Elucidating the mechanism of reversible oxiranations via magnetization transfer spectroscopy

Article abstract of DOI:10.1021/ol302596r

The reversible [2 + 1] cycloadditions between an N,N′-diamidocarbene (DAC) and eight aldehydes were examined using NMR spectroscopy. Variable temperature magnetization transfer experiments revealed higher exchange rates and lower activation barriers when electron-deficient aldehydes were employed. Likewise, competitive equilibrium studies indicated a thermodynamic preference for electron-deficient aryl and sterically unhindered alkyl aldehydes compared to more electron-rich or bulkier substrates. Collectively, these and other data collected were consistent with the oxiranation process proceeding in an asynchronous manner.

Full text of DOI:10.1021/ol302596r

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5510–5513
Elucidating the Mechanism of Reversible
Oxiranations via Magnetization Transfer
Spectroscopy
Daniel T. Chase,†,§ Jonathan P. Moerdyk,†,§ and Christopher W. Bielawski*,†,‡
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin,
Texas 78712, United States, and World Class University (WCU) Program of Chemical
Convergence for Energy & Environment (C2E2), School of Chemical and Biological
Engineering, Seoul National University, Seoul 151-742, Korea
bielawski@cm.utexas.edu
Received September 20, 2012
ABSTRACT
The reversible [2 þ 1] cycloadditions between an N,N0-diamidocarbene (DAC) and eight aldehydes were examined using NMR spectroscopy.
Variable temperature magnetization transfer experiments revealed higher exchange rates and lower activation barriers when electron-deficient
aldehydes were employed. Likewise, competitive equilibrium studies indicated a thermodynamic preference for electron-deficient aryl and
sterically unhindered alkyl aldehydes compared to more electron-rich or bulkier substrates. Collectively, these and other data collected were
consistent with the oxiranation process proceeding in an asynchronous manner.
Due to their high ring strain, oxiranes are important
precursors to a broad range of valuable small molecules
and polymers.1 Such three-membered cyclic ethers are
typically synthesized via one of four routes: (1) the ring
closure of an appropriately substituted alcohol, (2) the
monooxidation of an olefin, (3) the CoreyꢀChaykovsky
reaction, or (4) the [2 þ 1] cycloaddition of a carbene
with an aldehyde.2 Despite its high atom economy and
the availability of a wide range of aldehydes, the latter
process remains largely underdeveloped, mainly because
carbenes frequently react with carbonyl groups to give the
corresponding ylides rather than the desired cycloadducts.3
Moreover, most carbenes used in known oxiranation
reactions (e.g., dimethoxycarbene4) must be generated in
situ from unstable precursors.3a,5 As such, the mechanistic
details of the aldehyde/carbene cycloaddition process are
relatively unrefined and derived mainly from time-resolved
spectroscopic3c and computational studies.6
(3) (a) de March, P.; Huisgen, R. J. Am. Chem. Soc. 1982, 104, 4952.
(b) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263–309. (c)
Chateauneuf, J. E.; Liu, M. T. H. J. Am. Chem. Soc. 1991, 113, 6585–
6588.
(4) For excellent reviews and seminal contributions, see: (a) Hoffmann,
R. W. Angew. Chem., Int. Ed. 1971, 10, 529–537. (b) Moss, R. A.; Huselton,
J. K. J. Chem. Soc., Chem. Commun. 1976, 950–951. (c) Moss, R. A.;
Wzostowski, M.; Shen, S.; Krogh-Jespersen, K.; Matro, A. J. Am. Chem.
Soc. 1988, 110, 4443–4444. (d) Warkentin, J. Macromol. Symp. 1998, 134,
167–176. (e) Warkentin, J. Acc. Chem. Res. 2009, 42, 205–212.
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Soc. 1985, 107, 7204–7206. (b) Dawid, M.; Venneri, P. C.; Warkentin, J.
Can. J. Chem. 2001, 79, 110–113. (c) Moss, R. A.; Wang, L.; Sauers,
R. R. Tetrahedron Lett. 2007, 48, 5551–5554.
† The University of Texas at Austin.
‡ Seoul National University.
§ D.T.C. and J.P.M. contributed equally.
(1) (a) McMills, M. C.; Bergmeier, S. C. In Comprehensive Heterocyclic
Chemistry III; Padwa, A., Ed.; Pergamon: Oxford, 2008. (b) Bergmeier, S. C.;
Lapinsky, D. J. In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule,
J. A., Eds.; Elsevier: Oxford, 2009. (c) Krake, S. H.; Bergmeier, S. C.
Tetrahedron 2010, 66, 7337–7360.
