On the nature of rate acceleration in the synthesis and fragmentation of triazolines by Bronsted acid: Secondary catalysis by water (hydronium triflate)

Article abstract of DOI:10.1021/ja0779452

Rate acceleration of the addition of benzyl azide to an electron deficient olefin is characterized using in situ IR spectroscopy. Under strictly anhydrous conditions and at depressed temperature (-20°C), a triazoline intermediate is selectively formed. Th

Full text of DOI:10.1021/ja0779452

Published on Web 01/25/2008
On the Nature of Rate Acceleration in the Synthesis and
Fragmentation of Triazolines by Brønsted Acid: Secondary
Catalysis by Water (Hydronium Triflate)
Ki Bum Hong, Matthew G. Donahue, and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt UniVersity,
NashVille, Tennessee 37235-1822
Received October 16, 2007; E-mail: jeffrey.n.johnston@vanderbilt.edu
Abstract: Rate acceleration of the addition of benzyl azide to an electron deficient olefin is characterized
using in situ IR spectroscopy. Under strictly anhydrous conditions and at depressed temperature (-20
°C), a triazoline intermediate is selectively formed. The stability of this protonated triazoline intermediate at
-20 °C is indefinite, but warming of the reaction mixture to 0 °C or above results in its conversion to the
â-amino oxazolidine dione observed under conditions used in our earlier report. As an alternative to warming,
the same conversion can be effected by the addition of a single equivalent of water. Our experiments
collectively demonstrate the metastability of the protonated triazoline intermediate and secondary catalysis
of triazolinium ring fragmentation by water. This behavior is attributed to the ability of water to transfer a
proton from N3 to N1 of the triazoline, thereby allowing ring fragmentation and nitrogen expulsion.
Introduction
As part of a long-term goal to identify alternatives to osmium-
based methods for olefin aminohydroxylation,1 we recently
reported the conversion of electron deficient olefin 1 to â-amino
oxazolidine diones 2 using an electron-rich azide.2,3 The overall
reaction requires, and is therefore substantially accelerated by,
Brønsted acid (eq 1).4 The rate acceleration is consistent with
a mechanism in which the electron deficient olefin is activated
by Lewis acid complexation, thereby lowering the activation
barrier to reaction with the electron-rich (alkyl) azide. Azide-
olefin dipolar cycloadditions are often sluggish, but the desire
to use Lewis acid acceleration is typically compromised by the
strong, irreversible binding of azides to Lewis acids.5,6
development of the reaction’s scope with respect to the azide
and olefin components. Moreover, knowledge of the transition
state leading to formation of the first stereogenic carbon is a
prerequisite for rational design of an enantioselective variant.
In this first study of mechanism, we have successfully isolated
one pathway connecting 1 and 2 that clearly defines the ability
of acid to promote both [3+2] azide-olefin cycloaddition
(regioselectively) and subsequent decomposition of the triazo-
line, an intermediate and/or resting state, cleanly to oxazolidine
dione. Additionally, we haVe uncoVered a secondary accelera-
tion effect by molecular water in the triazoline ring opening
step.7
The overall reaction in eq 1 therefore stimulated our interest
in dissecting its mechanistic underpinning as a prelude to broader
(1) Li, G. G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35,
451. Andersson, M. A.; Epple, R.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 472. Muniz, K. Chem. Soc. ReV. 2004, 33, 166.
Donohoe, T. J.; Johnson, P. D.; Pye, R. J. Org. Biomol. Chem. 2003, 1,
2025. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkins Trans. 1 2002,
2733.
