Geminal repulsion disrupts Diels–Alder reactions of geminally substituted cyclopentadienes and 4H-pyrazoles

Article abstract of DOI:10.1016/j.tet.2021.132160

We have experimentally and computationally explored the sluggish Diels–Alder reactivities of the geminally substituted 5,5-dimethylcyclopentadiene and 5,5-dimethyl-2,3-diazacyclopentadiene (4,4-dimethyl-4H-pyrazole) scaffolds. We found that geminal dimethylation of 1,2,3,4-tetramethylcyclopentadiene to 1,2,3,4,5,5-hexamethylcyclopentadiene decreases the Diels–Alder reactivity towards maleimide by 954-fold. Quantum mechanical calculations revealed that the decreased Diels–Alder reactivities of gem-dimethyl substituted cyclopentadienes and 2,3-diazacyclopentadienes are not a consequence of unfavorable steric interactions between the diene and dienophile as reported previously, but a consequence of the increased repulsion within the gem-dimethyl group in the transition state. The findings have implications for the use of cyclopentadienes in “click” chemistry.

Full text of DOI:10.1016/j.tet.2021.132160

Tetrahedron 91 (2021) 132160
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Geminal repulsion disrupts DielseAlder reactions of geminally
substituted cyclopentadienes and 4H-pyrazoles
*
*
Brian J. Levandowski , Nile S. Abularrage, Ronald T. Raines
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 February 2021
Received in revised form
We have experimentally and computationally explored the sluggish DielseAlder reactivities of the
geminally substituted 5,5-dimethylcyclopentadiene and 5,5-dimethyl-2,3-diazacyclopentadiene (4,4-
dimethyl-4H-pyrazole)
scaffolds.
We
found
that
geminal
dimethylation
of
1,2,3,4-
9
April 2021
tetramethylcyclopentadiene to 1,2,3,4,5,5-hexamethylcyclopentadiene decreases the DielseAlder reac-
tivity towards maleimide by 954-fold. Quantum mechanical calculations revealed that the decreased
DielseAlder reactivities of gem-dimethyl substituted cyclopentadienes and 2,3-diazacyclopentadienes
are not a consequence of unfavorable steric interactions between the diene and dienophile as re-
ported previously, but a consequence of the increased repulsion within the gem-dimethyl group in the
transition state. The findings have implications for the use of cyclopentadienes in “click” chemistry.
Accepted 12 April 2021
Available online 24 April 2021
This manuscript is dedicated to Dale L.
Boger on the occasion of his winning the
2020 Tetrahedron Prize.
©
2021 Elsevier Ltd. All rights reserved.
Keywords:
DielseAlder
Click chemistry
Kinetics
Cycloaddition
Density functional theory
1
. Introduction
DielseAlder reactions of 5,5-dimethylcyclopentadiene have
been reported with highly reactive electron-deficient or strained
dienophiles such as benzyne [10], 2-chloroacrylonitrile [11], maleic
The rapid reactivity and excellent yield of cyclopentadienes in
normal-electron demand DielseAlder reactions are ideal for “click”
chemistry applications [1]. The DielseAlder reactivities of cyclo-
pentadienes and 2,3-diazacyclopentadienes (4H-pyrazoles) are
anhydride
[9,12],
and
maleimides
[12e14].
5,5-
Dimethylcyclopentadiene does not dimerize, even upon heating
ꢀ
to 200 C [9,15]. This stability is in contrast to cyclopentadiene,
tunable through hyperconjugative interactions of the diene
system with the substituents at the saturated center [2e5].
Hyperconjugative -donors stabilize the diene by inducing aro-
matic 6 -electron delocalization, whereas hyperconjugative -ac-
ceptors destabilize the diene by inducing antiaromatic 4 -electron
p
-
which is highly reactive as a DielseAlder diene towards a range of
dienophiles and dimerizes readily at room temperature [16,17].
