The mechanism of the reaction between an aziridine and carbon dioxide with no added catalyst

Article abstract of DOI:10.1002/poc.3735

The mechanism of the reaction at room temperature between an unactivated 2-alkyl aziridine and carbon dioxide to generate the corresponding oxazolidinone in glass has been studied. Theoretical calculations suggest that this reaction should not proceed at room temperature in the absence of a catalyst. In cases where a reaction was observed, kinetic studies show that the reaction displays a zero-order dependence with respect to aziridine, indicating that free aziridine is not involved in the rate-determining step. An ammonium salt generated in situ acts as a catalyst. The amount of this catalyst is diminutive, which prevented spectroscopic identification, and it is not readily removed from the starting material using chromatography.

Full text of DOI:10.1002/poc.3735

Received: 27 April 2017
DOI: 10.1002/poc.3735
Revised: 2 June 2017
Accepted: 5 June 2017
R E S E A R C H A R T I C L E
The mechanism of the reaction between an aziridine and carbon
dioxide with no added catalyst
Chau Phung1 | Dean J. Tantillo2 | Jason E. Hein3 | Allan R. Pinhas1
1 Department of Chemistry, University of
Abstract
Cincinnati, Cincinnati, OH, USA
The mechanism of the reaction at room temperature between an unactivated 2‐alkyl
aziridine and carbon dioxide to generate the corresponding oxazolidinone in glass
has been studied. Theoretical calculations suggest that this reaction should not pro-
ceed at room temperature in the absence of a catalyst. In cases where a reaction was
observed, kinetic studies show that the reaction displays a zero‐order dependence
with respect to aziridine, indicating that free aziridine is not involved in the rate‐
determining step. An ammonium salt generated in situ acts as a catalyst. The amount
of this catalyst is diminutive, which prevented spectroscopic identification, and it is
not readily removed from the starting material using chromatography.
2 Department of Chemistry, University of
California‐Davis, Davis, CA, USA
3 Department of Chemistry, University of
British Columbia, Vancouver, British
Columbia, Canada
Correspondence
Allan R. Pinhas, Department of Chemistry,
University of Cincinnati, Cincinnati, OH,
USA
Email: djtantillo@ucdavis.edu; jhein@chem.
ubc.ca; allan.pinhas@uc.edu
KEYWORDS
aziridine, calculations, carbon dioxide, catalysis, kinetics
1 | INTRODUCTION
(Scheme 1, R = PhCH2 and alkyl = CH3) with CO2 (3 atm)
gave oxazolidinones 2 + 3, albeit in very low yield. Because
According to recent reviews, in comparison to activated
aziridines, few papers have been published on the chemistry of
readily available unactivated N‐alkyl aziridines.[1] One reaction
of an N‐alkyl aziridine is the insertion of carbon dioxide into a
C–N bond to generate an oxazolidinone, which is an important
class of compounds used as chiral auxiliaries, as metal ligands,
and as pharmaceuticals (specifically as antibiotics).[2–4]
Although carbon dioxide is abundant, renewable, nonflamma-
ble, and inexpensive, due to its stability,[5,6] using this resource
as a synthetic feedstock typically requires difficult to synthesize
catalysts, high pressures (typically over 100 atm), and/or high
temperatures (typically over 100°C).[7–10] In addition, most of
these reactions only work with mono‐aryl substituted aziridines,
such as 4, and fail with alkyl‐substituted compounds, such as 1.
For the past several years, we have been investigating the
reactions shown in Scheme 1 in which both alkyl‐ and aryl‐
substituted unactivated aziridines (1 and 4) are converted to
the corresponding oxazolidinones at low pressure and tempera-
ture using a salt, such as LiI or NH4I, as a catalyst in THF.[11–14]
When a control experiment using no catalyst in THF was
allowed to go for an extended period (12 vs 4 h or less when a
salt is used) at room temperature, the reaction of compound 1
the aziridine is an oil and CO2 is a gas, the reaction was
attempted with no solvent. When aziridine 1 was stirred, with
no catalyst or solvent, under a CO2 pressure of 3 atm for
12 hours, the yield of oxazolidinones 2 + 3 increased to
37% from the 7% in THF. Increasing the applied pressure
of CO2 to 4 atm did not have a significant impact on the
observed yield, giving products 2 + 3 in approximately
40%. Under all conditions, compound 2 is the major isomer,
typically being formed with a product ratio of about 13:1. At
approximately the same time, it was reported in the literature
that N‐alkyl‐2‐aryl aziridines (4) will generate the corre-
sponding oxazolidinone (5) with no catalyst at high tempera-
ture and pressure.[15] These results led to an effort to discover
the mechanism of the conversion of an aziridine with CO2
into an oxazolidinone using no catalyst.