Results and Discussion
Our initial studies of olefin aziridination using triflic acid
were performed with commercial triflic acid and handling that
followed standard laboratory protocols. Additionally, these
reactions were initiated at -20 °C, but then allowed to warm
slowly to room temperature at the reaction’s end prior to quench
and purification. After some scrutinization of the reaction
variables, a new reaction product was observed, isolated, and
structurally characterized as triazoline 3. This intermediate could
be isolated as the sole product when the following constraints
(2) For examples of Lewis acid promoted azide-carbonyl reactions, see: (a)
Iyengar, R.; Schildknegt, K.; Morton, M.; Aube, J. J. Org. Chem. 2005,
70, 10645. (b) Zeng, Y. B.; Reddy, D. S.; Hirt, E.; Aube, J. Org. Lett.
2004, 6, 4993. (c) Hewlett, N. D.; Aube, J.; Radkiewicz-Poutsma, J. L. J.
Org. Chem. 2004, 69, 3439. (d) Katz, C. E.; Aube, J. J. Am. Chem. Soc.
2003, 125, 13948. (e) Reddy, D. S.; Judd, W. R.; Aube, J. Org. Lett. 2003,
5, 3899. (f) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.;
Milligan, G. L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226. (g) Rostami,
A.; Wang, Y.; Arif, A. M.; McDonald, R.; West, F. G. Org. Lett. 2007, 9,
703.
(3) For examples of the reaction of azides with carbenium ions, see: (a)
Pearson, W. H.; Fang, W. K. J. Org. Chem. 2001, 66, 6838. (b) Pearson,
W. H. J. Heterocycl. Chem. 1996, 33, 1489. (c) Pearson, W. H.; Fang, W.
K. J. Org. Chem. 1995, 60, 4960.
(4) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem. Soc. 2005,
127, 1354.
(7) For a recent demonstration of water catalysis in the gas phase, see:
Vohringer-Martinez, E.; Hansmann, B.; Hernandez, H.; Francisco, J. S.;
Troe, J.; Abel, B. Science 2007, 315, 497. Smith, I. Science 2007, 315,
470.
(5) Lewis acid-azide binding: Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.;
Fantauzzi, S.; Piangiolino, C. Coord. Chem. ReV. 2006, 250, 1234.
(6) L’Abbe, G. Chem. ReV. 1969, 69, 345.
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J. AM. CHEM. SOC. 2008, 130, 2323-2328
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A R T I C L E S
Hong et al.
Table 1. Effect of Added Water on the Product Distribution of
Triflic Acid Promoted Azide-Olefin Additions at Low Temperaturea
entry
X
2:3b
1c
2
0
0
95:5
5:95
3
4
5
10
100
200
71:29
90:10
95:5
a General conditions: BnN3 (1.5 equiv) and the olefin (1 equiv) in
CH3CN (0.33 M) were treated with triflic acid at -20 °C. The triflic acid
was first premixed with the indicated amount of water to create a stock
solution. b Measured by 1H NMR analysis of the crude reaction mixture
after reaction quench (Et3N, 2 equiv) at the reaction temperature and removal
of volatiles by high vacuum. c Reaction mixture was warmed to room-
temperature prior to quench.
Figure 1. Reaction course observed by in situ IR spectroscopy (thermal,
anhydrous variation).
Scheme 1. Triazoline Synthesis and Fragmentation Catalyzed by
Triflic Acid
were carefully followed: (1) the triflic acid was dried and
distilled (from Tf2O)8 prior to use, (2) transfer of the triflic acid
prevented absorption of ambient humidity, (3) the reaction
temperature was carefully maintained at -20 °C or below, and
(4) reaction quenching by anhydrous triethylamine was per-
formed at -20 °C.9 Following the reaction quench, the exclusion
of water was not as critical, but purification by flash chroma-
tography (SiO2) immediately followed with the removal of
volatiles in Vacuo as the only intervening step. This procedure
reproducibly furnishes the analytically pure triazoline 3 in 54%
yield.10
This behavior suggested that adventitious water promoted the
formation of 2, and this hypothesis was confirmed by several
experiments in which water was intentionally added to reactions
that otherwise followed the procedure outlined above (Table
1). We first verified our earlier observation that warming of
the reaction mixture, even with strictly anhydrous conditions,
produces the oxazolidine dione selectively (Table 1, entry 1)
To more accurately characterize the effect of water as an
additive, the mechanistic picture outlined in Scheme 1 was
hypothesized on the basis of the behavior described to this point
and in Table 1. We turned to in situ IR spectroscopy as a means
to monitor the reaction course across a series of procedural
changes. Two of the key experiments characterized spectro-
scopically are summarized in Figures 1-3.12
The first experiment focused on the findings that anhydrous
conditions lead to the formation of 2 when the reaction is
warmed to room temperature prior to quench, but that the
presence of water at -20 °C also allowed isolation of 2.
