Can transacylation reactions occur via SN2 pathways in the gas phase? Insights via ion-molecule reactions of N-acylpyridinium ions and ab initio calculations

Article abstract of DOI:10.1021/ol006060r

(equation presented) The gas-phase identity exchange reactions of N-acylpyridinium ions with pyridine have been examined experimentally in an ion trap mass spectrometer through the use of isotope labeling experiments. The nature of the acyl group plays a crucial role, with the bimolecular rates following the order acetyl > benzoyl > N,N-dimethylaminocarbamyl. The experimental results correlate with ab initio calculations on the simple model system RC(O)NH₃⁺ + NH₃, which also demonstrates that these are S_N2 like processes.

Full text of DOI:10.1021/ol006060r

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2567-2570
Can Transacylation Reactions Occur via
SN2 Pathways in the Gas Phase?
Insights via Ion−Molecule Reactions of
N-Acylpyridinium Ions and ab Initio
Calculations
Richard A. J. O’Hair* and N. K. Androutsopoulos
School of Chemistry, The UniVersity of Melbourne, ParkVille, Victoria 3010, Australia
r.ohair@chemistry.unimelb.edu.au
Received May 14, 2000
ABSTRACT
The gas-phase identity exchange reactions of N-acylpyridinium ions with pyridine have been examined experimentally in an ion trap mass
spectrometer through the use of isotope labeling experiments. The nature of the acyl group plays a crucial role, with the bimolecular rates
following the order acetyl > benzoyl > N,N-dimethylaminocarbamyl. The experimental results correlate with ab initio calculations on the simple
model system RC(O)NH + + NH , which also demonstrates that these are “SN2 like” processes.
3
3
Transacylation reactions play important roles in solution-
phase organic and bioorganic chemistry and can proceed
intramolecularly or intermolecularly.1 There has been con-
tinuing interest in the mechanisms of these reactions which
can range from dissociative (i.e., “SN1 like”) to “associative”
mechanisms. The gas phase is an ideal environment to study
intrinsic reactivity in the absence of solvent and counterion
effects, and several studies have examined bimolecular
reactions between nucleophiles and acylating agents.2 Of
these, the reactions between anionic nucleophiles and neutral
acylating agents3 have received more attention than those
between neutral nucleophiles and cationic acylating reagents.4
For the former class of reactions, it is difficult to experi-
mentally distinguish between mechanisms where the tetra-
hedral species is an intermediate versus those in which it is
a transition state (i.e., “SN2 like”). Indeed, recent ab initio
calculations on reactions between halide ions and acyl halides
(RC(O)X) indicate that the potential energy profiles can vary
from double wells (where the tetrahedral species is a
transition state which is separated by pre and post complexes)
to triple wells (where the tetrahedral species is an intermedi-
ate) depending upon the nature of the nucleophile, nucle-
ofuge, and acyl group.5
Determining the mechanisms of reactions between neutral
nucleophiles and protonated acylating reagents involves a
different challenge, namely “pinning down” the site of
protonation and how this effects the mode of reactivity.4 In
the gas phase, where solvent molecules cannot mediate
(1) For reviews and detailed discussions of the mechanisms of acylation
reactions in solution, see: (a) Satchell, D. P. N.; Satchell, R. S. In
Supplement B: The Chemistry of Acid DeriVatiVes; Patai, S., Ed.; Wiley:
New York, 1992; Volume 2, Chapter 13. (b) Page, M.; Williams, A. Organic
and Bioorganic Mechanisms; Longman: Harlow, 1997; pp 145-152.
(2) For a review, see: Riveros, J. M.; Jose, S. M.; Takashima, K. AdV.
Phys. Org. Chem. 1985, 21, 197.
(3) (a) Zhong, M.; Brauman, J. I.. J. Am. Chem. Soc. 1999, 121, 2508.
(b) Asubiojo, O. I.; Brauman, J. I. J. Am. Chem. Soc. 1979, 101, 3175. (c)
Van Doren, J. M.; DePuy, C. H.; Bierbaum, V. M. J. Phys. Chem. 1989,
93, 2508. (d) Fink, B. T.; Hadad, C. M. J. Chem. Soc., Perkin Trans. 2
1999, 2397.
(4) (a) Kim, J. K.; Caserio, M. C. J. Am. Chem. Soc. 1981, 103, 2124.
(b) Kim, J. K.; Caserio, M. C. In Nucleophilicity, ACS Monograph 215;
American Chemical Society: Washington, DC, 1987; Chapter 5.
(5) (a) Kim, C. K.; Li, H. G.; Lee, H. W.; Sohn, C. K.; Chun, Y. I.; Lee,
I. J. Phys. Chem. A 2000, 104, 4069. (b) Lee, I.; Lee, D.; Kim, C. K. J.
Phys. Chem. A 1997, 101, 879.
10.1021/ol006060r CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

