Strain-accelerated formation of chiral, optically active buta-1,3-dienes

Article abstract of DOI:10.1002/anie.201409289

The formal [2+2] cycloaddition-retroelectrocyclization (CA-RE) reactions between tetracyanoethylene (TCNE) and strained, electron-rich dibenzo-fused cyclooctynes were studied. The effect of ring strain on the reaction kinetics was quantified, revealing that the rates of cycloaddition using strained, cyclic alkynes are up to 5500 times greater at 298 K than those of reactions using unstrained alkynes. Cyclobutene reaction intermediates, as well as buta-1,3-diene products, were isolated and their structures were studied crystallographically. Isolation of a rare example of a chiral buta-1,3-diene that is optically active and configurationally stable at room temperature is reported. Computational studies on the enantiomerization pathway of the buta-1,3-diene products showed that the eight-membered ring inverts via a boat conformer in a ring-flip mechanism. In agreement with computed values, experimentally measured activation barriers of racemization in these compounds were found to be up to 26 kcalmol^-1.

Full text of DOI:10.1002/anie.201409289

Angewandte
Chemie
DOI: 10.1002/anie.201409289
Strained Molecules
Strain-Accelerated Formation of Chiral, Optically Active
Buta-1,3-dienes**
Melanie Chiu,* Boris H. Tchitchanov, Daniel Zimmerli, Italo A. Sanhueza,
Franziska Schoenebeck,* Nils Trapp, W. Bernd Schweizer, and FranÅois Diederich*
Abstract: The formal [2+2] cycloaddition–retroelectrocycli-
zation (CA–RE) reactions between tetracyanoethylene
under biological conditions. These precedents inspired us to
investigate the effect of ring strain on the formal [2+2]
(
TCNE) and strained, electron-rich dibenzo-fused cyclooc-
cycloaddition–retroelectrocyclization (CA–RE) reaction
between electron-poor alkenes and electron-rich alkynes,
which yields donor–acceptor-substituted buta-1,3-dienes.
tynes were studied. The effect of ring strain on the reaction
kinetics was quantified, revealing that the rates of cycloaddition
using strained, cyclic alkynes are up to 5500 times greater at
[6]
While products of CA–RE reactions using linear alkyne
substrates often exhibit remarkable optoelectronic and elec-
2
98 K than those of reactions using unstrained alkynes.
[
7]
Cyclobutene reaction intermediates, as well as buta-1,3-diene
products, were isolated and their structures were studied
crystallographically. Isolation of a rare example of a chiral
buta-1,3-diene that is optically active and configurationally
stable at room temperature is reported. Computational studies
on the enantiomerization pathway of the buta-1,3-diene
products showed that the eight-membered ring inverts via
a boat conformer in a ring-flip mechanism. In agreement with
computed values, experimentally measured activation barriers
of racemization in these compounds were found to be up to
trochemical properties, those obtained using cyclic alkyne
substrates presented the possibility of accessing new, chiral
buta-1,3-dienes that are configurationally stable at room
[
8]
temperature.
Numerous rotationally hindered buta-1,3-dienes have
been reported, but these are typically not separable into
their constituent enantiomers at ambient conditions due to
°
their relatively low racemization barriers (DG
< 20 kcal
98 K
2
ꢀ
1
[8]
mol ). The few examples of buta-1,3-dienes with racemi-
zation barriers above this threshold are stabilized by sterically
bulky substituents or intramolecular metal–p bonding, and
include only aliphatic substituents at the 1 and 4 positions of
ꢀ
1
2
6 kcalmol .