2 | RESULTS AND DISCUSSION
2.1 | Possible mechanisms
On the basis of literature precedent, we initially proposed
two possible mechanisms for these transformations, both
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PHUNG ET AL.
2.2 | Attempted trapping of intermediates
The trapping of any reaction intermediate by a dipolarophile
was next attempted. When dimethyl acetylenedicarboxylate
(DMAD) was added to the reaction mixture, no intermediate
was trapped. Instead, a dark intractable material was gener-
ated. This same material formed either when subjecting the
reaction to carbon dioxide or not. None of the oxazolidinone
was observed. Adding THF to dilute the solution and cooling
the reaction under ice did not help avoid the formation of the
intractable material. Another dipolarophile, ethyl
cyanoformate, was tested, and it also did not react with any
intermediate. The reaction proceeded as if no trapping
reagent was added.
To determine if the reaction between 1 and CO2 proceeds
by a polar mechanism or by a radical mechanism, one equiva-
lent of the radical trap 1,4‐cyclohexadiene was added to
aziridine 1. The reaction gave the exact same mixture of
2 + 3. Next 4 equivalents of 1,4‐cyclohexadiene were added
to the reaction of 1 and CO2. Over 30% of aziridine 1 was con-
verted to oxazolidiones 2 + 3 after 2 days. Thus, it is not likely
the reaction of 1 and CO2 follows a radical mechanism.
SCHEME
oxazolidinone
1
Conversion of an unactivated aziridine to an
involving an initial nucleophilic capture of CO2 by the
aziridine lone pair, giving acyl‐intermediate 6. The proposed
mechanisms then differ because of a different nucleophile
used for subsequent steps. One mechanism involves a varia-
tion of the mechanism proposed for the high‐temperature–
no‐catalyst reaction,[15] in which a second acyl‐aziridine 6
adds via nucleophilic attack of the carboxylate group (blue
arrows). The other is a variation of the mechanism proposed
in a recent study using an amino acid as the catalyst for the
aziridine to oxazolidinone conversion,[10] in which addition
of a second aziridine 1 occurs via the nitrogen lone pair
(red arrows). These proposed mechanisms are shown in
Scheme 2 for prototypical compound 1.
We did not consider the unimolecular reaction mecha-
nism in which the carboxylate in compound 6 attacks the 3‐
position to give compound 2 directly. For any unimolecular
cyclization to occur, the orbitals of the nucleophile and of
the electrophile must properly align. The molecular require-
ments for this type of alignment are illustrated by Baldwin's
Rules for ring closure.[16,17] This reaction would be classified
as 5‐endo‐tet, which is disfavored because of lack of proper
orbital overlap.
2.3 | Computational study
The lack of trapping could result from the absence of interme-
diates, ie, a concerted reaction, or intermediates with very short
lifetimes. Computational quantum chemistry was used to assess
the feasibility of these scenarios. Geometry optimizations and
frequency calculations were performed at the B3LYP/6‐
31 + G(d,p) level of theory[18–22] using the Gaussian09 soft-
ware suite.[23] Intrinsic reaction coordinate calculations were
used to confirm the connectivity of transition state structures
and minima on the potential energy surface.[24–27] Preliminary
calculations performed in the gas phase are described below.
1,2‐Dimethylaziridine was used for simplicity.
Without the benefit of polar solvent molecules, adduct 6
could not be located. Instead, a complex between 1 and
CO2 was found (Figure 1). This complex can rearrange
through a concerted (2 + 2) cycloaddition for which the
two bond‐forming events occur very asynchronously. The
free energy barrier for this process is predicted to be quite
large, approximately 50 kcal/mol, suggesting that it will not
occur in nonpolar environments. This reaction also has some
characteristics of a pseudopericyclic reaction,[28,29] ie, the
sigma bond and the orthogonal N lone pair are both involved.