(2) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353–1364. (b) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N.
J. Am. Chem. Soc. 1990, 112, 2801–2803. (c) Li, A.-H.; Dai, L.-X.;
Aggarwal, V. K. Chem. Rev. 1997, 97, 2341–2372. (d) Doyle, M. P.; Hu,
(6) (a) Illa, O.; Gornitzka, H.;Baceiredo, A.; Bertrand, G.; Branchadell,
~
V.; Ortuno, R. M. J. Org. Chem. 2003, 68, 7707–7710. (b) Illa, O.;
~
Gornitzka, H.; Branchadell, V.; Baceiredo, A.; Bertrand, G.; Ortuno,
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R. M. Eur. J. Org. Chem. 2003, 3147–3152. (c) Illa, O.; Alvarez-Larena,
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A.; Baceiredo, A.; Branchadell, V.; Ortuno, R. M. Tetrahedron: Asymme-
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r
10.1021/ol302596r
Published on Web 10/24/2012
2012 American Chemical Society

To expand the scope of the carbene/aldehyde cycload-
dition reaction and to gain additional insight into the
corresponding mechanism, the use of an isolable carbene7
as a cycloaddition partner is desirable. However, for the
past 20 years, the only known isolable carbenes capable of
reacting with aldehydes to give the corresponding oxiranes
were Bertrand’s phosphinosilyl carbenes.6,8 Recently,
we reported that diamidocarbenes (DACs; e.g., 1),9,10
which are also isolable and obtained from readily available
precursors, undergo [2 þ 1] cycloadditions with a wide
range of alkyl and aryl aldehydes (Scheme 1).11 Moreover,
the corresponding reactions were found to be rapid and
reversible under mild conditions (<80 °C). We reasoned
that additional insight into the [2 þ 1] cycloaddition
mechanism as well as the corresponding activation param-
eters may be obtained by probing the equilibration
process.
Figure 1. Competitive oxiranation equilibria. Conditions: [1]0 =
0.066 M, [aldehyde]0 = [aldehyde0]0 = 0.07 M, C6D6, 60 °C, 2 h.
With 2 in hand, subsequent efforts were directed toward
probing the oxiranation equilibria. Two different alde-
hydes (1.05 equiv each) were mixed with 1 in C6D6 ([1]0 =
0.066 M), and the product ratios were measured by
1H NMR spectroscopy over time. For every combination
of aldehydes studied (Figure 1), three separate experi-
ments were performed: (1) the addition of one aldehyde
followed by the other, (2) vice versa, and (3) the simulta-
neous addition of both aldehydes to 1. Afterward, the
mixture was allowed to stir for 20 min at rt. Following
1H NMR analysis, each solution was then heated to 60 °C
for 2 h, cooled to rt, and then reanalyzed. Similar product
ratios were observed regardless of the order of aldehyde
addition which indicated that the reactions were reaching
equilibrium.
Scheme 1. Known [2 þ 1] Cycloadditions of 1 with Aldehydes
Building upon our previous results,11 a range of aryl
and alkyl substituted diamidooxiranes (2) were first
synthesized by combining 1 with the appropriate aldehyde
at 23 °C. The formation of 2aꢀg was complete within
30 min, as determined by NMR spectroscopy, and the
new oxirane products 2b,c were isolated in good yield
(76ꢀ83%) in a manner similar to that used for previously
reported 2a,dꢀf.11,12 However, incomplete (<85%) con-
version was observed for 2h even in the presence of
excess pivaldehyde (10 equiv), presumably due to steric
inhibition.13
Table 1. Selected Product and Equilibrium Constant Ratios
Compared to 2da
b
entry
2
20
2:20
Keq/K0eq
1
2
3
4
5
6
7
2a
2b
2c
2e
2f
2d
2d
2d
2d
2d
2d
2d
76:24
55:45
55:45
29:71
71:29
68:32
<1:>99
8.9 ꢁ 100
1.4 ꢁ 100
1.4 ꢁ 100
1.9 ꢁ 10ꢀ1
5.6 ꢁ 100
4.3 ꢁ 100
<6.7 ꢁ 10ꢀ4
2g
2h
(7) For excellent reviews on stable carbenes, see: (a) Vignolle, J.;
€
€
Cattoen, X.; Bourissou, D. Chem. Rev. 2009, 109, 3333–3384. (b) Droge,
T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940–6952. (c) Melaimi,
M.; Soleilhavoup, M.; Bertrand, G. Angew. Chem., Int. Ed. 2010, 49,
8810–8849. (d) Martin, D.; Soleilhavoup, M.; Bertrand, G. Chem. Sci.