Rouse and Tyler proposed that the geminal dimethyl group of
5,5-dimethylcyclopentadiene “exerts a marked steric hindrance to
s
p
s
p
the approach of dienophiles.” [9] Yet, studies on the p-facial
delocalization [6,7]. The computationally generated magnetic, en-
ergetic, and geometric measures of aromaticity for cyclopentadiene
and 5,5-dimethylcyclopentadiene listed in Table 1 imply that the
cyclic hyperconjugative electron delocalization is less effective in
selectivity of 5-methylcyclopentadiene suggest that the methyl
substituent does not significantly hinder the approach of the
dienophile [3,18]. Scheme 1 shows that the DielseAlder reaction
between 5-methylcyclopentadiene and 4-phenyl-1,2,4-triazole-
3,5-dione forms a mixture of syn and anti cycloadducts with a
modest preference for the syn cycloadduct [18]. This observation is
consistent with a computational study from the Houk group on the
5
,5-dimethylcyclopentadiene than in cyclopentadiene [6,8]. This
decreased electron delocalization should promote DielseAlder
reactivity, but the literature indicates otherwise [9].
p
-facial selectivity of 5-substituted cyclopentadienes [3]. They re-
ported that the syn DielseAlder reaction of 5-
methylcyclopentadiene is kinetically favored by ~1 kcal/mol over
the anti cycloaddition when ethylene is the dienophile.
*
Corresponding authors.
E-mail addresses: levandbj@mit.edu (B.J. Levandowski), rtraines@mit.edu
Geminally substituted 5,5-dimethyl-2,3-diazacyclopentadienes
(
R.T. Raines).
https://doi.org/10.1016/j.tet.2021.132160
040-4020/© 2021 Elsevier Ltd. All rights reserved.
0

B.J. Levandowski, N.S. Abularrage and R.T. Raines
Tetrahedron 91 (2021) 132160
Table 1
Measuresa of the aromaticity of cyclopentadiene and 5,5-dimethylcyclopentadiene
[
6,8].
NICS(0)
L
ASE
BI
ꢁ3.1
ꢁ3.5
2.60
29
ꢁ2.2
ꢁ2.4
0.85
22
a
NICS(0), nuclear independent chemical shift; L, diamagnetic susceptibility
exaltation; ASE, aromatic stabilization energy (kcal/mol); BI, Bird Index.
Scheme 2. Second-order rate constants for the DielseAlder reactions of Me
Me Cp, and Me Cp with maleimide.
4
Cp,
5
6
M06e2X/6-31þG(d) level of theory in Gaussian16 Rev. C.01 [24,25].
The ground state structures of cyclopentadiene, 5,5-
dimethylcyclopentadiene, 2,3-diazacyclopentadiene, and 5,5-
dimethyl-2,3-diazacyclopentadiene are shown in Fig. 1. The angle
between the geminal substituents is represented by
q
2
. Geminal
ꢀ
ꢀ
dimethylation increases
q
2
from 106.4 in cyclopentadiene to 110.1
ꢀ
in 5,5-dimethylcyclopentadiene and from 107.6
in 2,3-
Scheme 1.
p
-Facial selectivity in the DielseAlder reaction of 5-methylcyclopentadiene
diazacyclopentadiene
to
111.2
ꢀ
in
5,5-dimethyl-2,3-
with 4-phenyl-1,2,4-triazole-3,5-dione [18].
diazacyclopentadiene. The increase in
2
q results in a decrease in
the angle between the ring substituents of C5, which is represented
ꢀ
by
1
q
1
. Specifically,
q
1
decreases from 103.2 in cyclopentadiene to
(
4,4-dimethyl-4H-pyrazoles) react poorly as DielseAlder dienes.
ꢀ
ꢀ
01.8 in 5,5-dimethylcyclopentadiene, and from 97.5 in 2,3-
Even with highly reactive strained dienophiles, DielseAlder re-
actions of 5,5-dimethyl-2,3-diazacyclopentadienes do not readily
proceed unless promoted with an acid catalyst [4,19e22]. To un-
derstand the poor DielseAlder reactivities of geminally substituted
ꢀ
diazacyclopentadiene
diazacyclopentadiene. The decrease in
to
96.3
in
5,5-dimethyl-2,3-
q
1
decreases the distance
between the diene termini of cyclopentadiene and 2,3-
diazacyclopentadiene, which is represented by r, by 0.02 and
.01 Å, respectively. These structural changes upon geminal
dimethylation are consistent with the ThorpeeIngold effect
26e28].