Complexation of imide 1 was evident from the shift of the
carbamate carbonyl from 1739 to 1788 cm-1 upon addition of
triflic acid to a cold (-20 °C) acetonitrile solution of 1 (Figure
1). Once benzyl azide is added, immediate movement of this
absorption to 1747 cm-1 was observed, and complete conversion
was achieved within a matter of minutes. Assignment of this
new species to triazoline salt 5 is consistent with absorptions
at 1711 cm-1 (amide CdO) and 1747 cm-1 (carbamate CdO).
1
as measured by H NMR of the crude reaction mixture after
reaction quench by the addition of dry triethylamine. The
protocol involving maintenance of the reaction and quench
(triethylamine) at -20 °C, however, provided solely triazoline
3 when no water is added to the reaction, and again using
anhydrous triflic acid (Table 1, entry 2). Increasing amounts of
added water provided a corresponding shift in the ratio toward
oxazolidine dione formation when reaction time was held
constant (Table 1, entries 3-5), and oxazolidine dione eventu-
ally became the sole product. Addition of water beyond the 200
mol % level ultimately led to complete hydrolysis of 1 without
production of either 2 or 3. This result highlighted the direct
correlation between water and a three-way balance of the
product distribution (triazoline, oxazolidine dione, and hydroly-
sis products).11
(8) Sagl, D. J.; Martin, J. C. J. Am. Chem. Soc. 1988, 110, 5827.
(9) In this discussion, quenching (anhydrous Et3N) temperature and reaction
temperature are always identical.
(10) Azide-olefin cycloadditions (thermal): Huisgen, R.; Szeimies, G.; Mobius,
L. Chem. Ber. 1966, 99, 475. Broeckx, W.; Overberg, N.; Samyn, C.; Smets,
G.; Labbe, G. Tetrahedron 1971, 27, 3527. Kadaba, P. K. J. Heterocycl.
Chem. 1976, 13, 1153.
(11) See the Supporting Information for the analogous series of experiments
with the crotonate derivative.
(12) A Mettler-Toledo iC-10 instrument was used for these studies. In situ IR
experiments for the following variations are provided in the Supporting
Information: (1) thermal conversion, (2) H2O16 catalyzed conversion, (3)
H2O18 catalyzed conversion, and (4) thermal conversion followed by H2O18
addition.
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Rate Acceleration of Triazolines by Brønsted Acid
A R T I C L E S
Scheme 2. Secondary Catalysis by Water: Characterization
Figure 2. Reaction course observed by in situ IR spectroscopy (water
additive variation).
was observed by IR.13 Neutralization of the reaction mixture
1
again led to observation of 2 by H NMR.
Figure 3 charts the decomposition of 5, and the formation of
2‚HOTf, as a function of time (a) when the temperature is raised
and (b) when water is added to initiate the conversion but the
temperature is maintained at -20 °C. Additional control
experiments confirmed that isolated triazoline behaved identi-
cally to that formed in situ (as in the experiments above), and
that water alone, without TfOH present, returned only unmodi-
fied triazoline even at room temperature. The role of water
therefore, is secondary to triflic acid which can catalyze the
conversion of 3f2 unassisted, if the proper amount of thermal
energy (above -20 °C) is supplied. Water alone is not a
competent catalyst, but the combination of triflic acid and water
will promote the conversion at -20 °C, clearly requiring less
thermal energy (Scheme 2).