2011, 2, 389–399.
a The product ratios and equilibrium constants shown were calcu-
lated from an average of three separate experiments. Conditions: [1]0 =
0.066 M, [aldehyde]0 = [aldehyde0]0 = 0.07 M, C6D6, 60 °C, 2 h. b Keq
/
K0eq = ([2][aldehyde0])/([20][aldehyde]). Representative aldehyde combi-
nations shown; see the SI for the results obtained from all other possible
combinations.
(8) (a) Igau, A.; Baceiredo, A.; Trinquier, G.; Bertrand, G. Angew.
Chem., Int. Ed. Engl. 1989, 28, 621–622. (b) Martin, D.; Illa, O.;
~
Baceiredo, A.; Bertrand, G.; Ortuno, R. M.; Branchadell, V. J. Org.
Chem. 2005, 70, 5671–5677.
(9) (a) Hudnall, T. W.; Bielawski, C. W. J. Am. Chem. Soc. 2009, 131,
16039–16041. (b) Hudnall, T. W.; Moerdyk, J. P.; Bielawski, C. W.
Chem. Commun. 2010, 46, 4288–4290.
Inspection of the results obtained from the aforemen-
tioned experiments (see Table 1 and the Supporting In-
formation (SI)) revealed the following trend in stability:
2f ≈ 2a > 2g ≈ 2b ≈ 2c > 2d > 2e . 2h. While the DAC 1
appeared to favor electron-deficient aryl aldehydes, the
formation of 2f (from 1 and cyclohexanecarboxaldehyde)
was similarly favored14 as 2a which we believe stemmed
(10) For other seminal papers that detail the development of diami-
ꢀ
docarbenes, see: (a) Cesar, V.; Lugan, N.; Lavigne, G. Eur. J. Inorg.
Chem. 2010, 361–365. (b) Hobbs, M. G.; Forster, T. D.; Borau-Garcia,
J.; Knapp, C. J.; Tuononen, H. M.; Roesler, R. New J. Chem. 2010, 34,
1295–1308. (c) Braun, M.; Frank, W.; Reiss, G. J.; Ganter, C. Organo-
metallics 2010, 29, 4418–4420.
(11) Moerdyk, J. P.; Bielawski, C. W. Nat. Chem 2012, 4, 275–280.
(12) Unfortunately, recrystallization or concentration of 2g,h fol-
lowed by washing with pentane returned 1 and precluded isolation.
(13) Analysis of the equilibrium between 2h and pivaldehyde/1
between 0 and 60 °C using VT 1H NMR spectroscopy revealed ΔH
(14) Likewise, a 48:52 mixture of 2a:2f was obtained by combining
4-nitrobenzaldehyde and cyclohexanecarboxaldehyde (1.05 equiv each)
with a C6D6 solution of 1 ([1]0 = 0.066 M) followed by heating to 60 °C
for 2 h; see the SI for additional details.
and ΔS values of ꢀ11.2 kcal molꢀ1 and ꢀ33.4 cal molꢀ1
3
K
ꢀ1, respec-
3
3
tively (see the SI).
Org. Lett., Vol. 14, No. 21, 2012
5511

from a slow dissociation process (see below). In addition to
electronics, sterics also prominently influenced the stability
of the diamidooxiranes (cf., entries 5 or 6 to 7).
nucleus was allowed to relax over time (see Figure 3 for an
illustrative example). The areas of the signals assigned to
the pulsed aldehyde starting material as well as the oxirane
product were monitored at various relaxation delays that
ranged between 0.001 and 30 s. Using the software pro-
gram CIFIT,19 the areas of the oxirane and aldehyde
signals were fitted to a nonlinear, least-squares equation
and an exchange rate, kald, was calculated for each alde-
hyde studied.
Unfortunately, due to the rapid rate of cycloaddition, all
attempts to expand upon the aforementioned equilibrium
studies and obtain the corresponding pseudo-first-order
1
rate constants (kobs) by variable temperature H NMR
spectroscopy were unsuccessful. For example, treating
a C7D8 solution of 1 ([1]0 = 0.066 M) with 10 equiv of
benzaldehyde was found to quantitatively form 2b within
60 s at ꢀ80 °C (kobs > 1.9 ꢁ 10ꢀ1 Mꢀ1 sꢀ1 at 99.9%
3
conversion).
Figure 2. Substrates used in the magnetization transfer spectro-
scopy experiments. Conditions: [1]0 = 0.066 M, [aldehyde]0 =
0.199 M, C7D8. The asterisk denotes the H NMR resonances
1
monitored during the magnetization transfer process. The rate-
determining step is the cycloreversion of the oxirane.
