Hyperconjugative Antiaromaticity Activates 4 H-Pyrazoles as Inverse-Electron-Demand Diels-Alder Dienes

Article abstract of DOI:10.1021/acs.orglett.9b03351

The Diels-Alder reactivity of 4,4-difluoro-3,5-diphenyl-4H-pyrazole was investigated experimentally and computationally with endo-bicyclo[6.1.0]non-4-yne. The computationally predicted rate enhancement from hyperconjugative antiaromaticity induced by fluo

Full text of DOI:10.1021/acs.orglett.9b03351

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hyperconjugative Antiaromaticity Activates 4H‑Pyrazoles as
Inverse-Electron-Demand Diels−Alder Dienes
Brian J. Levandowski,†,‡,§ Nile S. Abularrage,†,§ K. N. Houk,*,‡ and Ronald T. Raines*,†
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: The Diels−Alder reactivity of 4,4-difluoro-3,5-
diphenyl-4H-pyrazole was investigated experimentally and computa-
tionally with endo-bicyclo[6.1.0]non-4-yne. The computationally
predicted rate enhancement from hyperconjugative antiaromaticity
induced by fluorination of cyclopentadienes at the 5-position extends
to five-membered heterocyclic dienes containing a saturated center.
4,4-Difluoro-4H-pyrazoles are new electron-deficient dienes with
rapid reactivities toward strained alkynes.
Scheme 1. Diels−Alder Reaction of 4,4-Dimethyl-3,5-
diphenyl-4H-pyrazole and Cyclopentadiene (Cp) with or
without an Acid Catalyst9
yclopentadienes have been explored as a new class of bio-
Corthogonal dienes with rapid reactivities and robust
biological stabilities.1 Tetrachlorocyclopentadiene ketal
(TCK) does not dimerize2 and can be synthesized in one step
from readily available starting materials. As an ambiphilic diene,
TCK reacts with both electron-deficient and electron-rich
dienophiles and is stable toward biological nucleophiles. The
rate constant for the Diels−Alder reaction of TCK with endo-
bicyclo[6.1.0]non-4-yne (BCN) at room temperature in
methanol is 0.26 M−1 s−1. TCK cycloadditions are as fast as
the most rapid azide−alkyne cycloadditions3 but slower than
the inverse-electron-demand Diels−Alder reactions of 3,6-
diphenyl- and 3,6-dipyridyl-1,2,4,5-tetrazines with BCN, which
have rate constants in MeOH at room temperature of 3.3 and
44.8 M−1 s−1, respectively.4
pyrazoles have yet to be studied, the destabilizing effects of
hyperconjugative antiaromaticity invoked by the geminal fluoro
groups suggest that 4,4-difluoro-4H-pyrazoles would be highly
reactive as Diels−Alder dienes.
The rapid Diels−Alder reactivity of cyclopentadienes is the
result of the minimal distortion of the cyclopentadiene ground-
state geometry required to achieve the transition-state
geometry.5 The Diels−Alder reactivities of cyclopentadienes
can be tuned by substitution at the 5-position.6 Negative
hyperconjugation at the saturated center of a cyclopentadiene
enhances the Diels−Alder reactivity of the diene by producing
antiaromatic 4π-electron destabilization.7 This destabilization,
which is especially strong when a fluoro group is the substituent,
attracted our attention to the 4,4-difluoro-4H-pyrazole scaffold.
We have studied computationally and experimentally the
Diels−Alder reactivity of 4,4-dimethyl-3,5-diphenyl-4H-pyra-
zole (DMP), 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP), and
3,6-diphenyl-1,2,4,5-tetrazine (Tz) with BCN (Scheme 2). We
find that fluorine substitution enhances the Diels−Alder
reactivity of DFP, making it more reactive than Tz toward BCN.
We began by evaluating the aromaticity of the 4H-pyrazole
scaffold by using nuclear independent chemical shift (NICS)10
calculations. Our intent was to determine if the hyper-
conjugative aromaticity and antiaromaticity observed in cyclo-
pentadienes extends to 4H-pyrazoles. NICS(0) calculations
measure the magnetic shielding at the center of the ring and have
been shown to correlate well with the Diels−Alder reactivities of
Hu
̈
nig8 and Adam9 have studied the Diels−Alder reactions of
3,5-dimethyl- and 3,5-diaryl-substituted 4,4-dimethyl-4H-pyr-
azoles extensively and found that acid catalysis is needed to
promote the reaction, even with highly strained and electron-
rich dienophiles. As shown in Scheme 1, the Diels−Alder
reaction of 4,4-dimethyl-3,5-dimethyl-4H-pyrazole with cyclo-
pentadiene (Cp) proceeds only in the presence of an acid
catalyst.8a Though Diels−Alder reactions of 4,4-difluoro-4H-
Received: September 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03351
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
computed activation free energies differing by only 0.1 kcal/
mol in favor of DFP.