The first steps in the triazoline decomposition14 (isomerization
of 5 to 6, and of 6 to 7) do not require consumption of water.
However, formation of 2 can occur by either cleavage of the
methyl-oxygen bond in 7 by SN2 attack of a nucleophile (e.g.,
CH3CN), or hydrolysis of 7 (leading to the production of
MeOH). Since oxazolidine dione 2‚TfOH was the next spec-
troscopically observed and isolated product from both anhydrous-
thermal and low temperature water catalyzed reactions, its
formation under these very different conditions from putative
intermediate salt 7 needed to be rectified. The operative
pathways were identified using three experiments and the use
of H218O.
Figure 3. Reaction course observed by monitoring oxazolidine dione 2‚
TfOH formation (1830 cm-1, in situ IR) from triazoline 5 using (a) thermal
or (b) water-catalyzed conditions.
The corresponding absorptions in triazoline 3 are 1704 and
1740 cm-1, respectively. Intermediate 5 is indefinitely stable
at -20 °C in solution, and triazoline 3 was isolated when this
reaction mixture was quenched with triethylamine. When the
low temperature bath was replaced with a 25 °C water bath, a
change in the IR spectrum occurs (Figure 1). The aforemen-
tioned peaks were replaced by new absorptions at 1830 and
1754 cm-1 over the course of several minutes. Visually, gas
evolution (N2) occurred when the reaction temperature was in
the 0-25 °C range (Figure 3a and Supporting Information,
movie A). Importantly, nitrogen evolution consistently paired
with the appearance of the 1830/1754 cm–1 IR absorptions. The
IR spectrum of the new species is consistent with product
2‚HOTf, which was converted to its free base in the crude
reaction mixture by triethylamine addition (examination by 1H
NMR).
The thermal procedure for decomposition of the intermediate
triazoline was applied, and H218O was added prior to the usual
quench. In this case, the spectrum of 2 (16O) was observed
(Figure 4a,c), as in the analogous case when H216O was used.
This behavior is consistent with nucleophilic cleavage of the
methyl-oxygen bond by acetonitrile solvent. Indeed, an absorp-
tion at 2418 cm-1 in this experiment (in situ IR) prior to reaction
quench is consistent with the formation of [CH3NCCH3]+.15
When the heavy isotope was used as the water additive at
In a separate experiment (Figure 2), the same conditions and
procedures were applied until the stability of 5 was again
apparent (Figure 3b, 0-10 min). Instead of warming the reaction
mixture at this point, one equivalent of water was added to the
reaction mixture ([H2O]max ) 0.4 mM). The changes in the IR
spectrum were both immediate and identical to those induced
by warming of the reaction mixture to room temperature
(Supporting Information, movie B). In most cases, the conver-
sion was complete within several minutes, and no further change
(13) Note that times and intensity in Figures 3 and 5 are relative to allow the
overlay of separate experiments.
(14) Smith, R. H.; Wladkowski, B. D.; Taylor, J. E.; Thompson, E. J.; Pruski,
B.; Klose, J. R.; Andrews, A. W.; Michejda, C. J. J. Org. Chem. 1993, 58,
2097. Hunig, S.; Schmitt, M. Liebigs Ann. 1996, 559. Schmiedekamp, A.;
Smith, R. H.; Michejda, C. J. J. Org. Chem. 1988, 53, 3433.
9
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A R T I C L E S
Hong et al.
Scheme 3. Isotope Labeling Experiments to Ascertain Role and
Fate of Water in Both Thermal and Water-Catalyzed Triazolinium
Fragmentations
CdO shifted from 1819 to 1799 cm-1, consistent with 8 (Figure
4c). The 13C for 8 also exhibits the characteristic isotope-induced
chemical shift for the carbamate oxygen, consistent with ∼66%
18O enrichment (Figure 4b).16 The transformations depicted in
Scheme 3 summarize this behavior in the context of mechanism
following the triazolinium fragmentation.
