Mechanical Force Induces Ylide-Free Cycloaddition of Nonscissible Aziridines

Article abstract of DOI:10.1002/anie.201915438

The application of aziridines as nonvulnerable mechanophores is reported. Upon exposure to a mechanical force, stereochemically pure nonactivated aziridines incorporated into the backbone of a macromolecule do not undergo cis–trans isomerization, thus suggesting retention of the ring structure under force. Nonetheless, aziridines react with a dipolarophile and seem not to obey conventional reaction pathways that involve C?C or C?N bond cleavage prior to the cycloaddition. Our work demonstrates that a nonvulnerable chemical structure can be a mechanophore.

Full text of DOI:10.1002/anie.201915438

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Accepted Article
Title: Mechanical Force Induces Ylide-Free Cycloaddition of
Nonscissible Aziridines
Authors: Hyo Jae Yoon and Sangmin Jung
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915438
Angew. Chem. 10.1002/ange.201915438
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Mechanical Force Induces Ylide-Free Cycloaddition of
Nonscissible Aziridines
Sangmin Jung, and Hyo Jae Yoon*
Abstract: Reported herein is that aziridines can be a nonvulnerable
mechanophore. Upon exposure to mechanical force,
Cycloaddition reactions of aziridines under thermal and
photochemical conditions usually depend on the formation of
reactive species before the event of addition reaction, such as i)
azomethine ylides resulting from the cleavage of C-C bond in the
aziridine ring,[17] ii) zwitterionic 1,3-dipoles from the cleavage of C-
N bond,[18] iii) aziridinium ions from the reaction on the nitrogen,[19]
and iv) metalla-azetidines from the oxidative addition of metal
(Figure S1 in the Supporting Information).[20] For the first two
cases, the formation of reactive species necessitates a reversible
bond cleavage in the ring structure, which is evidenced by cis-
trans isomerization of aziridine, often inducing undesirable side-
reactions.[21]
a
stereochemically pure nonactivated aziridines incorporated into the
backbone of macromolecule do not undergo cis-trans isomerization,
suggesting the retention of ring structure by the force. Nonetheless,
aziridines react with
a dipolarophile and seem not to obey
conventional reaction pathways that involve C-C or C-N bond
cleavage prior to the event of cycloaddition. Our work demonstrates
that a nonvulnerable chemical structure can be a mechanophore.
In mechanochemically responsive polymers[1], strong pulling or
shearing forces along the backbone of macromolecules
transduced by a mechanical force trigger chemical reactions over
mechanophores embedded on the backbone. These polymers
have found several applications, including structure
engineering,[2] catalysis,[3] sensors,[2a] patterning,[4] recycling of
resources,[5] materials transfer,[6] and gating to regulate other
reactions.[7] Such systems can activate covalent and coordination
bonds,[2a-f, 3, 5, 6b, 7-8] and change electrical and optical properties.[2a,
4, 9]
The activation of mechanophores also allows one to steer
chemical reactions into the routes that are inaccessible under
10]
traditional thermal and photochemical conditions.[2c-f,
The
common approach for mechanochemical studies is to harness
vulnerable chemical structures, as mechanophores, that have
weak bond energies[3, 11] or high strains.[2e, 2f, 5, 7a] Thus, most of
mechanophores usually exhibit irreversible bond scission upon
12]
exposure to mechanical forces.[9,
A limited number of
mechanophores often undergoes isomerization (see Figure 1a for
exemplary cases).[2c, 2f]
Highly
strained
ring
structures,
much
like
gem-
dihalocyclopropanes[13] and epoxides,[14] are attractive
mechanophores. Aziridine is the smallest saturated heterocycle
containing a nitrogen atom, and its reactivity largely differs from
those of gem-dihalocyclopropanes and epoxides.[14-15] Depending
Figure 1. a) Exemplary cases of mechanochemical isomerization of gem-
difluorocyclopropane (gDFC) and epoxide. b) No isomerization of aziridines
(cis-2 and trans-2) under a mechanochemical condition, thereby leading to
highly stereoselective cycloaddition reactions with dipolarophile (dimethyl
acetylenedicarboxylate, denoted as DMAD).
on the electronic structure of N-substituent, the reactivity of
16]
aziridine can be tunable.[15f,
For example, incorporation of
electron-donating moiety into the N-substituent yields highly
robust non-activated aziridines whereas electron-withdrawing N-
substituent leads to activated aziridines whose ring structure can
be easily opened under mild conditions.
