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Title
Diels-Alder reactions of allene with benzene and butadiene: concerted, stepwise, and
ambimodal transition states.
Permalink
https://escholarship.org/uc/item/33m5w5vc
Journal
The Journal of organic chemistry, 79(19)
ISSN
0022-3263
Authors
Pham, Hung V
Houk, KN
Publication Date
2014-10-01
DOI
10.1021/jo502041f
Peer reviewed
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University of California
Diels−Alder Reactions of Allene with Benzene and Butadiene:
Concerted, Stepwise, and Ambimodal Transition States
Hung V. Pham and K. N. Houk*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
*
S
Supporting Information
ABSTRACT: Multiconfigurational complete active space methods (CASSCF and
CASPT2) have been used to investigate the (4 + 2) cycloadditions of allene with
butadiene and with benzene. Both concerted and stepwise radical pathways were
examined to determine the mechanism of the Diels−Alder reactions with an allene
dienophile. Reaction with butadiene occurs via a single ambimodal transition state
that can lead to either the concerted or stepwise trajectories along the potential
energy surface, while reaction with benzene involves two separate transition states
and favors the concerted mechanism relative to the stepwise mechanism via a
diradical intermediate.
■
INTRODUCTION
Allenes readily undergo thermal pericyclic reactions, including
Diels−Alder, 1,3-dipolar, and (2 + 2) cycloadditions.
1
There is
some evidence that these reactions are stepwise, although few
systematic investigations are available. We report multi-
configurational complete active space (CAS) computational
studies of the reactions of allene with butadiene and with
benzene, aliphatic and aromatic dienes in Diels−Alder reactions
(Figure 1).
2,3
For the butadiene−allene reaction, we have
discovered that a single ambimodal transition state leads to a
path bifurcation to either the (4 + 2) cycloadduct, via a
concerted reaction, or to a diradical intermediate that can
subsequently give either Diels−Alder or (2 + 2) adduct. In
contrast, benzene and allene react through a transition state
that leads only to a concerted pathway, forming both C−C
bonds simultaneously and avoiding the loss of aromaticity in an
intermediate. A higher energy transition state leads to a
diradical intermediate.
■
BACKGROUND
Pericyclic reactions involving allenes are known and have been
used extensively in the syntheses of natural products.
4
These
reactions include [1,n]-, [2,3]-, and [3,3]-sigmatropic shifts
5
and electrocyclizations.
6
The relative reactivity of allenes,
alkynes, and alkenes in these processes have been the subject
of some interest. For instance, the Cope rearrangement was
found to proceed through similar transition structures,
independent of the identity and degree of unsaturation of the
π-components.
7
Allenes also participate in (4 + 2) cyclo-
additio ns, 1,3-dipolar cycload ditions, and (2 + 2) cyclo-
additions; examples of each of these studied experimentally
are shown in Figure 2. Maier utilized both cyclopentadiene and
Boc-protected pyrrole with monosubstituted allenes to generate
bridged bicyclic compounds through the Diels−Alder reaction.
8
The 1,3-dipolar cycloaddition of C-phenyl-N-methylnitrone
with electron-deficient allenes produces methyleneisoxazoli-
dines at 40 °C.
9
Allene dimerization has been known for
decades,
10
and Dolbier investigated the preference for
formation of 1,2-dimethylenecyclobutane over the 1,3-
regioisomer.
11
Computational mechanistic studies of allenes as reaction
partners in 1,3-dipolar
12
and (2 + 2) cycloadditions
13
have been
reported. There are, however, limited theoretical investigations
of allenes as dienophiles in (4 + 2) reactions. Venuvanalingam
studied the concerted Diels−Alder cycloadditions of dienes
with allenes and fluoroallenes as dienophiles with semiempirical
AM1 and PM3 methods.
14
Gandolfi studied concerted Diels−
Alder cycloadditions of allene and fluoroallene with cyclo-
Received: September 3, 2014
Published: September 12, 2014
Figure 1. Diels−Alder and (2 + 2) cycloaddition reactions of allene
with butadiene and benzene.
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pentadiene and furan with the ab initio Hartree−Fock method
and MP3 single-point calculations.
15
Houk and co-workers
conduc ted a DFT stu dy of the concerted and stepwise
pathways of the parent butadiene−allene cycloaddition as
well as some furan cycloadditions with allene but were unable
to locate a number of important stationary points.
16
In light of
the numerous studies contrasting the Diels−Alder reactions of
alkene and alkyne dienophiles,
17
we have undertaken a
thorough investigation of the butadiene−allene system.