We propose two roles for water in this reaction. A full
equivalent is ultimately consumed in the hydrolysis of oxonium
intermediate 7. Additionally, the evidence suggests that water
accelerates the triazoline fragmentation, particularly by cata-
lyzing the preceding isomerization (a nonhydrolytic process).
The irreversible expulsion of nitrogen allows these two roles
to be deconvoluted since the visual evolution of N2 allows us
to pinpoint rate acceleration at the triazoline ring-opening step
(see movies A and B). Were this not the case, an alternate
explanation for the observed water effect would normally be
the existence of an equilibrium whose product is consumed by
water in a chemical reaction, thereby leading to the disappear-
ance of the monitored species through reconstitution of the
equilibrium. These observations are consistent with secondary
catalysis of the triazoline decomposition step by water.17 It is
also important to note that reactions to which water is added at
the beginning typically result in slower overall conversion of
1f2. Since the first step is Lewis acid catalyzed, this behavior
is consistent with hydronium’s lower Lewis acidity relative to
triflic acid. This character is clearly reversed in the second step
where the Lewis acidity of hydronium triflate and triflic acid
are unchanged, but their mobility is the determinant of rate.
Triazoline Stability and Additional Effects. Scheme 2
summarizes the behavior of the intermediate triazoline. The free
(16) 95% H218O (Aldrich) was used. Both HRMS and 13C NMR indicated
incorporation of 18O (ca. 65%: acetonitrile conversion of 7 to 2 is
competitive with hydrolysis of 7). See Supporting Information for complete
details. Isotope 13C induced shift: Risley, J. M.; Vanetten, R. I. J. Am.
Chem. Soc. 1979, 101, 252. Vederas, J. C. J. Am. Chem. Soc. 1980, 102,
374.
(17) For examples where added water modifies a catalyst, thereby adversely
affecting reactivity and/or selectivity, see the following reviews: (a) Ribe,
S.; Wipf, P. Chem. Commun. 2001, 940. (b) Lindstrom, U. M. Chem. ReV.
2002, 102, 2751. (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002,
35, 209. Selected examples: (d) Gao, Y.; Hanson, R. M.; Klunder, J. M.;
Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765. (e) Narasaka, K.; Tanaka, H.; Kanai, F. Bull. Chem. Soc. Jpn. 1991,
64, 387. (f) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990,
112, 3949. (g) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.;
Sodeoka, M. Org. Lett. 2004, 6, 1861. (h) Nyberg, A. I.; Usano, A.; Pihko,
P. M. Synlett 2004, 1891. (i) Maruoka, K.; Hoshino, Y.; Shirasaka, T.;
Yamamoto, H. Tetrahedron Lett. 1988, 29, 3967. (j) Tottie, L.; Baeckstrom,
P.; Moberg, C.; Tegenfeldt, J.; Heumann, A. J. Org. Chem. 1992, 57, 6579.
(k) Denmark, S. E.; Sweis, R. F. Org. Lett. 2002, 4, 3771. (l) Davis, F. A.;
Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833. (m) Xia, Y. Z.; Liang, Y.;
Chen, Y. Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y. H.; Yu, Z. X.
J. Am. Chem. Soc. 2007, 129, 3470.
Figure 4. Comparison of 2 (16O) respectively 8 (18O:16O ≈ 2:1), and
H218O-catalyzed experiments (Scheme 3). 13C NMR (125 MHz) spectra of
oxazolidine dione (a) 2 (16O) formed from thermal triazoline decomposition
(H218O quench), and (b) 8 formed by H218O-catalyzed triazoline decomposi-
tion at -20 °C; (c) IR of oxazolidine diones formed from the thermal
experiment and three variations, including H218O catalyzed triazoline
decomposition leading to 18O incorporation.