[
9]
R
ing strain, the increase in the heat of formation of a cyclic
the buta-1,3-diene moiety.
molecule relative to that expected for a strain-free reference
molecule with the same number of atoms, can be exploited to
Our strategy for stabilizing the conformation of buta-1,3-
dienes, on the other hand, is to constrain their flexibility by
using an eight-membered-ring scaffold. With two directives in
mind—studying how strain acceleration affects CA–RE
reactivity and obtaining functionalized, configurationally
stable, chiral buta-1,3-dienes—we explored the reactivity of
[
1]
accelerate or enhance chemical reactivity. Examples of this
strategy include the nucleophilic ring opening of epoxides and
aziridines, alkene and alkyne metathesis polymerizations,
and catalyst-free, 1,3-dipolar cycloaddition reactions of cyclo-
[
2]
[3]
[4]
[5]
octynes and cycloheptynes that are facile enough to occur
dibenzo-fused
cyclooctynes
with
tetracyanoethylene
(TCNE). We herein report kinetic studies on strain-acceler-
ated CA–RE reactions, as well as computational and exper-
imental investigations on the conformational dynamics of the
reaction intermediates and products.
[
+]
[+]
[
*] Dr. M. Chiu, B. H. Tchitchanov, I. A. Sanhueza, Dr. N. Trapp,
Dr. W. B. Schweizer, Prof. Dr. F. Diederich
Laboratorium fꢀr Organische Chemie, ETH Zurich
Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland)
E-mail: melanie.chiu@org.chem.ethz.ch
Upon treating various dibenzo-fused cyclooctyne deriva-
tives with TCNE or other electron-deficient alkenes (see the
Supporting Information, Section S3 for further details), we
found that reactions using TCNE and either methoxy-
substituted cyclooctyne 1 or cyclooctadiyne 2 proceeded
cleanly to yield well-defined, monomeric products. Cyclo-
octyne 1 reacted at room temperature to furnish cyclobutene
intermediate 3, which was isolated and subsequently heated
to induce RE and formation of diene 4 in quantitative yield
with respect to 1 (Scheme 1). Similarly, diyne 2 reacted with
diederich@org.chem.ethz.ch
D. Zimmerli
Discovery Technologies, Bldg 92/5.64C, F. Hoffmann-La Roche Ltd.
070 Basel (Switzerland)
4
I. A. Sanhueza, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
+
[
] These authors contributed equally to this work.
[
**] We thank Prof. Felix Fisher and Prof. Colin Nuckolls for samples of
dibenzo-fused cyclooctynes, and Dr. Aaron Finke, Dr. Igor Pochor-
ovski, and Dr. Jeremy Feldblyum for manuscript editing and helpful
discussions. Fellowships from the ETH Research Council (M.C.)
and the Scholarship Fund of the Swiss Chemical Industry (B.H.T.)
are gratefully acknowledged. This work was also supported by the
ERC Advanced Grant No. 246637 (“OPTELOMAC”).
2
equiv TCNE to produce tetraene (ꢁ)-5 as a deep purple
solid in 90% yield. Reaction intermediates 6–8 were observed
by H NMR; cyclobutene 6 and cyclobutene-diene 8 were
1
isolated (Scheme 1). Notably, 6 did not undergo RE under
a variety of conditions; only [2+2] CA of 6 with a second
equivalent of TCNE to yield bis(cyclobutene) 7 was observed,
followed by consecutive RE reactions to afford tetraene
(ꢁ)-5.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409289.
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eight-membered rings with two opposing torsion angles fixed
at zero degrees (see the Supporting Information, Section S4
for further details about the single-crystal structures and
[12]
conformational space of known eight-membered rings).
Computational studies confirm that the twist conformations
of 4 and 5 are favored (see Figure 2 and the Supporting
Information, Section S9 for additional computational
details). Finally, the structures of 3, 6, and 8 represent rare
crystallographic characterizations of cyclobutene intermedi-
ates for a CA–RE reaction, which have been observed
[13]
primarily as unstable, transient species.