Scheme 2. Structures of 4,4-Dimethyl-3,5-diphenyl-4H-
pyrazole (DMP), 4,4-Difluoro-3,5-diphenyl-4H-pyrazole
(DFP), 3,6-Diphenyl-1,2,4,5-tetrazine (Tz), and endo-
Bicyclo[6.1.0]non-4-yne (BCN)
We synthesized DFP in one step and high yield (93%) from
commercial starting materials by a route reported previously.13
To evaluate how the reactivity of the 4,4-difluoro-4H-pyrazole
scaffold compares to that of the tetrazine scaffold, we measured
pseudo-first-order kinetics for the Diels−Alder reactions of DFP
and Tz with BCN in 9:1 methanol/water at room temperature.
A plot of the observed rate constants with respect to the BCN
concentration is shown in Figure 2. The 4,4-difluoro-4H-
pyrazole scaffold is more reactive than is the tetrazine scaffold
toward BCN, with second-order rate constants of 5.2 and 3.2
M−1 s−1 for DFP and Tz, respectively. The rapid reactivity of
DFP arises from the antiaromatic 4π-electron delocalization
invoked by negative hyperconjugation of the fluoro substitu-
ents.7 To provide confirmation for hyperconjugative antiar-
omaticity as the source of the high reactivity of DFP, we stirred
DMP with BCN; we detected no reaction after 2 h by NMR
spectroscopy.
To discern if hyperconjugative antiaromaticity compromises
the stability of DFP in a biological context, we incubated DMP
and DFP in phosphate-buffered saline (PBS) containing fetal
bovine serum (FBS; 10% v/v) at 37 °C. After 8 h, 42% of the
DFP and 98% of the DMP remained intact (Figure S1). Thus,
hyperconjugative antiaromaticity also increases the reactivity of
the diene toward biological nucleophiles but not to a substantial
detriment.
The DFP−BCN cycloadduct loses N2(g) spontaneously to
yield a 5,5-difluorocyclopentadiene product that we charac-
terized by NMR spectroscopy and mass spectrometry. The
geminal fluoro groups at the saturated cyclopentadiene center of
the 5,5-difluorocyclopentadiene product induce hyperconjuga-
tive antiaromaticity.6 To see if this hyperconjugative anti-
aromaticity compromises stability, we incubated the cyclo-
adduct in PBS containing FBS (10% v/v) at 37 °C. After 8 h, no
decomposition of the cycloadduct was apparent by UV−vis
spectroscopy (Figure S1).
In conclusion, we have experimentally confirmed the
computationally predicted rate-enhancing effects of hyper-
conjugative antiaromaticity on the Diels−Alder reactivity of
five-membered cyclic dienes. The use of hyperconjugative
antiaromaticity to tune the Diels−Alder reactivity of five-
membered cyclic dienes and three-membered cyclic dieno-
heteroaromatic azadienes.11 Negative NICS values are asso-
ciated with a diatropic (aromatic) ring current, whereas positive
NICS values are indicative of a paratropic (antiaromatic) ring
current. The NICS(0) value of 0.5 ppm for the unsubstituted
4H-pyrazole suggests that the 4H-pyrazole scaffold is not
aromatic (Table S1). Fluorination of the 4H-pyrazole leads to
antiaromatic electron delocalization (NICS(0) = 6.2 ppm),
whereas silylation induces aromatic electron delocalization
(NICS(0) = −3.3 ppm).
The antiaromaticity of 4,4-difluoro-4H-pyrazoles led us to
believe that they would be highly reactive as inverse-electron-
demand Diels−Alder dienes. We computationally surveyed the
Diels−Alder reactivities of DFP, DMP, and Tz toward BCN at
the M06-2X/6-31G(d)//M06-2X/6-311++(d,p)-SMD(H2O)
level of theory.12 Gas-phase energies are listed in Table S2.