The transition state structures and Gibbs free energies of acti-
5
,5-dimethylcyclopentadienes
and
5,5-dimethyl-2,3-
0
diazacyclopentadienes, we have computationally and experimen-
tally studied the effect of the gem-dimethyl substitution on reac-
tivity. Our results provide new insight on the basis for the sluggish
reactivity of these dienes.
[
z
vation (DG ) for the DielseAlder reactions of cyclopentadiene (TS-
1
), 5,5-dimethylcyclopentadiene (TS-2), 2,3-diazacyclopentadiene
2
. Results and discussion
(TS-3), and 5,5-dimethyl-2,3-diazacyclopentadiene (TS-4) with
ethylene are shown in Fig. 2. Geminal dimethylation decreases the
To quantify the effect of geminal dimethylation on DielseAlder
DielseAlder
reactivity
of
cyclopentadiene
and
2,3-
reactivity, we experimentally determined the second-order rate
diazacyclopentadiene by 310- and 35-fold, respectively [29].
Geminal dimethylation has little influence on the reaction energies.
To understand the origin of the decreased reactivity upon the
geminal dimethylation of the cyclopentadiene and 2,3-
diazacyclopentadiene scaffolds, we analyzed the DielseAlder re-
actions of cyclopentadiene, 5,5-dimethylcyclopentadiene, 2,3-
diazacyclopentadiene, and 5,5-dimethyl-2,3-diazacyclopentadiene
with the distortion/interactioneactivation strain model [30]. This
model dissects the electronic energies into the distortion energies
and interaction energies. The distortion energies represent the
energy required to deform the ground state structures of the re-
actants into the geometries of the transition state. The interaction
energies are the energies of interactions that occur between the
diene and dienophile during the course of bond formation. These
interactions include steric (i.e., Pauli-repulsion), orbital, electro-
static, and dispersive interactions. The transition states of the gem-
dimethyl substituted dienes occur later than those of the unsub-
stituted dienes. To account for the different timing of the transition
constants
for
the
DielseAlder
reactions
(Me Cp),
Cp),
of
1,2,3,4-
1,2,3,4,5-
tetramethylcyclopentadiene
pentamethylcyclopentadiene
hexamethylcyclopentadiene (Me
4
(Me
5
and
1,2,3,4,5,5-
6
Cp) with maleimide. Second-
order reaction kinetics were assessed with UVevis spectroscopy
for Me Cp and Me Cp. NMR spectroscopy was used for Me Cp
4
5
6
because the reaction was too slow to observe the reaction rates
otherwise. We note that an experimental comparison between the
DielseAlder reactivity of a 5,5-dimethyl-2,3-diazacyclopentadiene
and a 2,3-diazacyclopentadiene without substituents at the satu-
rated center is not possible because unsubstituted 2,3-
diazacyclopentadienes rapidly isomerize into 1H-pyrazoles [23].
The experimental second-order rate constants for the DielseAlder
reactions of Me
dienophile are 124, 85, and 0.13 M
4 5 6
Cp, Me Cp, and Me Cp with maleimide as the
ꢁ
1 ꢁ1
s
, respectively (Scheme 2).
Thus, the presence of a gem-dimethyl group on the saturated center
reduces the DielseAlder reactivity of the diene by approximately 3
orders of magnitude.
state
structures,
we
performed
the
distortion/inter-
To understand the origin of the decreased DielseAlder reactivity
actioneactivation strain analysis along the intrinsic reaction coor-
dinate (IRC) defined by the average length of the forming bonds
[31]. The results from the analysis are shown in Fig. 3. The distor-
tion/interactioneactivation strain analysis indicates that the
in
5,5-dimethylcyclopentadienes
and
5,5-dimethyl-2,3-
diazacyclopentadienes, we studied computationally the reactions
of these dienes and their unsubstituted counterparts with ethylene.
Calculations were performed at the M06e2X/6e311þþG(d,p)//
2

B.J. Levandowski, N.S. Abularrage and R.T. Raines
Tetrahedron 91 (2021) 132160
Fig. 1. M06e2X/6-31þG(d)-optimized ground state structures of (left to right) cyclopentadiene, 5,5-dimethylcyclopentadiene, 2,3-diazacyclopentadiene, and 5,5-dimethyl-2,3-
diazacyclopentadiene.
geminally substituted dienes. For 5,5-dimethylcyclopentadiene and
ꢀ
5
,5-dimethyl-2,3-diazacyclopentadiene,
q
2
decreases by ꢁ4.3
ꢀ
and ꢁ3.7 , respectively. The compression of
2
q during the reaction
amplifies the geminal repulsion within the gem-dimethyl group.