proton transfer reactions, the thermodynamically favored site
of protonation (e.g., O-protonated amide) may not be
kinetically favored in terms of transacylation, since a high-
energy 1,3 proton transfer is required in order for the
tetrahedral intermediate A to decompose to products (Path
A, Scheme 1). Indeed, ab initio calculations reveal this to
and nucleofuge are the same (i.e., an identity exchange
reaction), then the intrinsic barrier will be unperturbed by
differences in their nucleophilicity.9 While gas-phase kinetic
studies have been carried out for identity exchange transcy-
lation reactions between 37Cl- and acyl chlorides,3a-c none
have been reported for positively charged systems. This has
prompted us to report our results on the reactions shown in
eq 1 both experimentally (X ) C5H5N or C5D5N; Y ) C5D5N
or C5H5N) and theoretically (X ) Y ) NH3) for the acyl
systems R ) Me, Ph, and Me2N.
Scheme 1
Electrospray ionization using dry acetonitrile as the solvent
affords the desired N-acylpyridinium ions, which are readily
mass selected in the ion trap mass spectrometer.10 An
important observation is that these ions are extremely stable
in the gas phase and can be trapped in the mass spectrometer
for up to 10 s without any losses due to decompositions (e.g.,
via “SN1 like” pathways). In fact, cleavage of the acyl-
pyridinium bond to give acyl cations (in the cases of the
N-benzoyl and N,N-dimethylaminocarbamyl systems) or
protonated pyridine (for the acetyl case) can only be induced
via collisional activation.
Introduction of a reactive neutral into the mass spectrom-
eter allows the gas-phase bimolecular reactivity of mass-
selected N-acylpyridinium ions to be probed. We have
examined six different identity exchange systems of reaction
1: (a) [MeC(O)NC5H5]+ + NC5D5; (b) [MeC(O)NC5D5]+
+ NC5H5; (c) [PhC(O)NC5H5]+ + NC5D5; (d) [PhC(O)-
NC5D5]+ + NC5H5; (e) [Me2NC(O)NC5H5]+ + NC5D5; (f)
[Me2NC(O)NC5D5]+ + NC5H5. Reaction 1 was observed for
systems a-d as the sole reaction channel.11 Systems e and
f yield no new products, suggesting that these acylpyridinium
ions are unreactive toward pyridine under our experimental
conditions.
be the case for the hydrolysis of protonated formamide, in
which transacylation via a double well “SN2” pathway
(transition state B in Path B, Scheme 1) is preferred.6 One
way of overcoming the site of protonation issue which has
been exploited in solution is through the use of fixed charged
derivatives such as N-acylpyridinium salts.7 We were thus
intrigued by a recent report in which the transacylation
reaction of C did not occur (Scheme 2) in the gas phase.8 If
To quantify the order of reactivity, we have examined the
rates of systems b and d. The pyridine concentration in the
ion trap was maintained at a constant pressure, and both rates
were measured followed by a rate measurement of a known
proton-transfer reaction involving pyridine (eq 2).12 Since
Scheme 2
the rate constant for reaction 2 is known, the rates of 1b and
1d were converted to rate constants, thereby allowing their
efficiencies to be compared. Each of the experimental rate
measurements, the derived rate constants and reaction
efficiencies are given in Table 1. The reaction efficiency (RE)
shows dependence on the nature of the acyl group (RC(O)),
(9) DePuy, C. H.; Gronert, S.; Mullin, A.; Bierbaum, V. M. J. Am. Chem.
Soc. 1990, 112, 8560.
such reactions do proceed via “SN2 like” pathways, then a
likely explanation is that the energy of the transition state is
above that of separated reactants. Provided the nucleophile
(10) The N-acylpyridinium salts were prepared by a literature procedure
(King, J. A., Jr.; Bryant, G. L., Jr. J. Org. Chem. 1992, 57, 5136) and were
used immediately without further purification. Ion-molecule reactions were
carried out using a LCQ mass spectrometer which was modified to allow
the introduction of neutral reagents through the end cap of the quadrupole
ion trap. The neutrals were introduced through a leak valve.
(11) We find no evidence for the bimolecular elimination of ketene from
the acetyl systems a and b.
(6) Krug, J. P.; Popelier, P. L. A.; Bader, R. F. W. J. Phys. Chem. 1992,
96, 7604.
(7) For a review, see: Sheinkman, A. K.: Suminov, S. I.; Kost, A. N.
Russ. Chem. ReV. 1973, 42, 642.
(8) Katrizky, A. R.; Burton, R. D.; Shipkova, P. A.; Qi, M.; Watson, C.
H.; Eyler, J. R. J. Chem. Soc., Perkin Trans. 2 1998, 835.
(12) Aue, D. H.; Bowers, M. T. In Gas-Phase Ion Chemistry; Bowers,
M. T., Ed.; Academic Press: New York, 1979; Volume 2, Chapter 9, p 11.
2568
Org. Lett., Vol. 2, No. 17, 2000