The observation, isolation, and characterization of these
cyclobutene intermediates, combined with the clean and
quantitative nature of the [2+2] CA–RE reactions, all
signified amenability to kinetic studies. The reactions of
TCNE with four alkynes of interest, dibenzo-fused cyclo-
octynes 1 and 2, and their respective acyclic analogues,
diarylethynes 9 and 10 (Scheme 1), were monitored by
1
H NMR spectroscopy at various temperatures; the kinetic
data were subjected to Eyring analysis (Table 1). Comparison
of activation parameters and rates of reactions using cyclic
Table 1: CA–RE reaction activation parameters at 298 K in (CDCl )
determined by monitoring the respective reaction using H NMR
spectroscopy and subsequent Eyring analysis.
2
2
1
[
a]
°
°
°
Reaction
DG
kcalmol
DH
[kcalmol
DS
[calmol
Scheme 1. [2+2] Cycloaddition—retroelectrocyclization reactions
explored in this work. a) TCNE (1.00 equiv), 258C, 24 h; b) 808C, 12 h,
yield (4): 99% over 2 steps; c) [2]=10 m, TCNE (1.00 equiv), 258C,
ꢀ1
ꢀ1
ꢀ1 ꢀ1
[
]
]
K
]
ꢀ3
1+TCNE!3
3!4
20.1ꢁ0.2
26.9ꢁ0.3
19.1ꢁ0.6
21.6ꢁ0.6
27.6ꢁ0.6
24.9ꢁ0.5
24.2ꢁ0.4
9.17ꢁ0.17
27.2ꢁ0.2
5.0ꢁ0.4
ꢀ36.7ꢁ0.5
ꢀ0.7ꢁ0.7
ꢀ47.4ꢁ1.3
ꢀ25.4ꢁ1.4
ꢀ0.9ꢁ1.2
ꢀ45.7ꢁ1.1
ꢀ46.3ꢁ0.8
1
2 h; d) TCNE (1.00 equiv), 408C, 16 h; e) 808C, 12 h, yield ((ꢁ)-5):
9
0% over four steps (one pot); f) TCNE (1.00 equiv), 808C, 24 h, yield
2+TCNE!6
6+TCNE!7!8
8!(ꢁ)-5
(12): 99%; g) TCNE (1.00 equiv), 808C, 24 h, yield (14): 89%. All
14.0ꢁ0.5
27.3ꢁ0.4
11.3ꢁ0.4
10.4ꢁ0.3
reactions were performed in (CDCl ) .
2
2
9
1
+TCNE!12
0+TCNE!14
Single crystals of reaction products 4 and (ꢁ)-5, and of
intermediates 3, 6, and 8 were studied by X-ray diffraction;
[
a] All CA reactions with TCNE were found to be second order, and all RE
reactions were found to be first order.
[
10]
their molecular structures are shown in Figure 1. Interest-
ingly, the eight-membered rings in these compounds exhibited
a uniform and unprecedented preference for the twist (4 and
versus linear substrates enabled quantification of strain
acceleration. A qualitative reactivity difference between the
two classes of substrates was immediately apparent: 9 and 10
converted directly to their respective buta-1,3-diene products,
12 and 14, without accumulation of cyclobutene intermedi-
ates. This observation indicates that the rate-determining step
in the [2+2] CA–RE using 9 and 10 is the initial cycloaddition,
which is consistent with previous experimental and computa-
5) or twistoid (3 and 8) conformations, which have previously
been proposed only as high-energy intermediates in the
[11]
pseudorotation of eight-membered rings.
The buta-1,3-
diene moieties in 4, 5, and 8 are strongly skewed by ca. 1068,
which is presumably due to mutual repulsion of the terminal
cyano groups; this torsional strain sets the preferred con-
formation of the eight-membered ring. In contrast, only chair,
twist-boat, or rarely, boat conformations have been observed
in crystal structures of all other known compounds containing
[
6d]
tional results.
Figure 1. X-ray single-crystal structures of intermediates 3, 6, and 8, and diene products 4 and 5. Only one enantiomer each of 3, 4, 5, and 8 are
shown; both enantiomers were found in the crystals. Thermal ellipsoids are shown at the 50% probability level. Selected torsion angles: C17-C1-
C16-C22 ꢀ105.5(1)8 (4); C17-C1-C2-C22 ꢀ105.9(1)8 (5).