A stepwise mechanism in which a second molecule of
aziridine attacks in the same step as CO2 addition was also
examined (6 + 1 giving 7 in Scheme 2), but this pathway also
has a high‐predicted free energy barrier, 43 kcal/mol (see
Supporting Information for details). In short, our computa-
tional results are not consistent with the observed reaction
occurring in nonpolar environments. While additional
SCHEME 2 Initially proposed mechanism for the conversion of 1 to 2

PHUNG ET AL.
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pressure, and thus, the concentration of CO2 constant, any
driving force due to CO2 will be incorporated into the rate
constant k. Therefore, we will be measuring the intrinsic driv-
ing force of the aziridine.[31,32]
The concentration of aziridine 1 and products 2 + 3 were
monitored by GC‐MS with hexamethylbenzene used as an
internal standard (the concentration data are shown in the
Tables S1‐S3). Interestingly, the reaction profile shows that
the rate of product formation and the rate of aziridine
consumption are constant for the entire process. Thus, the
reaction displays no sensitivity to the concentration of
compound 1 (see Figures S3‐S14).
Running the experiment in triplicate illustrated that the
rate of conversion to the oxazolidinone is very reproducible
for this particular batch of aziridine (Figures 2 and 3). In
addition, the concentration of product matched the quantity
expected by the measured quantity of aziridine 1 consumed.
This confirms that the reactions display excellent mass
balance with nearly all consumed aziridine being transformed
to product (Figure 4).
FIGURE 1 Stationary points involved in concerted addition of CO2
to 1,2‐dimethylaziridine. Selected distances are shown in Å, and
relative energies are shown in kcal/mol. Note that the free energy barrier
in dichlormethane (SMD‐B3LYP/6‐31 + G(d,p)) is predicted to be
33 kcal/mol
calculations that treat solvent effects can be pursued, our
subsequent experiments (vide infra) suggest that a simple
solvent effect is not responsible for the observed reactivity.
2.4 | Experiments with different solvents
To provide insights into whether or not the reactions involve
polar transition state structures, reactivity in different
solvents was examined. When aziridine 1 was subjected to
4 atm CO2 at room temperature for 24 hours in different
solvents, the results shown in Table 1 were obtained. The
trend of the yield is consistent with the polarity/dielectric
consstant of the solvents.[30] These results suggest that the
reaction does indeed involve a rate‐determining transition
state structure that is more polar than the reactants.
FIGURE 2 Overlaid plot of aziridine 1 concentrations vs time from
experiments 1‐3
2.5 | Kinetic study
To determine if the reaction follows the proposed stepwise
mechanism, a determination of the rate law of the reaction
with respect to aziridine concentration was attempted. All
reactions were run in a thick‐walled glass bottle and held at
4 atm pressure through a connection to a CO2 tank. While
we anticipate that the mechanism does display an intrinsic
dependence on the partial pressure of CO2, by holding the
TABLE 1 The effect of solvent polarity on the yield of the reaction of
1 and carbon dioxide (4 atm)
Pentane Toluene Ether THF CH2Cl2
Dielectric constant
1.84
2.38
6
4.27 7.52
18
9.08
32
FIGURE 3 Overlaid plot of products 2 + 3 concentrations vs time
from experiments 1‐3
Oxazolidinones yield, % Trace
7

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PHUNG ET AL.
cases any trace impurity accounts for much less than 1 % of
the starting material (Figure S17).
Additional batches of aziridine 1 were synthesized to
determine, if in any of them, the amount of impurities was
large enough to be observed spectroscopically. However, no
impurity could be observed. All of these batches reacted with
CO2 in the presence of a salt catalyst, but in the absence of an
added salt, many of these batches, even before purification,
did not react with CO2. The addition of 0.1 mL of water
did not affect the reactivity, ie, those batches that reacted still
reacted and those batches that did not react still did not react
in the absence of an added salt catalyst.
It was suspected that the NH4Cl used in the work‐up step
may catalyze the reaction. Reactive aziridine 1 was therefore
washed with a large amount of water (3 × 25 mL water to
wash 25‐mL ether) to eliminate the salt. However, reactive
1 still gave nearly quantitative conversion after reacting with
CO2 for 24 hours.