This increase in geminal repulsion destabilizes the geminally
substituted dienes and provides an explanation for their higher
distortion energies and decreased DielseAlder reactivities relative
to the unsubstituted dienes.
To study the effects of geminal repulsion on the DielseAlder
reactivity further, we computationally investigated the
DielseAlder
reactions
of
5-methylcyclopentadiene,
5,5-
dimethylcyclopentadiene
and 5-methyl-5-t-butyl-cyclo-
pentadiene with ethylene. The transition state structures with the
Gibbs free activation and reaction energies for these DielseAlder
reactions are shown in Fig. 5. Replacing the methyl group in 5,5-
dimethylcyclopentadiene with a hydrogen atom decreases the
activation energy by 3.2 kcal/mol, which corresponds to a rate in-
crease of 220-fold. Notably, the computed Gibbs free energies of
activation
for
the
DielseAlder
reactions
of
5-
methylcyclopentadiene and cyclopentadiene with ethylene are
nearly identical, differing by only 0.2 kcal/mol. In contrast to a
hydrogen atom, replacing the methyl group in 5,5-
dimethylcyclopentadiene with a t-butyl group increases the acti-
vation energy by 6.2 kcal/mol, which corresponds to a rate decrease
of 35,000-fold. Between the ground state and transition state ge-
ometries, the geminal repulsion increases as
q
2
in 5-methyl-5-t-
ꢀ
ꢀ
butyl-cyclopentadiene compresses from 112.6 to 107.1 . Overall,
the increased geminal repulsion from replacing the hydrogen atom
in 5-methylcyclopentadiene with a t-butyl group results in a pre-
dicted 7.8 million-fold decrease in reactivity.
3. Conclusions
z
rxn
DG ) and reaction (DG )
Fig. 2. Transition state structures and Gibbs free activation (
energies in kcal/mol for the DielseAlder reactions of ethylene with cyclopentadiene
TS-1), 5,5-dimethylcyclopentadiene (TS-2), 2,3-diazacyclopentadiene (TS-3), and 5,5-
The effect of gem-dimethyl substitution on the DielseAlder
reactivity of the cyclopentadiene scaffold was investigated by
experiment and computation. Experimentally, we found that the
DielseAlder reactivity of 1,2,3,4-tetramethylcyclopentadiene to-
wards maleimide decreased by 954-fold upon geminal dimethyla-
tion. A distortion/interactioneactivation strain analysis revealed
that the poor DielseAlder reactivities of geminally substituted 5,5-
(
dimethyl-2,3-diazacyclopentadiene (TS-4).
decrease in reactivity upon geminal dimethylation of the dienes is
related to an increase in the distortion energies.
The distortion/interactioneactivation strain analysis revealed
that the gem-dimethylesubstituted dienes require more energy to
deform into their transition state geometries than do the unsub-
dimethylcyclopentadienes
and
5,5-dimethyl-2,3-
diazacyclopentadienes result from the increased geminal repul-
sion between the gem-dimethyl group in the transition state.
Geminally substituted peralkylcyclopentadienes are often used
as “click” reagents because they do not readily dimerize or isom-
erize [32]. We conclude that switching from gem-dimethyl substi-
tution to 1,2,3,4,5-pentaalkylcyclopentadienes will result in faster
DielseAlder reactions while discouraging dimerization or
stituted dienes. The values of
tion state structures of the geminally substituted dienes are listed
in Fig. 4. The values of decrease as ethylene approaches the
2
q from the ground state and transi-
q
2
3

B.J. Levandowski, N.S. Abularrage and R.T. Raines
Tetrahedron 91 (2021) 132160
Fig. 3. Distortion/interactioneactivation strain analysis for the DielseAlder reactions of ethylene with cyclopentadiene and 5,5-dimethylcyclopentadiene (A), and 2,3-
diazacyclopentadiene and 5,5-dimethyl-2,3-diazacyclopentadiene (B). The analysis was carried out along the intrinsic reaction coordinate (IRC) defined by the average distance
of the forming bonds in Ångstroms. (Solid lines: Electronic energies; Short dashed lines: Distortion energies; Long dashed lines: Interaction energies).
point for transition state structures and a minimum for the ground
state structures.