2
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ꢀ1
Figure 2. Proposed mechanisms for the enantiomerization of compounds a) 4 and b) 5. Free enthalpy profiles (DG
the COSMO-RS ((CHCl ) ) M062X/6-31+G(d)//B3LYP/6-31G(d) level of theory. Experimental values are given in parentheses.
2 2
in kcalmol ) calculated at
98K
2
[
15]
We commenced quantitative studies using cyclooctyne
because it possesses only one reactive alkyne moiety. Both
ing to rate enhancements of 5500- and 80-fold, respectively, at
298 K.
1
the second-order CA (1 + TCNE!3) and first-order RE (3!
) steps of the overall transformation could be monitored
separately (Table 1). For the second, rate-determining RE
Having experimentally quantified the rate acceleration in
[2+2] CA–RE reactions using cyclic substrates 1 and 2, we
turned our attention to investigating the potential enantio-
merization pathways of the exocyclic butadiene products 4
4
°
ꢀ1
step, DG = 26.9 kcalmol , wherein the primary contribution
°
ꢀ1
[15]
was enthalpic (DH = 27.2 kcalmol , Table 1). Strain accel-
and 5 using density functional theory computations (see the
°
ꢀ1
[16]
erates the CA step: j DDG j= 4.8 kcalmol
for CA of
Supporting Information, Section S9 for details).
Two
cyclooctyne 1 with TCNE relative to the analogous reaction
enantiomerization pathways were considered: 1) a direct
ring flip (Scheme 2a) and 2) a pericyclic sequence involving
ring-closure of one butadiene enantiomer to give a planar
cyclobutene intermediate, followed by ring-opening to give
the other enantiomer (Scheme 2b). The former was found to
be the lowest-energy enantiomerization pathway for all
compounds investigated, and is illustrated for butadiene 4 in
[14]
using linear alkyne 9.
This difference corresponds to
a roughly 3300-fold rate enhancement at 298 K. For the
overall CA–RE transformation at 383 K, a temperature at
which reactions using cyclooctyne 1 and linear alkyne 9 could
be monitored under identical conditions, strain contributes to
ꢀ4
ꢀ1 ꢀ1
a 16-fold rate enhancement: k = 3.13 ꢀ 10
m
s
und
1
!4
ꢀ
5
ꢀ1 ꢀ1
k9 = 4.94 ꢀ 10
m
s .
Figure 2a. Twist conformation 4 isomerizes to a twist-boat
!12
T
Strain acceleration was even more pronounced in reac-
tions using cyclooctadiyne 2. Quantitative studies on this
system (results shown in Table 1), which possesses two
reactive CꢂC bonds, required careful selection of reaction
conformation (4TB) via transition state 4-TST-TB. Inversion
conditions such that clean conversion to each intermediate
and the final product could be individually monitored.
Monoaddition of TCNE with 2 yielded 6 quantitatively,
followed by a second CA step to form bis-adduct 7, which
spontaneously converted to cyclobutene-butadiene inter-
mediate 8. The final RE step (8!(ꢁ)-5) was shown to be
the rate-determining step of the overall transformation
°
ꢀ1
(
DG = 27.6 kcalmol ). Strain substantially lowers the acti-
vation free enthalpy of CA of cyclooctadiyne 2 compared to
Scheme 2. Potential pathways for enantiomerization of butadienes,
studied computationally: a) direct ring flip; b) pericyclic ring closure
followed by ring opening.
°
ꢀ1
linear alkyne 10: j DDG j= 5.1 kcalmol for the first CA
ꢀ1
step, and 2.6 kcalmol for the second CA step, correspond-
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Communications
then occurs via a boat transition state (4-TSINV), with an
Table 2: Activation parameters at 298 K for the racemization of cyclo-
butene 3 and dienes 4 and 5.
ꢀ1
overall activation barrier of 20.1 kcalmol to yield the
[
17]
°
°
°
enantiomeric intermediate 4TB*.