Our calculations reveal that fluorine substitution significantly
enhances the reactivity of the 4H-pyrazole scaffold. The reaction
of DFP with BCN is predicted to be 5.2 × 105 faster and 12.5
kcal/mol more exergonic than the cycloaddition of DMP with
BCN (Figure 1). The increased reactivity and exergonicity of the
DFP cycloaddition are consistent with DFP being antiaromatic.
The lowest unoccupied molecular orbital (LUMO) energies of
DFP and DMP were calculated to be −2.1 and −1.3 eV,
respectively. Decreasing the LUMO results in more favorable
frontier molecular orbital interactions and is an additional factor
that contributes to the increased reactivity of DFP as an inverse-
electron-demand diene.
We also compared the reactivity of the 4,4-difluoro-4H-
pyrazole scaffold to the highly reactive tetrazine scaffold. We
found that the 4,4-difluoro-4H-pyrazole and tetrazine scaffolds
have similar predicted reactivities toward BCN, with the
Figure 1. Transition-state geometries and calculated Gibbs free energies of activation (ΔG⧧) and reaction (ΔGrxn) computed at the M06-2X/6-
31G(d)//M06-2X/6-311++G(d,p)-SMD(H2O) level of theory for the Diels−Alder reactions of 4,4-dimethyl-3,5-diphenyl-4H-pyrazole (DMP), 4,4-
difluoro-3,5-diphenyl-4H-pyrazole (DFP), and 3,6-diphenyl-1,2,4,5-tetrazine (Tz) toward BCN. The lengths (Å) of forming bonds are shown. Values
of krel were calculated at 298 K with the Arrhenius equation.
B
DOI: 10.1021/acs.orglett.9b03351
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Figure 2. Reaction of BCN (1, 5, or 10 mM) with DFP (0.1 mM) or Tz (0.1 mM) in 9:1 methanol/water. Values of kobs are the mean SEM for
reactions performed in triplicate. Second-order rate constants as calculated from a linear fit of the data were k2 = 5.2 M−1 s−1 for DFP (R2 = 0.97) and k2
= 3.2 M−1 s−1 for Tz (R2 = 0.99).
philes14 will be useful to click chemistry applications that require
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03351.
(3) Dommerholt, J.; Rutjes, F. P. J. T.; van Delft, F. L. Strain-
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Chem. Commun. 2012, 48, 1736−1738.
(5) Levandowski, B. J.; Houk, K. N. Theoretical Analysis of Reactivity
Patterns in Diels−Alder Reactions of Cyclopentadiene, Cyclo-
hexadiene, and Cycloheptadiene with Symmetrical and Unsymmetrical
Dienophiles. J. Org. Chem. 2015, 80, 3530−3537.
(6) (a) Nyulaszi, L.; Schleyer, P. v. R. Hyperconjugative π-
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Tables S1 and S2; Figure S1; computational methods and
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(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
*E-mail: houk@chem.ucla.edu.
*E-mail: rtraines@mit.edu.
ORCID
́
́
Soc. 1999, 121, 6872−6875. (b) Fernandez, I.; Wu, J. I.; von Rague
Schleyer, P. Substituent Effects on “Hyperconjugative” Aromaticity and
Antiaromaticity in Planar Cyclopolyenes. Org. Lett. 2013, 15, 2990−
2993.
Brian J. Levandowski: 0000-0002-8139-9417
Nile S. Abularrage: 0000-0002-3112-2591
K. N. Houk: 0000-0002-8387-5261
Ronald T. Raines: 0000-0001-7164-1719
Author Contributions
§B.J.L. and N.S.A. contributed equally to this work.
Notes
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substituted cyclopentadienes. J. Comput. Chem. 2016, 37, 117−123.
(b) Levandowski, B. J.; Zou, L.; Houk, K. N. Hyperconjugative
Aromaticity and Antiaromaticity Control the Reactivities and π-Facial
Stereoselectivities of 5-Substituted Cyclopentadiene Diels−Alder
Cycloadditions. J. Org. Chem. 2018, 83, 14658−14666.
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Diazabicyclo[2.2.1]heptenen. Chem. Ber. 1984, 117, 517−533.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research was supported by Grants R01 GM044783 (NIH)
and CHE-1764328 (NSF). Computational resources were
provided by the UCLA Institute for Digital Research and
Education (IDRE) and the Extreme Science and Engineering
Discovery Environment (XSEDE),15 which is supported by
Grant ACI-1548562 (NSF).
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DOI: 10.1021/acs.orglett.9b03351
Org. Lett. XXXX, XXX, XXX−XXX