A variety of substituted dienes undergo Diels−Alder
reactions with allenes. As shown in Figure 3, Danishefsky
dienes 1 react with unsymmetrically 1,3-disubstituted allenes 2
to give aromatic products 4 and 5.
18
These reactions were
thought to involve Diels−Alder cycloadditions via intermediate
3. However, Jung and co-workers have shown for similar cases
that (2 + 2) adducts may precede Diels−Alder adduct
formation.
19
Reactions of dienes 6 with allenoic ester 7 give
exo-methylenevinylcyclobutane intermediates 8, formal (2 + 2)
adducts, when the reaction time is 5 h (Figure 4). These
adducts undergo formal Cope rearrangements to give the
Diels−Alder products 9 and 10 after extended reaction times.
The Cope rearrangement of the unsubstituted exo-methyl-
enevinylcyclobutane was found in previous computational
studies by Houk and co-workers to rearrange to the Diels −
Alde r adduct in a stepwise fashi on through a bis-allylic
diradical.
20
Based on previous studies and experimental results
in the literature, it is proposed that (4 + 2) reactions of this
nature are stepwise and proceed first through a formal (2 + 2)
cycloaddition, followed by a formal 1,3- or 3,3-shift to afford
the Diels−Alder adduct.
Himbert and Henn have shown that intramolecular (4 + 2)
cycloadditions between allenyl amides and tethered aryl groups
occur efficiently at elevated temperatures, despite the required
disruption of aromaticity (Figure 5a).
21
The polar stepwise
mechanism was ruled out by the insensitivity of the kinetics of
the reaction to varying electron-donating and electron-with-
drawing groups on the benzene and allene moieties. However,
although a concerted mechanism was initially proposed, a
Figure 2. (4 + 2), 1,3-dipolar, and (2 + 2) cycloadditions of allenes.
Figure 3. Diels−Alder reactions of dimethyl 1,3-allenedicarboxylate 2 with Danishefsky dienes 1.
Figure 4. Formation of exo-methylenevinylcyclobutane intermediate prior to rearrangement to Diels−Alder adducts.
The Journal of Organic Chemistry Featured Article
dx.doi.org/10.1021/jo502041f | J. Org. Chem. 2014, 79, 8968−89768969
stepwise diradical mechanism could not be ruled out.
Vanderwal has recently explored this dearomatizing intra-
molecular D iels−Alder reaction and has incorporated a
subsequent ring-rearranging metathesis to form complex
polycyclic scaffolds (Figure 5b).
22
Together, our groups
uncovered important mechanistic insights into these intra-
molecular cycloadditions of allene to benzene derivatives.
23
In
order to understand the energetics of concerted and stepwise
pathways in benzene−allene cycloadditions and to make direct
comparisons with nonaromatic diene reactions, we have
undertaken a systematic investigation of the benzene-allene
and butadiene-allene reac tions with multiconfigurational
CASSCF and CASPT2 methods.
■
COMPUTATIONAL METHODOLOGY
We have studied these reactions with complete active space (CAS)
multiconfigurational meth ods. Stationary point structures were
optimized using the CASSCF(8,8)/6-31G(d)
24
and CASSCF-
(10,10)/6-31G(d) methods in Gaussian 09
25
for the butadiene/allene
and benzene/allene systems, respectively. Single-point calculations
with second-order perturbation theory CASPT2/6-31G(d)
26
were
carried out on the optimiz ed structures, using the program
MOLCAS
27
version 7.4, to account for dynamic electron correlation.
CASSCF thermal corrections and zero-point energies are included in
the CASPT2 electronic energies. Vibrational frequencies were
computed for all optimized structures in order to verify that they
are minima or transition states. Intrinsic reaction coordinate (IRC)
calculations were also performed on several transition structures to
verify that these transition structures originated from the correct
reactants and led to the expected intermediates or products. CASSCF
and CASPT2 has been found by Houk and co-workers to provide
reasonable energetics for various diradical and pericyclic reactions.
28
DFT methods were also employed for optimizations, but we had
difficulty locating relevant stationary points.
16
Furthermore, several
unrestricted DFT methods gave unrealistically high energy diradicals
for the benzene−allene reaction. Consequently, we have used more
robust multiconfigurational methods for the entirety of the
investigation. A summary of our DFT results can be found in the
Supporting Information.
■
RESULTS/DISCUSSION
Mechanism of the Reaction of Butadiene and Allene.
The reaction of butadiene 16 with allene 17 can occur by either
a concerted or stepwise radical mechanism (Figure 6). The
concerted pathway has previously been studied using semi-
empirical
14
as well as UB3LYP methods.