Compound
DG
[kcalmol
DH
[kcalmol
DS
[calmol
ꢀ1
ꢀ1
ꢀ1 ꢀ1
Analogous studies on tetraene 5, which possesses two
chiral axes, suggest that enantiomerization proceeds in a two-
step fashion. The increased rigidity of tetraene 5 relative to
butadiene 4 is manifested in higher-energy intermediates and
activation energies associated with racemization (Figure 2b).
Similar to butadiene 4, twist conformation 5T converts to
]
]
K
]
[a]
3
10.40ꢁ0.07
17.3ꢁ1.8
26.4ꢁ2.0
9.80ꢁ0.05
15.2ꢁ1.4
37.6ꢁ1.6
ꢀ2.01ꢁ0.17
ꢀ7.0ꢁ4.0
37.4ꢁ5.0
[a]
4
[
b]
5
[
a] Determined using iterative lineshape fitting of variable-temperature
1
H NMR spectra recorded in CD Cl (3) or (CDCl ) (4) and subsequent
2
2
2 2
twist-boat conformation 5 , which does not directly race-
mize, but must first overcome a 24.7 kcalmol activation
Eyring analysis. [b] Determined using Eyring analysis on variable-
temperature ECD measurements in (CHCl
TB
ꢀ
1
) .
2 2
barrier to reach the achiral, C -symmetric boat intermediate
s
5B. Thus, enantiomers of 5 were predicted to be configura-
tionally stable at room temperature. Given these insights, we
sought to probe the conformational dynamics of these
compounds experimentally.
where we predicted that the additional exocyclic butadiene
moiety might render the eight-membered ring more rigid.
Separation of enantiomers of tetraene (ꢁ)-5 by chiral
HPLC was extremely challenging due to the very low
solubility of the compound in solvents that enabled optical
resolution, causing partial crystallization on the column
(Supporting Information, Section S7). However, enantiomer-
ically enriched samples of 5 were isolated ((+)-5: 14% ee and
(ꢀ)-5: 21% ee) and their electronic circular dichroism (ECD)
spectra were recorded. Figure 4 shows the ECD spectra for
1
At room temperature in (CDCl ) , the H NMR spectrum
2
2
of butadiene 4 showed two signals corresponding to the
geminal methylene protons on the eight-membered ring,
indicating that enantiomer interconversion was slow on the
NMR timescale. Coalescence of these signals was observed at
elevated temperatures (Figure 3a). Conversely, in cyclobu-
Figure 4. ECD spectra of enantiomerically pure P,P-(+)-5 (gray) and
M,M-(ꢀ)-5 (black line) in (CHCl ) at 298 K, calculated from the
2
2
1
Figure 3. Variable-temperature H NMR spectra (500 MHz) of a) buta-
experimental spectra measured for enantiomerically enriched samples
(see the Supporting Information, Section S7).
diene 4 in (CDCl ) , and b) cyclobutene 3 in CD Cl .
2
2
2
2
tene intermediate 3, the geminal methylene protons on the
the enantiomerically pure compounds, which were calculated
from the experimental spectra of the enantiomerically
enriched samples. The absolute configurations of the enan-
tiomers, P,P-(+)-5 and M,M-(ꢀ)-5, were assigned by compar-
ison of simulated ECD spectra (CAM-B3LYP/6-31G(d)) with
the experimental spectra (Supporting Information, Sec-
eight-membered ring gave rise to only one signal in the
1
H NMR spectrum in CD Cl at room temperature; decoa-
2
2
lescence to two signals occurred upon cooling (Figure 3b). By
1
performing iterative lineshape analysis on H NMR spectra of
these compounds acquired at varied temperatures, we derived
rate constants for enantiomer interconversion at each temper-
ature. Free enthalpies of activation for enantiomer intercon-
version were determined using Eyring analysis.
tion S10). Because tetraene 5 is a D -symmetric molecule
2
and lacks diastereotopic protons, dynamic NMR techniques
could not be used to monitor the enantiomer interconversion.