We herein show that nonactivated aziridines can act as a
mechanophore and likely obeys an ylide-free reaction pathway.
Upon application of mechanical force via ultrasound sonication,
stereochemically pure aziridines do not undergo cis-trans
isomerization (Figure 1b). Intuitively, enough mechanochemical
reactivity would not be anticipated in such robust molecular
structures. However, the aziridines unexpectedly allow access to
S. Jung, and Prof. H. J. Yoon*
Department of Chemistry
Korea University
Seoul, 02841, South Korea
E-mail: hyoon@korea.ac.kr
Supporting information for this article is given via a link at the end of the
document
force-induced cycloaddition reactions with
a dipolarophile
(dimethyl acetylenedicarboxylate, DMAD; Figure 1b). This is
counterintuitive considering that the typical cycloaddition of
1
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aziridines follows reaction pathways involving C-C or C-N bond
cleavages before the event of addition (as described above).
the 1:1 molar ratio was straightforwardly translated into the
monomer ratio in the polymer chain. The copolymers cis-2 and
trans-2 exhibited the proton resonances at δ = 3.02 ppm and 3.42
ppm, respectively (Figure 2b). These proton resonances were
consistent with those of the aziridine in the monomers. This
confirms the intact ring structure and the retention of
stereochemistry after the completion of polymerization. Figure 2c
shows size exclusion chromatography (SEC) traces for the
polymers. From the traces, we estimated the number average
molecular weight (Mn) and polydispersity index (PDI): 58.5 kDa
and 1.89 for cis-2 and 51.8 kDa and 2.74 for trans-2.
Figure 3. a, b) 1H NMR spectra of cis-2 and trans-2 before and after 2 h of
sonication at 30% amplitude.
Our aziridines did not undergo cis-trans isomerization. Each
solution of cis-2 and trans-2 in THF (1 mg/mL) was sonicated at 4
- 8 oC with a high intensity probe (20 kHz, 30% amplitude; pulse
sequence: 1 sec on and 1 sec off) under N2 atmosphere. After 2
h ultrasound sonication, we observed no changes in 1H NMR
spectra for cis-2 and trans-2 (Figure 3a, b). This finding evidenced
no significant isomerization of aziridine under mechanochemical
condition.
Intuitively, we hypothesized that non-isomerizable robust
aziridines may not be a good mechanophore. To test this
hypothesis, each of cis-2 and trans-2 was reacted with 0.2 M
DMAD under the identical mechanochemical condition used for
the isomerization experiment. After 2 h sonication, apparent
changes in 1H NMR spectra were unexpectedly observed. For the
reaction of cis-2, new proton resonances at δ = 6.61, 5.52, 4.07,
3.83, and 3.72 ppm appeared (a-e in Figure 4a); similarly, 1H NMR
spectra for the reaction of trans-2 showed new proton resonances
at δ = 6.71 and 5.28 ppm (a, b in Figure 4b). The integration ratio
of the new proton resonances was a:b:c:d:e = 1.5:1:1:2:3 and a:b
= 1:1 for cis-2 and trans-2, respectively (Figure S2 in the
Supporting Information). The1H NMR spectra of copolymers were
compared with those of [3+2] cycloaddition products (pyrrolines),
analogous polymers separately synthesized with cis-2 and trans-
2 under thermal condition (denoted as trans-3-heat and cis-3-
heat; see the Supporting Information for details about synthesis
and characterization of these polymers). The comparison
indicated that the newly formed proton resonances in the
mechanochemical products (denoted as trans-3 and cis-3)
corresponded to pyrrolines. Note that cis-2 and trans-2 were
converted into trans-3 and cis-3, respectively. Interestingly, no
mixture of cis- and trans-products was observed for both reactions
(Figure 4), indicating that our mechanochemical reactions were
highly stereoselective. In conjunction with the observation of no
cis-trans isomerization, our result surprisingly implies that force
induces the cycloaddition of nonactivated aziridines, probably,
without the formation of azomethine ylides[17] that result from C-C
Figure 2. a) Synthesis of N-(4-methoxyphenyl) cis- and trans-aziridine
copolymers (denoted as cis-2 and trans-2) from the macrocyclic monomers (cis-
1 and trans-1) via entropically-driven ring opening metathesis copolymerization
(ED-ROMP). b) Comparison of 1H NMR spectra for the monomers and polymers.