-20 °C, the IR of the oxazolidine dione that resulted was similar
to that observed when using H216O, but with the carbamate
(15) Booth, B. L.; Jibodu, K. O.; Proenca, M. F. J. Chem. Soc., Chem. Commun.
1980, 1151.
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A R T I C L E S
base is indefinitely stable to water in the absence of added
Brønsted acid. In our experience, the triazoline is also indefi-
nitely thermally stable up to temperatures of (at least) 100 °C.18
This behavior contrasts that of the triflic acid salt, which is
indefinitely stable at low temperature (-20 °C) when anhydrous,
but will convert concomitant with nitrogen evolution when
warmed to room temperature. These three behaviors indicate
that the triazoline stability is primarily controlled by the
polarization provided by Brønsted acid. However, the effect of
water further accelerates the rate of triazoline decomposition,
and this can be clearly quantified at -20 °C. The overall
transformation produces oxonium ion 7, which then consumes
one equivalent of water. Water is still a catalyst for the
triazolinium fragmentation, since the isomerization and cycliza-
tion steps do not consume water. The evolution of nitrogen
provides a corroborating indicator that fragmentation is catalyzed
under these conditions.19
Figure 5. Comparison of water catalyzed triazolinium fragmentations
(monitoring oxazolidine dione formation at 1830 cm-1) using (a) 1 equiv
and (b) 2 equiv of triflic acid (water added at 10 min).
It was not clear to us why the triazolinium intermediate might
exhibit this behavior, since its stability would need to be
rationalized by a reluctant proton transfer. Calculations have
determined N3-protonation can be favored over N1 by as much
as 10 kcal/mol, but N1 protonation is in equilibrium and leads
to irreversible triazoline decomposition in studies of the
triazoline-aziridine interconversion.14 The stability of 5a/b is
therefore surprising, particularly since a number of capable
proton carriers can be identified in the reaction mixture,
including a second triazolinium or simply the abundant aceto-
nitrile solvent. Proton “immobilization” is often perceived to
require the design of special Brønsted bases20,21 that bear no
resemblence to the intermediates at play here.
Water Catalysis. Water may specifically lower the barrier
to isomerization of 5b to 5c.14c,22 The stability of 5b may be a
general phenomenon of anhydrous triazoline salts or may be
due to a bidentate proton chelate.23 It is not possible to further
discriminate details of the isomerization process. For example,
the water molecule could shuttle the proton (as hydronium) from
N3 to N1 of the triazoline. Alternatively, it could competitively
bind to the carbamate system, allowing an agent such as solvent
to play the role of shuttle.24
Although the mechanism advanced in Scheme 1 suggests a
discrete diazonium ion 6, we cannot exclude the possibility that
this intermediate is bypassed by a single transition state in which
carbon-oxygen bond formation is concomitant with triazoline
fragmentation. The depressed rate of formation of oxazolidine
dione observed when using excess triflic acid is consistent with
this possibility as well.
The role of water in chemical transformations has been
studied under innumerable circumstances, leading to a broad
range of effects.17,19 In particular, scrutiny of the integrated
behavior of water, as both substrate and ancillary catalyst, in
the hydrolysis of ester derivatives has been studied in numerous
contexts as well, and with methods both experimental25 and
computational26 in nature. Furthermore, studies of proton-
transfer catalysis range from mechanistic27 to biochemical28
contexts and have been used as a basis to explain a wide range
of phenomena. The case described here is unique to our
knowledge in that water catalyzes a nonhydrolytic step in a
nonaqueous solvent. The circumstances allow a clear demon-
A final test of this reasoning was made by monitoring the
water catalysis phenomenon under conditions of excess triflic
acid. If protonation at N3 is nonlabile and electronically
stabilizes the triazoline toward N1-N2 fragmentation, then
excess triflic acid would not be expected to overcome this effect;
although protonation at N1 might be possible (to form the
doubly protonated triazoline), protonation at N3 would prevent
proper polarization for N1-N2 fragmentation. Furthermore,
addition of water to the bis(salt) would enhance proton mobility,
but oxazolidine dione formation might be slower because of
protonation of the carbamate oxygen in the cyclization step or
because of slower triazoline fragmentation (via formation of
monosalt 5c from a bis(salt). Both of these predictions were
confirmed by experiment (Figure 5). The triazoline was
indefinitely stable toward two equivalents of triflic acid at
-20 °C in the absence of water. And addition of water promoted
triazoline fragmentation again, but oxazolidine dione formation
was markedly slower (Figure 5b) than the rate observed with a
single equivalent of triflic acid (Figure 5a).