However, first-order rate constants for the racemization
process of the enantiomerically enriched samples were
obtained by monitoring the ECD signal decay over time at
various temperatures in (CHCl ) . Subsequent Eyring analy-
ꢀ1
A value of 10.4 kcalmol was obtained for cyclobutene 3,
ꢀ1
while that for butadiene 4 was 17.3 kcalmol (Table 2). The
latter is in agreement with the computed value, but insuffi-
cient for enantiomer separation at room temperature. We
hypothesized that the ethylene bridge of the eight-membered
ring was the source of conformational fluxionality in buta-
diene 4, and therefore turned our attention to tetraene 5,
2
2
°
ꢀ1
sis showed that DG = 26.4 ꢁ 2 kcalmol for racemization of
tetraene 5, which is in good agreement with the computa-
[18]
tionally predicted value (Table 2). Compared to previously
4
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Angewandte
Chemie
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value is among the highest observed.
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[
8,9]
6
In summary, we have demonstrated and quantified strain-
accelerated reactivity in the context of a formal [2+2]
cycloaddition–retroelectrocyclization (CA–RE) sequence
between electron-deficient alkenes and electron-rich alkynes;
in addition, we isolated a rare example of a chiral buta-1,3-
diene that is optically active and configurationally stable at
room temperature. Isolation of reaction intermediates ena-
bled kinetic studies on these systems, revealing that the rates
of cycloaddition using strained alkynes are up to 5500 times
greater at 298 K than those of unstrained systems. Computa-
tional studies elucidated the enantiomerization mechanism of
the resulting buta-1,3-diene products, indicating that enan-
tiomerization of these eight-membered rings occurs via
a direct ring-flip mechanism involving initial isomerization
to a boat conformer. In agreement with computed values,
experimentally measured activation barriers to racemization
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1
were found to be up to 26 kcalmol in the case of tetraene 5.
Having isolated members of this new class of configuration-
ally stable, chiral buta-1,3-dienes, and studied the mechanism
for their formation and enantiomerization, we envision future
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[
19]
[20]
applications in chiral sensors, chiral molecular magnets,
[
21]
and chiral memory units, and as novel atropisomeric diene
ligands for asymmetric catalysis.
[
22]
Received: September 19, 2014
Published online: && &&, &&&&
[8] For an overview of previously reported chiral buta-1,3-dienes,
see M. Yamada, P. R. Fuentes, W. B. Schweizer, F. Diederich,
Angew. Chem. Int. Ed. 2010, 49, 3532 – 3535; Angew. Chem.
Keywords: chirality · click chemistry · cycloadditions · kinetics ·
.
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
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[
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a chair intermediate was found to be much higher in energy than
[
[
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°
the pathway occurring via a boat intermediate (DDG = 35 kcal
ꢀ
1
mol ; see the Supporting Information, Section S9.3 for further
details).
6
[
18] The half-life of racemization of tetraene 5 is 2.56 ꢀ 10 s at 298 K,
¯
which far exceeds the benchmark defined by Oki, wherein
88, 945 – 952.
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6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Strained Molecules
M. Chiu,* B. H. Tchitchanov, D. Zimmerli,
I. A. Sanhueza, F. Schoenebeck,*
N. Trapp, W. B. Schweizer,
F. Diederich*
&&&& — &&&&
Strain-Accelerated Formation of Chiral,
Optically Active Buta-1,3-dienes
No strain, no gain: Strain induces up to
a chiral, configurationally stable buta-1,3-
4
1
0 -fold rate acceleration of the [2+2]
diene was isolated. The activation barrier
to racemization was determined experi-
cycloaddition–retroelectrocyclization
reaction between tetracyanoethylene and
dibenzo-fused cyclooctynes relative to
unstrained systems. A rare example of
ꢀ1
mentally to be up to 26 kcalmol at
298 K.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!