c) Size exclusion chromatography (SEC) traces of cis-2 and trans-2. Insets
show the full SEC plots.
We synthesized 14-membered macrocyclic monomers that
contained cis- and trans-N-(4-methoxyphenyl) aziridines (cis-1
and trans-1 in Figure 2a) from cis- or trans-diethyl 1-(4-
methoxyphenyl)aziridine-2,3-dicarboxylates in two steps. The
desired structures and stereochemistry of monomers were
confirmed by 1H and 13C NMR spectroscopies and high-resolution
mass spectrometry (HR-MS) (see the Supporting Information for
details on synthetic procedures and characterization of the
monomers). The protons of aziridine carbons in cis-1 and trans-1
showed the resonances at δ = 3.04 and 3.40 ppm, respectively,
confirming the formation of aziridine ring structures (Figure 2b).
Aziridine-containing polymers (cis-2 and trans-2) were
synthesized by entropically-driven ring opening metathesis
copolymerization with 1:1 molar ratio of cis-cyclooctene and the
monomer (cis-1 or trans-1) in the presence of Grubbs 2nd
1
generation catalyst (Figure 2a). H NMR analysis confirmed that
2
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Figure 4. a, b) The molecular structures of mechanochemical products formed
from cis-2 and trans-2 reactants (denoted as trans-3 and cis-3), and the
corresponding thermal products (trans-3-heat and cis-3-heat). Comparison of
1H NMR spectra between these.
or C-N bond cleavage. It is noteworthy that cycloaddition of intact
aziridine has not been reported before.
Control experiments were also conducted over small molecule
systems. Large extensional shear forces are generated by pulsed
ultrasound[1], and this is usually facilitated by a polymer backbone.
Under the same sonication conditions as those of polymeric
systems, cis- and trans-N-(4-methoxyphenyl) aziridine small
molecules (denoted as cis-aziridine and trans-aziridine) did not
react with DMAD, evidenced by no detectable change in 1H NMR
spectra (Figure 5a, b). This result confirms that the cycloaddition
reactions by pulsed ultrasound of the aziridine copolymers were
caused by the extensional shear force along the polymer
backbone, not by high-pressure energy and elevated temperature
generated by ultrasonic waves.
Figure 5. a, b) 1H NMR spectra of cis- and trans-aziridine model compounds
(the corresponding small molecules without the macromolecular backbone)
before and after 2 h of sonication under the same condition.
To explain the mechanism of our mechanochemical reactions,
we conducted CoGEF (Constrained Geometries for simulating
External Force) calculations using density functional theory (DFT)
at B3LYP/6-31G*.[22] To simulate force induced structural
changes, the straight-line distance between the methoxy
substituents (d, Å) increased gradually as shown in Figure 6a. The
increased Δd (the change in d relative to intact aziridine) led to i)
increased relative energy of aziridines (Figure 6b), ii) elongated
C-C bond in aziridines (Figure 6c), iii) reduced negative charge
character on carbon atoms of aziridine (Figure 6d), and iv)
increased negative charge character on nitrogen atom (Figure 6e).