Figure 3. Plot of the measured magnetization signal versus time
for 2a (monitored at 3.9 ppm, blue squares) and 4-nitrobenzal-
dehyde (monitored at 9.45 ppm, red circles) and their magnetiza-
tion values calculated from the best-fit parameters (black lines).
Inset: Representative NMR spectra for (top) 2a (monitored
at 3.9 ppm) and (bottom) 4-nitrobenzaldehyde (monitored
at 9.45 ppm) over time. Conditions: [1]0 = 0.066 M, [4-nitro-
benzaldehyde]0 = 0.199 M, C7D8, 100 °C.
To circumvent this limitation and to measure the rates
of the exchange processes at equilibrium, we con-
sidered magnetization transfer spectroscopy.15 This one-
dimensional NMR technique involves the monitoring of
a nucleus undergoing chemical exchange as it relaxes from
a selective 180° pulse. While magnetization transfer has
been previously utilized in biological,16 organometallic,17
and other physical chemistry18 studies, it has not been
employed to study CꢀC bond forming reactions to the
best of our knowledge.
The aforementioned experiments were then repeated
with the exception that the 1H NMR resonance assigned
to the oxirane (2.61ꢀ3.9 ppm) was selectively inverted
instead of the aldehyde. Likewise, monitoring the signal
areas over time provided the corresponding exchange
rate, kox. The overall exchange rate, kexc, was taken as
the numerical average of kald and kox. As shown in Figure 4
and summarized in Table 2 (as well as the SI), the exchange
rates for 2aꢀe were measured at 5 °C intervals from 85
to 100 °C; the exchange rates for 2fꢀh were not measured
due to premature decomposition observed at elevated
temperatures.
Using the VT NMR data, Eyring plots were constructed
to determine the activation energies for the cyclorever-
sion reactions of 2aꢀe. The corresponding ΔH‡ and ΔS‡
values were calculated to be large and positive (Table 2),
and the exchange rate was found to be independent of the
aldehyde concentration (see the SI). These data indicated
that the dissociative cycloreversion was the rate-limiting
step of the equilibration process. Additionally, the more
To test the viability of the magnetization transfer tech-
nique as a means to measure the exchange rates of the
reactions summarized in Figure 2, a C7D8 solution of 1
([1]0 = 0.066 M) and 3 equiv of an aldehyde were heated to
a predetermined temperature in the NMR probe. Next,
a selective 180° pulse was applied to the equilibrated
1
sample at the H NMR resonance frequency assigned
to the aldehyde (9.4ꢀ9.6 ppm), and the corresponding
(15) Morris, G. A.; Freeman, R. J. Magn. Reson. 1978, 29, 433–462.
(16) (a) London, R. E.; Gabel, S. A. Biophys. J. 1995, 69, 1814–1818.
(b) Kruiskamp, M. J.; van Vliet, G.; Nicolay, K. Magn. Reson. Med.
2000, 43, 657–664.
(17) (a) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 749–750. (b) Hascall, T.; Murphy, V. J.; Parkin, G. Organo-
metallics 1996, 15, 3910–3912. (c) Muhandiram, D. R.; Kiel, G.-Y.;
Aarts, G. H. M.; Saez, I. M.; Reuvers, J. G. A.; Heinekey, D. M.;
Graham, W. A. G.; Takats, J.; McClung, R. E. D. Organometallics 2002,
21, 2687–2704.
(18) (a) Brown, A. B.; Whitlock, H. W., Jr. J. Am. Chem. Soc. 1989,
111, 3640–3651. (b) Perrin, C. L.; Thoburn, J. D.; Kresge, A. J. J. Am.
Chem. Soc. 1992, 114, 8800–8807. (c) Wiberg, K. B.; Rablen, P. R.;
Rush, D. J.; Keith, T. A. J. Am. Chem. Soc. 1995, 117, 4261–4270. (d)
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(19) Bain, A. D.; Cramer, J. A. J. Magn. Reson. 1996, 118, 21–27.