(22) Krishtalik, L. I. Biochem. Biophys. Acta 2000, 1458, 6.
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A. J.; Rosenberg, A. Biochemistry 1983, 22, 910.
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secondary catalysis described here, for example: Hayashi, Y. Angew.
Chem., Int. Ed. 2006, 45, 8103. Kjaer, A. M.; Sorensen, P. E.; Ulstrup, J.
J. Chem. Soc., Perkins Trans. 2 1978, 51. Pirrung, M. C.; Das Sarma, K.
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A R T I C L E S
Hong et al.
stration of the interplay between Brønsted acid and water on
both cycloaddition and triazoline fragmentation steps.
excess water can lead to hydrolysis of the imide. A con-
clusion from this study is a cautionary one in that the feasi-
bility of a proton-catalyzed process cannot be established (or
studied) by protonation state alone but must also include charged
ligands (the counterion) and perhaps neutral ligands such as
water.
Conclusion
In summary, we have identified the intervening steps in the
Brønsted acid-catalyzed conversion of olefin 1 to oxazolidine
dione 2. Significant rate acceleration is provided by triflic acid
to the azide-olefin addition step, leading to an intermediate
triazoline under anhydrous conditions that has been characterized
by in situ IR spectroscopy.29 Triazoline‚HOTf (5a/b) is, at a
minimum, a resting state along this pathway, and its stability is
significantly altered by the presence of water. Our current
hypothesis is that the isomerization of triazoline to oxazolidine
dione requires protonation of N1, and that bidentate complex
5b is favored under anhydrous conditions at low temperature
(-20 °C).
We have further characterized the effect of water on
the triazolinium stability in which it works in concert with
triflic acid at low temperature to promote triazoline frag-
mentation in a nonhydrolytic step. There is a balance to be
observed, however, in the overall conversion: triazoline forma-
tion is most rapid with conditions of high Lewis acidity and
anhydrous TfOH, whereas triazoline fragmentation is most
rapid with a single equivalent of TfOH and water. Furthermore,
excess triflic acid retards triazoline fragmentation, and
This work provides an experimental basis for the discovery
and characterization of other organic reactions in which water
might play the role of a secondary catalyst in the condensed
phase,7 and may help to explain similar phenomena involving
hydrogen bond acceptors. Regardless, these findings comple-
ment the classic examples of Alder20 and Lehn21 in which unique
ligands were developed to immobilize the proton by tight
binding.
Acknowledgment. This work was supported by the NSF
(Grant CHE 0415811) and through the generosity of the Eli
Lilly Grantee program. The iC-10 IR instrument was purchased
with funds from the VICB. We thank Prof. Gary Sulikowski
for suggesting the use of H2O18. This paper is dedicated to
Professor David Hart on the occasion of his 60th birthday.
Supporting Information Available: Preparation, analytical
data, and spectra for all new compounds; full data sets for the
experiments described; movies corresponding to experiments
in Figures 1-3 at the point of nitrogen evolution.
(29) Azide-olefin cycloaddition solvent effects: Kadaba, P. K. Tetrahedron 1969,
25, 3053. Kadaba, P. K. Tetrahedron 1966, 22, 2453.
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2328 J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008