At the end of calculation, cis- and trans-aziridines underwent C-C
bond cleavage at Δd = 1.70 and 1.65 Å, respectively.
The stereoselective feature in our mechanochemical reactions is
an unexpected observation. Unraveling detailed mechanisms of
mechanochemical reactions is a significant chemical challenge.
Indeed, despite the CoGEF calculation, our current understanding
is insufficient to fully explain the mechanism of our reactions.
Recently, a stimulating study by Martinez and Xia et al.[23] has
shown that a newly developed ab initio steered molecular
dynamics can be useful for investigating mechanistic hypotheses
of mechanochemical reactions. Further study using this new
simulation method may be needed to explain the mechanism of
our reactions.
3
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trans-aziridines are formed, obeying Baldwin’s rules, (Figure S4c
in the Supporting Information). Intramolecular cyclization of these
intermediates affords only cis-pyrroline for both cis- and trans-
aziridine.
In summary, we have demonstrated that the robust ring structure
of aziridines surprisingly reacts with a dipolarophile under a
mechanochemical condition. This unprecedented finding
suggests that a nonvulnerable chemical structure can be
considered as a mechanophore for not only solving the problems
in mechanochemical reactions with vulnerable mechanophores
but also exploring unconventional reaction routes that are
inaccessible under traditional reaction conditions. The trivalent
nitrogen atom in aziridine makes it possible to control the
chemical and electronic structure of N-substituent, which
promises to modulate the mechanochemical reactivity of aziridine
mechanophore.
Acknowledgements
This research was supported by the NRF of Korea (NRF-
2016R1D1A1A02937504; NRF-2019R1A6A1A11044070; NRF-
2019R1A2C2011003).
Keywords: Mechanochemistry • Nonvulnerable mechanophore
• Nonscissible aziridine • Highly stereoselective cycloaddition •
Ylide-free
[1]
[2]
M. M. Caruso, D. A. Davis, Q. Shen, S. A. Odom, N. R. Sottos,
S. R. White, J. S. Moore, Chem. Rev. 2009, 109, 5755-5798.
a) D. A. Davis, A. Hamilton, J. Yang, L. D. Cremar, D. V. Gough,
S. L. Potisek, M. T. Ong, P. V. Braun, T. J. Martínez, S. R. White,
J. S. Moore, N. R. Sottos, Nature 2009, 459, 68–72; b) S.
Akbulatov, Y. Tian, Z. Huang, T. J. Kucharski, Q.-Z. Yang, R.
Boulatov, Science 2017, 357, 299-303; c) J. M. Lenhardt, M. T.
Ong, R. Choe, C. R. Evenhuis, T. J. Martinez, S. L. Craig,
Science 2010, 329, 1057-1060; d) C. R. Hickenboth, J. S.
Moore, S. R. White, N. R. Sottos, J. Baudry, S. R. Wilson,
Nature 2007, 446, 423–427; e) J. M. Lenhardt, A. L. Black, S. L.
Craig, J. Am. Chem. Soc. 2009, 131, 10818-10819; f) H. M.
Klukovich, Z. S. Kean, A. L. B. Ramirez, J. M. Lenhardt, J. X.
Lin, X. Q. Hu, S. L. Craig, J. Am. Chem. Soc. 2012, 134, 9577-
9580; g) W. M. Huang, X. Wu, X. Gao, Y. F. Yu, H. Lei, Z. S.
Zhu, Y. Shi, Y. L. Chen, M. Qin, W. Wang, Y. Cao, Nat. Chem.
2019, 11, 310-319.
Figure 6. a) Simulation of tensile stress induced structural changes in cis- and
trans-aziridines. The beeline distance between methoxy groups (d, ꢀ) increased
from 0.0 to 2.05 ꢀ. b) Plots of relative energy between as a function of the
change in d relative to intact aziridine (Δd). c) Plots of bond lengths between
aziridine carbons as a function of Δd. d) Plots of natural atomic charge (NAC)
of aziridine’s carbon atoms as a function of Δd (C1-C2 and C3-C4 for cis- and
trans-aziridines, respectively). e) Plots of NAC of aziridine’s nitrogen atom as a
function of Δd.