Org. Lett., Vol. 14, No. 21, 2012
5512

Table 2. Summary of the Activation Parameters
kexc (sꢀ1
)
ΔH‡
ΔS‡
ΔG‡ (298 K)
oxirane (100 °C) (kcal molꢀ1
)
(cal molꢀ1 Kꢀ1
)
(kcal molꢀ1
)
3
3
3
3
2a
2b
2c
2d
2e
4.4
23.9 ( 1.9
23.0 ( 1.4
23.1 ( 0.9
26.2 ( 1.4
23.8 ( 1.9
8 ( 5
4 ( 4
4 ( 2
12 ( 4
5 ( 5
22 ( 2
21.7 ( 1.8
21.8 ( 1.1
22.6 ( 1.9
22 ( 2
2.13
2.06
1.3
1.45
Scheme 2. Proposed Mechanism for the Reversible Oxiranation
Figure 4. Measured exchange rates versus temperature. Condi-
tions: [1]0 = 0.066 M, [aldehyde]0 = 0.199 M, C7D8.
electron-deficient 2a exchanged at nearly triple the rate
as those measured for 2d and 2e at 100 °C. The higher
exchange rates and slightly lower ΔG‡ for the more electron-
deficient derivatives reflected a partial buildup of negative
charge in the transition state stabilized by the proximal
electron-withdrawing aryl substituents (Scheme 2). Based
on these results, the mechanism of the oxiranation was
consistent with a process wherein the aldehyde underwent
attack by the nucleophilic carbene in an asynchronous
manner.
In summary, the dynamic equilibria of 1 with various
aryl and alkyl aldehydes was investigated and the corre-
sponding thermodynamic parameters were measured.
Competitive equilibrium studies revealed a thermody-
namic preference for electron-deficient aryl aldehydes 2a,
b and sterically unhindered alkyl aldehydes 2f,g while the
formation of sterically hindered oxiranes was strongly
disfavored. Similarly, magnetization transfer experiments
showed that the electron-deficient oxiranes underwent
faster exchange than their electron-rich analogues. Collec-
tively, the exchange rates and activation energies were
consistent with an asynchronous mechanism that involved
the buildup of partial negative charge at the aldehyde
oxygen (and, by extension, buildup of partial positive
charge within the N-heterocycle) in the transition state.20
With knowledge of the exchange rates and thermodynamic
equilibria in hand, we believe the DAC/aldehyde cycload-
dition reaction is poised for use in dynamic covalent21
applications (e.g., sensing22,23) wherein the rapid, reversi-
ble oxiranation process may be advantageous.24 Beyond
elucidating the mechanism of the aforementioned [2 þ 1]
cycloaddition reaction, magnetization transfer spectro-
scopy was applied for the first time to a dynamic covalent
organic reaction.
(20) For comparison, NHCs often afford zwitterions that rearrange
to the corresponding Breslow intermediates when treated with aldehydes
(see: Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522). In
contrast, the low-lying LUMO of the DAC may facilitate ring closure
(see: Hudnall, T. W.; Moorhead, E. J.; Gusev, D. G.; Bielawski, C. W.
J. Org. Chem. 2010, 75, 2763–2766).
(21) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders,
J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898–952. (b)
Lehn, J.-M. Chem. Soc. Rev. 2007, 36, 151–160.
(22) (a) Zhang, C.; Wang, Q.; Long, H.; Zhang, W. J. Am. Chem. Soc.
2011, 133, 20995–21001. (b) Jin, Y.; Voss, B. A.; Jin, A.; Long, H.;
Noble, R. D.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 6650–6658.
(23) (a) You, L.; Berman, J. S.; Anslyn, E. V. Nat. Chem. 2011, 3,
943–948. (b) Carroll, C. N.; Coombs, B. A.; McClintock, S. P.; Johnson,
C. A., II; Berryman, O. B.; Johnson, D. W.; Haley, M. M. Chem.
Commun. 2011, 47, 5539–5541. (c) Engle, J. M.; Carroll, C. N.; Johnson,
D. W.; Haley, M. M. Chem. Sci. 2012, 3, 1105–1110.
Acknowledgment. We acknowledge the NSF (CHE-
0645563), the Welch Foundation (F-1621), and the WCU
program through the NRF of Korea (R31-10013) for their
support. J.P.M. is grateful to the UT-Austin for a Powers
Fellowship. We also thank Steve Sorey (UT-Austin) for
assistance with the magnetization experiments.
Supporting Information Available. Synthetic and char-
acterization details for 2c,d,g,h, additional equilibrium
data, VT NMR and magnetization transfer data, and
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
(24) (a) Nitschke, J. R.; Schultz, D.; Bernardinelli, G.; Gerard, D.
ꢀ
J. Am. Chem. Soc. 2004, 126, 16538–16543. (b) Arico, F.; Chang, T.;
Cantrill, S. J.; Khan, S. I.; Stoddart, J. F. Chem.;Eur. J. 2005, 11, 4655–
4666. (c) Chichak, K. S.; Cantrill, S. J.; Stoddart, J. F. Chem. Commun.
2005, 3391–3393.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5513