16
Alternatively, the
reaction can give diradical 18 that can subsequently cyclize to
Diels−Alder adduct 19 or to the (2 + 2) adduct 3-
methylenevinylcyclobutane 20. The (2 + 2) adduct can reopen
to 18 and then cyclize to yield 19. This Cope rearrangement to
the Diels−Alder adduct of the unsubstituted 3-methylenevi-
nylcyclobutane was found in previous computational studies by
Houk and co-workers to occur in stepwise fashion through a
bis-allylic diradical intermediate.
29
The stereoselectivity was
postulated to be governed by dynamic effects. Reaction of the
diene in the s-cis conformation is necessary to permit cyclization
to the Diels−Alder adduct; the transoid diradical 18(trans)
could be formed and undergo bond rotation around the partial
double bond to furnish the cisoid diradical 18(cis) , which can
then cyclize to 19, but this would require rotation around the
partial double bond of the allyl radical.
Four possible react ion pathways were examined using
CASPT2//CASSCF(8,8) calculations. The active space was
chosen to include the electrons involved in the formation of
new bonds, namely the eight π-electrons of butadiene and
allene. A schematic of the energy surface was generated from
the quantum-chemically calculated values and is shown in
Figure 7. Reported energies are relative to the lowest energy
conformations of separated allene and s-trans butadiene. At the
left of the diagram, the s-cis and s-trans butadiene reactants are
shown. The s-cis butadiene is 3.0 kcal/mol higher in energy,
consistent with the 2.6−4.0 kcal/mol values for the gauche
conformation of s-cis butadiene found in prior calculations and
experiments.
30
The barrier to interconversion is approximately
6 kcal/mol to switch from s-trans butadiene to s-cis butadiene.
To the right of the diagram in Figure 7 are shown the electronic
energies of the stationary points. Free energies calculated at
room temperature (25 °C) have also been included, since
reaction rates are determined from free energies through
transition state theory. Because of the entropic penalty (−TΔS
Figure 5. Intramolecular Diels−Alder reaction of arenes and allenes.
Figure 6. Possible mechanisms of butadiene 16 and allene 17.
The Journal of Organic Chemistry Featured Article
dx.doi.org/10.1021/jo502041f | J. Org. Chem. 2014, 79, 8968−89768970
term in free energy) of bringing two molecules together, ΔG
values are uniformly 11−14 kcal/mol higher than the
corresponding ΔE values for all stationary points other than
the separated reactants. Consequently, the reaction surfaces
generated from both electronic and free energies have similar
topologies, and we will proceed by referring to electronic
energies for consistency.
Along the lower border, the concerted Diels−Alder reaction
pathway is shown. 19
‡
is the concerted transition state at 27.7
kcal/mol but is described in detail in the next section; this is
also the transition state leading to the cis-diradical 18(cis).
Several Diels−Alder reactions of two dienes involving
bifurcations are known.
31
Singleton has also studied a
bifurcation that occurs in the Diels−Alder reactions of ketenes
with cyclopentadiene which leads to an intermediate or a
cycloadduct, as found here.
32
At 28.1 kcal/mol, the transition
state leading to the trans-diradical, 18
‡
(trans) will compete
with 19
‡
. Both the trans and cis diradicals can give the 3-
vinylmethylenecyclobutane 20 through transition states of only
10−11 kcal/mol. The transition state for formation of Diels−
Alder product, 19
‡
(closure), is 7.7 kcal/mol with respect to the
reactant and only 0.9 kcal/mol higher in energy than the
diradical intermediate 18(cis). Our calculations predict that
Diels−Alder adduct 19 and 3-vinylmethylenecyclobutane 20
should both be formed thermally, with the former being the
thermodynamically and kinetically favored major product.
In order to understand the region around 19
‡
, a detailed
potential energy surface was generated (Figure 8). The energies
Figure 7. Schematic of the potential energy surface for the reaction between butadiene and allene. CASPT2//CASSCF(8,8)/6-31G* gas-phase
energies are shown in kcal/mol. Red arrows refer to the stepwise pathways, the blue arrow is the concerted pathway, and black arrows are for cis/
trans and s-cis/s-trans interconversions.
Figure 8. Left: Potential energy surface (PES) region of the possible transition states of initial bond formation, generated with CASSCF(8,8)/6-
31G*. Energy levels are designated by the following color spectrum: red = high energy, violet = low energy. The red arrows outline the stepwise
pathway from ambimodal transition state 19
‡
, while the blue arrow outlines the concerted pathway. Right: Side view of the PES, demonstrating the
saddle point for 19
‡
.
The Journal of Organic Chemistry Featured Article
dx.doi.org/10.1021/jo502041f | J. Org. Chem. 2014, 79, 8968−89768971