FIGURE 4 Overlaid plot of concentrations of products 2 + 3 from
direct measurement and concentration of products 2 + 3 calculated
from the fractional concentration of 1 from experiments 2 and 3 (from
the data in Tables S2 and S3)
To determine if the pH caused an unreactive aziridine to
react and because NaOH is a stabilizer in the n‐BuLi, to a
reaction of 1 and CO2 was added a 0.1 mL of NaOH solution
or 0.1 mL of H2SO4 solution. Changing the pH also did not
promote the reaction. (This result is consistent with our pre-
vious study,[13] in which adding trifluoroacetic acid had no
effect on the rate of the reaction.)
The byproduct of the SN2 reaction in the synthesis of
aziridine 1 is LiBr. It is known that alkali halide salts catalyze
the reaction of an aziridine and carbon dioxide,[12,13] and so
it could be the amount of any residual LiBr that has caused
the reaction of 1 and CO2 to be inconsistent. To determine
the amount of LiBr as an impurity in “reactive” and in
“unreactive” aziridine 1, as shown in Table 2, ICP‐MS was
used to measure the concentration of lithium and bromide ions.
There is no correlation between the concentration of
lithium and the reactivity of aziridine 1. Sample 2 has less
Li+ than sample 3, but sample 2 is “reactive” whereas sample
3 is “unreactive.” Therefore, Li+ is not a catalyst for the reac-
tion. In contrast, there is a trend in the amount of bromide and
the reactivity of aziridine 1. In addition, note that the amount
of bromide is much larger than the amount of lithium, so
there is another source of Br‐ in addition to LiBr.
2.6 | Batches of aziridine 1 that did not react
1‐Benzyl‐2‐methyl aziridine 1 is readily synthesized from 2‐
methylaziridine (90% pure) and butyllithium (1.6M in
hexanes) to generate the aziridine anion followed by an SN2
reaction with benzyl bromide (98% pure). For the work‐up,
the reaction mixture was washed several times with aqueous
NH4Cl and then dried with anhydrous K2CO3. It was discov-
ered while performing the kinetic studies that some batches of
newly synthesized aziridine 1 did not give any oxazolidinone
product while others worked perfectly. For all the kinetics
studies in the previous section, several reactive batches of
aziridine 1 were combined to make a large reactive batch.
To determine if the purification somehow destroyed the
reactive aziridine, one batch of 1 was synthesized and
purified by silica gel chromatography using a 7:3 ratio of
hexane : EtOAc as eluents. The purified aziridine 1 did not
react with carbon dioxide even after 40 hours. A possibility
is that the column chromatography may have done something
to the aziridine and transformed it into an “unreactive
aziridine.” An NH4I catalyst[13] was then added to this reac-
tion of aziridine 1 and CO2, and an almost quantitative yield
of a mixture of oxazolidinones 2 + 3 was obtained. There-
fore, this aziridine is not “spoiled” by the column.
To further investigate the reaction, a 50/50 mixture of a
reactive batch of 1 and an unreactive batch of 1 was made.
Another possibility is an impurity in the starting material
catalyzes the CO2 insertion reaction. It is possible that when a
sample of aziridine 1 is purified this catalyst is eliminated and
the reaction does not work anymore. Another batch of
aziridine was synthesized, purified, and subjected to reaction
with carbon dioxide. However, in contrast to the previous
case, this time the clean aziridine was still reactive with car-
bon dioxide. The NMR spectra of both purified aziridines
were compared, and there are no differences (Figures S15
and S16). In addition, GC‐MS and HPLC showed in both
TABLE 2 Lithium and bromide concentrations in different samples
of aziridine 1
Aziridine
1 + CO2
Reaction
Concentration
of Li+,
mmoles/L
Concentration
of Br−,
mmoles/L
Sample 1
Sample 2
Sample 3
Sample 4
Active
12.5
0.40
0.69
0.49
413
138
44
Active
Inactive
Inactive
82

PHUNG ET AL.
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There are 3 possible outcomes from the reaction of this mix-
ture with CO2. If the product mixture consists of 50%
oxazolinone and 50% aziridine, then there is something
wrong with one batch of 1 and it does not show up spectro-
scopically. If the product mixture is 100% aziridine 1, then
there is something that inhibits the reaction. If the product
mixture is 100% oxazolidinones 2 + 3, then it supports the
idea that there is a catalyst in some batches of aziridine that
makes them reactive. When this catalyst is absent, the reac-
tion does not work. The experimental result is that 100% of
aziridine 1 converts to the oxazolidinones; however, the reac-
tion took about twice as longer time to go to completion in
comparison to the original reactive aziridine 1.
