalmol–1. for C–H insertion reaction between carbenoid 2 and 1,4-
The barriers for hydride transfer (TS-5) and C–C bond for- cyclohexadiene or THF are very low, the predicted barriers
mation (TS-7) remain low, but significant at 1.0 and for cyclopropanation of styrene with carbenoid 2 are even
2.2 kcalmol–1, respectively.
lower. The two diastereomeric transition states represent
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H. T. Bonge, T. Hansen
SHORT COMMUNICATION
Scheme 5. Mechanism for C–H insertion reaction with THF.[12] The energies are zero-point corrected sums of electronic and thermal
energies at 25 °C, reported in kcalmol–1.
barriers of 0.7 and 1.8 kcalmol–1, respectively. The differ-
ence in barrier heights was confirmed by experimental com-
petition experiments (Scheme 6) by using the standard con-
ditions for C–H insertion and cyclopropanation reac-
tions.[4,5] Ethyl bromodiazoacetate (1) was decomposed by
[14]
Rh2(esp)2
in the presence of an excess amount of both
styrene and either 1,4-cyclohexadiene or THF. For THF,
the predicted rate-limiting barriers for C–H insertion reac-
tion with 2 are 3.4 (Path a) and 1.9 kcalmol–1 (Path b), in
both cases higher than the predicted barriers for cyclopro-
panation of styrene. This corresponds nicely with the exper-
imental results: the competition experiment with styrene
and THF gave only cyclopropanation product; no C–H in-
sertion product was observed. In the case of 1,4-cyclohexa-
diene, the predicted rate-limiting barrier is lower than with
THF; it is 1.7 kcalmol–1. The lower barrier is reflected in
the results of the competition experiment with styrene and
1,4-cyclohexadiene. Both C–H insertion and cyclopropan-
ation takes place, but cyclopropanation is the predominant
reaction; the cyclopropane and C–H insertion products are
formed in a 3:1 ratio.
Scheme 6. Competition experiments.
and 0.25–0.30 for C–H and C–C bond formation, the tran-
sition states for C–H insertion with 1,4-cyclohexadiene and
THF are, albeit still quite early, later than those for cyclo-
propanation. The transition state for reaction with meth-
ane, on the other hand, has C–H and C–C BOs of about
0.5, and is thus substantially later than any of the other
transition states.
Another notable difference between the reactions is their
mechanisms. The C–H insertion reaction can follow dif-
ferent mechanistic extremes depending on which substrate
Conclusions
In summary, we have presented a full computational
is used: reaction with methane follows a concerted path study of C–H insertion reactions between ethyl bromodi-
with synchronous C–H and C–C bond formation, and reac- azoacetate (1) and three different substrates. The mechan-
tions with 1,4-cyclohexadiene and THF follow a two-step istic path of the C–H insertion has been shown to be de-
path with C–H bond formation preceding C–C bond for- pendent on the substrate: reaction with methane follows a
mation. For the cyclopropanation reaction, only one concerted mechanism, whereas reactions with 1,4-cyclo-
mechanism was observed. This mechanism places in be- hexadiene and THF follow a two-step mechanism in which
tween the two extremes: concerted, but highly asynchro- complete hydride transfer precedes C–C bond formation.
nous. The transition states for cyclopropanation are very To the best of our knowledge, this is the first example of
early; the two forming C–C bonds have BOs of below 0.1 an intermolecular C–H insertion reaction shown to follow
and around 0.1–0.2, respectively. With BOs of 0.15–0.20 a two-step mechanism.
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Computational Study of C–H Insertion Reactions
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Density functional theory (DFT) was employed to investigate the
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An initial complex between 2 and methane was found, but it
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The structures shown in Scheme 4are the stationary structures
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gies to the depicted structures, were also identified.
The use of other methods may change the height and signifi-
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Acknowledgments
We acknowledge Dr. Andreas Krapp for helpful discussions and
technical support.
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Received: April 16, 2010
Published Online: June 25, 2010
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