[3]
[4]
[5]
[6]
A. Piermattei, S. Karthikeyan, R. P. Sijbesma, Nat. Chem. 2009,
1, 133-137.
Q. Wang, G. R. Gossweiler, S. L. Craig, X. Zhao, Nat. Commun.
2014, 5, 4899-4908.
C. E. Diesendruck, L. Y. Zhu, J. S. Moore, Chem. Commun.
2014, 50, 13235-13238.
a) Y. Ren, A. A. Banishev, K. S. Suslick, J. S. Moore, D. D. Dlott,
J. Am. Chem. Soc. 2017, 139, 3974-3977; b) M. D.
Giannantonio, M. A. Ayer, E. Verde‐Sesto, M. Lattuada, C.
Weder, K. M. Fromm, Angew. Chem. Int. Ed. 2018, 57, 11445-
11450.
a) A. L. B. Ramirez, Z. S. Kean, J. A. Orlicki, M. Champhekar,
S. M. Elsakr, W. E. Krause, S. L. Craig, Nat. Chem. 2013, 5,
757-761; b) J. Wang, T. B. Kouznetsova, R. Boulatov, S. L.
Craig, Nat. Commun. 2018, 7, 13433-13441; c) X. Hu, M. E.
McFadden, R. W. Barber, M. J. Robb, J. Am. Chem. Soc. 2018,
140, 14073-14077; d) M. Zhang, G. D. Bo, J. Am. Chem. Soc.
2018, 140, 12724-12727.
We believe, however, that the following possibilities in the
reaction mechanism could be eliminated because the
stereochemical information in products is not consistent with the
experimentally observed one. i) If the activated aziridines obey
concerted [3+2] cycloaddition reaction routes, cis- and trans-
aziridines would be converted into cis- and trans-pyrrolines,
respectively, as summarized in Figure S4a in the Supporting
Information. ii) If the aziridines are converted into ylides under the
mechanochemical condition (this seems not true according to our
experiment), disrotatory and conrotatory ring opening of cis- and
trans-aziridines yields the same W-shaped azomethine ylide,
[3+2] cycloaddition of this ylide with DMAD affords only cis-
pyrroline (Figure S4b in the Supporting Information). iii) If the
electron-rich nitrogen atom resulting from the increased C-N
dipole pushes a pair of electrons into the carbon atom and
subsequently the C-C  bond attacks DMAD in a transition state,
dipolar intermediates with the same stereochemistry for cis- and
[7]
[8]
R. Stevenson, G. D. Bo, J. Am. Chem. Soc. 2017, 139,
16768−16771.
4
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10.1002/anie.201915438
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[9]
Z. Chen, J. A. M. Mercer, X. Zhu, J. A. H. Romaniuk, R. Pfattner,
L. Cegelski, T. J. Martinez, N. Z. Burns, Y. Xia, Science 2017,
357, 475-479.
[10] J. Wang, T. B. Kouznetsova, Z. Niu, M. T. Ong, H. M. Klukovich,
A. L. Rheingold, T. J. Martinez, S. L. Craig, Nat. Chem. 2015, 7,
323-327.
[11] a) K. Wei, Z. C. Gao, H. R. Liu, X. J. Wu, F. Wang, H. X. Xu,
ACS Macro. Lett. 2017, 6, 1146-1150; b) Y. Sha, Y. D. Zhang,
E. H. Xu, Z. Wang, T. Y. Zhu, S. L. Craig, C. B. Tang, ACS
Macro. Lett. 2018, 7, 1174-1179; c) B. Lee, Z. B. Niu, J. P. Wang,
C. Slebodnick, S. L. Craig, J. Am. Chem. Soc. 2015, 137,
10826-10832.
[12] a) J. P. Wang, T. B. Kouznetsova, Z. B. Niu, A. L. Rheingold, S.