Table 1. Rates and Rate Constants for Various Gas-Phase
Reactions
rate (s-1),
× 10-3
k × 10-11
reaction
efficiencyc
reaction
(cm3 molecule-1 s-1
)
1b
1d
2
0.77
0.15
2.79
14.6a
2.9a
53b
0.07
0.02
0.20
a The rate constant was calculated by multiplying the ratio of the rates
of eqs 1 and 2 by the published rate constant (ref 12) for eq 2. b Taken
from ref 12. c Reaction efficiencies are calculated by dividing the observed
rate constant by the theoretical rate constant (ref 13).
with the most efficient reaction being observed for the acetyl
group (R ) Me, RE ) 0.07), followed by the benzoyl group
(R ) Ph, RE ) 0.02). Given these results, and that the
dimethylaminocarbamyl group is unreactive, this suggests
the intrinsic reactivity order for the acyl groups of MeC(O)
> PhC(O) > Me2NC(O).
To confirm this reactivity order and to verify that these
reactions proceed via “SN2 like” transition states, we have
carried out ab initio calculations on the simpler systems
where the nucleophile and nucleofuge are both NH3.14 As
the benzoyl system is computationally demanding, we have
used the CBS-4M method15 throughout to determine the
barrier heights relative to separated reactants.16 The optimized
geometries of the transition states are shown in Figure 1.
As might be expected for an identity exchange reaction, the
nucleophile and nucleofuge show identical bond lengths.
While this suggests a similarity to an SN2 reaction, the
nucleophile-acyl carbon-nucleofuge are not collinear but
have bond angles closer to the expected tetrahedral geometry.
Both the structures of these transition states and their
imaginary frequencies are similar to those reported for
anionic acylation reactions.3a,5 The most important results
are the transition state energies relative to separated reactants,
(13) Chesnavich, W. J.; Su, T.; Bowers, M. T. J. Chem. Phys. 1980, 72,
2641.
Figure 1. Transition states for transacylation reactions: (a) acetyl
system has an imaginary frequency of -324.7 cm-1 and lies -3.3
kcal mol-1 below reactants; (b) benzoyl system has an imaginary
frequency of -307.6 cm-1 and lies -1.1 kcal mol-1 below
reactants; (c) N,N-dimethyaminocarbamyl system has an imaginary
frequency of -283.7 cm-1 and lies +12.4 kcal mol-1 above
reactants
(14) All calculations were carried out using the Gaussian 98 suite of
programs: Gaussian 98, Revision A.7, M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski,
J. A. Montgomery, Jr., R. E. Stratmann, J. C. Burant, S. Dapprich, J. M.
Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S.
Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma,
D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J.
Cioslowski, J. V. Ortiz, A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challa-
combe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L. Andres,
C. Gonzalez, M. Head-Gordon, E. S. Replogle, and J. A. Pople, Gaussian,
Inc., Pittsburgh, PA, 1998.
which were calculated at 298 K (Figure 1). Only the acetyl
and benzoyl systems lie below reactants, while the N,N-
dimethyaminocarbamyl transition state lies over 10 kcal
mol-1 aboVe the reactants.
(15) Ochterski, J. W.; Petersson, G. A.; Montgomery, J. A. J. Chem.
Phys. 1996, 104, 2598.
(16) The “double well” potential energy profiles for these systems require
the formation of pre and post complexes (i.e., ion-molecule complexes)
of the type [RC(O)NH3+‚‚‚NH3]. IRC runs on each of the transition states
indicates that they are likely to connect to such species. Unfortunately,
optimizations of these complexes have proved to be impossible using the
modest HF/3-21G* basis set. For example, the [CH3C(O)NH3+‚‚‚NH3]
complex fails to converge after 700 steps. At higher levels of theory, such
complexes have, however, been found to connect to the SN2 like transition
Thus, the ab initio results are in total accord with the
experimental observations, supporting the following intrinsic
reactivity order for acyl groups: MeC(O) > PhC(O) > Me2-
NC(O). Interestingly, the same reactivity order of MeC(O)
> PhC(O) has been reported for related gas-phase identity
exchange reactions between chloride ions and acyl chlorides3b
and for condensed-phase reactions between amines and acyl
chlorides.17a In contrast, the hydrolysis of acyl chlorides
+
state for the HC(O)NH3 + NH3 system (O’Hair, R. A. J. Manuscript in
preparation). Finally, we find no evidence for the existence of stable
tetrahedral intermediates.
Org. Lett., Vol. 2, No. 17, 2000
2569