4.2. General experimental
All chemicals were from commercial sources and were used
without further purification. NMR spectra were acquired with an
Avance Neo 400 spectrometer from Bruker (Billerica, MA). UVevis
experiments were carried out with a Cary 60 UVevis spectrometer
from Agilent Technologies (Santa Clara, CA) with measurements
every 0.1 s for kinetic experiments. The phrase “concentrated under
reduced pressure” refers to the removal of solvents and other vol-
atile materials using a rotary evaporator at water aspirator pressure
2
Fig. 4. Calculated values of q for the ground state (GS) and transition state (TS) during
the DielseAlder reactions with ethylene of 5,5-dimethylcyclopentadiene and 5,5-
dimethyl-2,3-diazacyclopentadiene.
ꢀ
isomerization side reactions.
(<20 Torr) while maintaining a water-bath temperature of 40 C.
Residual solvent was removed from samples by the vacuum
(
<0.1 Torr) achieved by a mechanical belt-drive oil pump. All pro-
4
. Experimental section
ꢀ
cedures were performed in air at ambient temperature (~22 C) and
pressure (1.0 atm) unless indicated otherwise.
4.1. Computational methods
Calculations were performed in Gaussian 16 Rev. C.01 using the
4.3. Reaction of maleimide with 1,2,3,4-tetramethylcyclopentadiene
M06e2X functional [24,25]. Geometries were obtained with the 6-
1þG(d) basis set. Energetics were calculated using the
(Me
4
Cp)
3
6
e311þþG(d,p) basis set. Normal mode analysis of each structure
Stock solutions of Me Cp (200 mM) and maleimide (200 mM)
were prepared in MeOH. Aliquots (0.5 mL) of each reactant were
4
was used to verify that each stationary point is a first-order saddle
z
Fig. 5. Transition state structures and Gibbs free activation (
D
G ) and reaction (
DG
rxn) energies in kcal/mol for the DielseAlder reactions of 5-methyl-5-t-butyl-cyclopentadiene
(
TSe5), 5,5-dimethylcyclopentadiene (TSe2), and 5-methylcyclopentadiene (TSe6) with ethylene.
4

B.J. Levandowski, N.S. Abularrage and R.T. Raines
Tetrahedron 91 (2021) 132160
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ꢁ1
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(
pentamethylcyclopentadiene (Me Cp)
5
5
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[
[
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Stock solutions of Me Cp (20 mM) and maleimide (20 mM) were
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ꢁ1
reaction was carried out in triplicate. A plot of [maleimide] versus
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[
4
.6. Synthesis of 1,2,3,4,5,5-hexamethylcyclopentadiene (Me
6
Cp)
[
Lithium pentamethylcyclopentadienide (2.905 g, 20.5 mmol)
1296e1299.
was transferred to a flask that had been purged with vacuum and
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39.9
mg
(0.266
mmol, 1.3%)
of
1,2,3,4,5,5-
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1
H NMR (400 MHz, CDCl
C NMR (101 MHz, CDCl
3
,
d): 1.79 (s, 6H), 1.75 (s, 6H), 0.91 (s, 6H).
13
€
,
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3
)
Declaration of competing interest
2
041e2051.
21] W. Adam, H.M. Harrer, W.M. Nau, K. Peters, Electronic substituent effects on
2] cycloaddition of isopyrazoles with cyclo-
[
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
the acid-catalyzed [4þ
þ
pentadiene and the photochemical and thermal denitrogenation of the
resulting 1,4-diaryl-7,7-dimethyl-2,3-diazabicyclo[2.2.1]hept-2-ene azoal-
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B.J.L. was supported by postdoctoral fellowship F32 GM137543
NIH). N.S.A. was supported by a graduate research fellowship from
[
(
(
the NSF (grant no. 1745302). This work was supported by Grant R01
GM044783 (NIH). Computational resources were provided by the
Extreme Science and Engineering Discovery Environment (XSEDE)
Bridges at the Pittsburgh Supercomputing Center through alloca-
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132160.
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