L. Craig, J. Org. Chem. 2015, 80, 11895-11898; b) J. H. Yang,
M. Horst, J. A. H. Romaniuk, Z. X. Jin, L. Cegelski, Y. Xia, J.
Am. Chem. Soc. 2019, 141, 6479-6483; c) M. E. McFadden, M.
J. Robb, J. Am. Chem. Soc. 2019, 141, 11388-11392; d) H. M.
Klukovich, Z. S. Kean, S. T. Iacono, S. L. Craig, J. Am. Chem.
Soc. 2011, 133, 17882-17888; e) G. R. Gossweiler, G. B.
Hewage, G. Soriano, Q. M. Wang, G. W. Welshofer, X. H. Zhao,
S. L. Craig, ACS Macro. Lett. 2014, 3, 216-219.
[13] M. Fedorynski, Chem. Rev. 2003, 103, 1099-1132.
[14] R. E. Parker, N. S. Isaacs, Chem. Rev. 1959, 59, 737-799.
[15] a) J. P. Bell, J. Appl. Polym. 1970, 14, 1901-1906; b) I. T. Smith,
Polymer 1961, 2, 95-108; c) M. J. Tozer, T. F. Herpin,
Tetrahedron 1996, 52, 8619-8683; d) D. L. S. Brahms, W. P.
Dailey, Chem. Rev. 1996, 96, 1585-1632; e) I. H. Wani, S. H.
M. J. logoad, J. Warna, A. Hayat, H. Li, V. A. Shukla, A.
Orthaber, A. Grigoriev, R. Ahuja, K. Leifer, Nanoscale 2019, 11,
6571-6575; f) S. Kang, H. K. Moon, H. J. Yoon, Macromolecules
2018, 51, 4068-4076.
[16] a) S. Jung, S. Kang, J. Kuwabara, H. J. Yoon, Polym. Chem.
2019, 10, 4506-4512; b) H. K. Moon, S. Kang, H. J. Yoon, Polym.
Chem. 2017, 8, 2287-2291; c) H. J. Jang, J. T. Lee, H. J. Yoon,
Polym. Chem. 2015, 6, 3387-3391; d) H. J. Yoon, Y. W. Kim, B.
K. Lee, W. K. Lee, Y. Kim, H. J. Ha, Chem. Commun. 2007, 79-
81.
[17] a) T. Hashimoto, K. Maruoka, Chem. Rev. 2015, 115, 5366-
5412; b) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev.
2006, 106, 4484-4517; c) L. M. Stanley, M. P. Sibi, Chem. Rev.
2008, 108, 2887-2902.
[18] P. Dauban, G. Malik, Angew. Chem. Int. Ed. 2009, 48, 9026-
9029.
[19] P. F. Lu, Tetrahedron 2010, 66, 2549-2560.
[20] M. Shipman, Synlett 2006, 3205-3217.
[21] a) R. Huisgen, W. Scheer, H. Huber, J. Am. Chem. Soc. 1967,
89, 1753-1755; b) P. J. S. Gomes, C. M. Nunes, A. A. C. C. Pais,
T. M. V. D. P. E. Melo, L. G. Arnaut, Tetrahedron Lett. 2006, 47,
5475-5479; c) A. L. Cardoso, T. M. V. D. P. E. Melo, Eur. J. Org.
Chem. 2012, 6479-6501.
[22] M. K. Beyer, J. Chem. Phys. 2000, 112, 7307-7312.
[23] Z. Chen, X. Zhu, J. Yang, J. A. M. Mercer, N. Z. Burns, T. J.
Martinez, Y. Xia, Nat. Chem. 2020, DOI:10.1038/s41557-019-
0396-5.
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Entry for the Table of Contents
(5.5 cm × 1.18 cm)
Mechanical force-induced cycloaddition of intact aziridines with a dipolarophile does not obey reaction pathways that occur in traditional
thermal and photochemical conditions. Our results demonstrate that nonvulnerable chemical structure can be an attractive
mechanophore.
6
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