To determine if the catalyst is stable after the reaction, the
oxazolidinone product was mixed with “unreactive” aziridine
1, and then subjected to CO2. All of the aziridine converted to
oxazolidinones, and thus, the catalyst persists after the reac-
tion and stays reactive.
Until now, benzyl bromide (BnBr) was not considered as
a catalyst or catalyst precursor because it has never been
suggested in the literature that an alkyl halide can act as the
catalyst or the precursor to the catalyst for the reaction of
an aziridine with CO2. In addition, NMR spectroscopy,
HPLC, and GC‐MS show that our starting aziridine is clean
and contains no benzyl bromide. However, the possibility
that BnBr reacts with aziridine 1 to give ring‐opened amine
9 has not been ruled out (Scheme 3). An ammonium salt
has been shown to be a good catalyst for the reaction of
aziridine 1 with CO2. If compound 9 picks up a proton either
in the work‐up or by deprotonating another molecule of 9 in
an E2 reaction, then an ammonium salt can be generated.
To obtain proof for this hypothetical catalyst, a synthesis
of aziridine 1 using two equivalents of BnBr was set up. Then,
this newly synthesized aziridine
1 was mixed with
“unreactive” aziridine 1 and subjected to CO2. All the starting
material converted to products 2 + 3 after 12 hours. (Twelve
hours is the time that the reaction of aziridine 1 with CO2
and less than 1% of an ammonium salt is known to take.[13]
)
In an even more conclusive experiment, a catalytic
amount of BnBr was added to “unreactive” aziridine 1 and
then subjected to CO2. After 12 hours, all of the starting
material converted to oxazolidinones 2 + 3. The BnBr was
not observed in the NMR spectrum of the product (see
Figures S18 and S19).
This reaction mixture was then injected into a high‐
resolution FT‐mass spectrometer with electrospray ionization.
As can be seen in Figure S20, peaks with a molecular formula
consistent with compound 9 and consistent with the alkene
from the E2 reaction discussed above were observed.
Therefore, we believe that compound 9 and/or corresponding
alkene catalyzes the conversion of aziridine
1
to
oxazolidinones 2 + 3.
On the basis of the proposed catalyst, the mechanism for
the reaction using ammonium halide salts as the catalyst, and
the fact that an amine is about 20 times more basic than an
aziridine,[13] two possible mechanisms for oxazolidinone for-
mation are proposed (Schemes 4 and 5).
In the first step in Scheme 4, aziridine 1 forms a hydrogen
bonding with the catalyst to give complex 11. A nucleophilic
halide opens the aziridine ring to give intermediate 12. A
carbon dioxide adds to give intermediate 13. Finally, product
2 is formed by ring closure. Alternatively, as shown in
SCHEME 3 Reaction of 1 with benzyl bromide
SCHEME 4 Possible mechanism for the
conversion of 1 to 2

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PHUNG ET AL.
SCHEME 5 Second possible mechanism
for the conversion of 1 to 2
Scheme 5, complex 11 could add carbon dioxide first to give
intermediate 14. The halide then opens the ring to give inter-
mediate 13, and the cycle continues as in Scheme 4.
Both of the proposed mechanisms fit the observation that
the reaction proceeds faster in the more polar solvents
because all of the intermediates are charged species. The
observed zero order with respect to aziridine 1 suggests that
the rate controlling step does not involve the isolated
aziridine. Instead, it is likely that we are observing saturation
kinetics with the addition of CO2 being the rate limiting step.
In either possible mechanism, the large excess of carbon
dioxide, held at constant pressure, masks any driving force
that it may exert. This result does not allow us to distinguish
between the two possible pathways involving either initial
capture of CO2 or ring opening by X− from the catalyst
(Schemes 4 or 5).
ACKNOWLEDGEMENTS
The authors thank Ms Anna Donnell for performing the
ICP‐MS experiment and Mr Matthew Mower for his input
on the project.
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[33] The reviewers asked the question about whether our findings also
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Thus, an even smaller amount of any catalyst would probably be
needed for a 2‐aryl aziridine reaction.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in
the supporting information tab for this article.
How to cite this article: Phung C, Tantillo DJ, Hein
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an aziridine and carbon dioxide with no added catalyst.
J Phys Org Chem. 2017;e3735. https://doi.org/
10.1002/poc.3735
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