follows the order MeC(O) > Me2NC(O) > PhC(O),17b but
the behavior of Me2NC(O)Cl has been ascribed to an SN1
like mechanisms. Further gas-phase studies of identity
exchange reactions could unravel the contributions of
electronic and steric effects of the RC(O) group.
We are continuing our studies on the transacylation
reactions of peptides18,19 and will report our results on the
reactions between neutral nucleophiles and protonated pep-
tides20 in due course.
Acknowledgment. We thank the Australian Research
Council for generous financial support (Grant A29930202)
and the University of Melbourne for funds to purchase the
LCQ. We also thank Mr. Gavin E. Reid for modifying the
LCQ and Mr. Shane Tichy for help with the design of the
neutral reagent gas inlet system.
OL006060R
(19) The methoxymethyl cation cleaves the peptide bonds in acylpeptides
via an intramolecular transacylation reaction of the [M + CH3OCH2]+
adduct: Freitas, M. A.; O’Hair, R. A. J.; Dua, S. Bowie, J. H. Chem.
Commun. 1997, 1409.
(20) Tabet, J. C.; Jankowski, K.; Grossman, P.; Virelizier, H.; Gaudin,
D.; Le Meillour, S. Spectrosc. Int. J. 1987, 5, 253.
(17) (a) Venkataraman, H. S.; Hinshelwood, C. N. J. Chem. Soc. 1960,
4977. (b) Ugi, I.; Beck, F. Chem. Ber. 1961, 94, 1839.
(18) Neighboring group reactions facilitate peptide bond cleavage of
protonated peptides. See: Reid, G. E.; Simpson, R. J.; O’Hair, R. A. J.,
Int. J. Mass Spectrom. 1999, 190/191, 209 and references therein.
2570
Org. Lett., Vol. 2, No. 17, 2000