Wiitala et al.
significantly puckered nature of the â-lactam ring in the fused
bicyclic penam skeleton places the carboxylic acid essentially
in the plane of the lactam carbonyl group, which makes the
formation of intermediates analogous to 10 and 11 improbable
because of the poor attack trajectory.
The reaction pathways for anionic16a and neutral16b forms of
5′ and 7′ were explored and found to have transition states too
high in energy to be relevant. By contrast, protonated structures
provided reaction coordinates (Figures 3 and 4) consistent with
the experimental observation of decarbonylation. In each case,
we considered protonation of the lactam at two sites and found
that the tautomer derived from N-protonation (5′b or 7′b) was
lower in free energy than that derived from O-protonation (5′a
or 7′a, see Table 1), owing in part, presumably, to the pyrami-
dalization of the nitrogen atom enforced by the penam ring
system. In the case of 7′, the N-protonated tautomer 7′b is
additionally stabilized by hydrogen bonding to a carbonyl
oxygen of the maleimide moiety. From the N-protonated
tautomer, TS structures 5′c or 7′c for ring opening to the
corresponding protonated anhydrides 5′d or 7′d were found. The
activation free energies of each of these steps were small (8.3
and 9.1 kcal/mol, respectively). Surprisingly and interestingly,
the computational results for the cationic pathway indicated a
low-energy transition state for the direct conversion (i.e., without
an intermediate) of both 5′b to 5′d and 7′b to 7′d. This process
is in distinct contrast to that involving a classical tetrahedral
intermediate (i.e., the N-protonated analogue of 10) analogous
to our initial mechanistic hypothesis (cf. Scheme 1). Finally,
no energetically viable paths involving the O-protonated species
Computational Studies. To explore whether the proposed
decarbonylation reaction pathway (Scheme 1) is energetically
reasonable, we computed various likely intermediates and some
of the associated transition states for their interconversion. Since
decarbonylation was observed under several different experi-
mental conditions (LiI, EtOAc at reflux for 5; EtOAc at reflux
for 7; and neat melt for 7) it is not possible to know the exact
state of protonation of the key event(s). Therefore, anionic,
neutral, and cationic pathways were explored for both 5 and 7.
That is, we considered pathways beginning from the carboxylate,
from the neutral carboxylic acid capable of tautomerizing to
zwitterionic intermediates, and from the protonated substrate,
recognizing what can occur at various sites. We did not enforce
a unimolecular pathway for interconversion between any
tautomeric pairs. The phthalimido moieties in 5 and 7 were
replaced by maleimido substructures to enhance computational
efficiency. We will refer to these truncated structures as 5′ and
7
′, respectively.
For the characterization of the various decarbonylation
1
7
5
′a or 7′a were found.
The anhydrides themselves are also subject to a tautomeric
reaction coordinates, the geometry of each molecular structure
was fully optimized in the gas phase at the density functional
level of theory using the M06 hybrid meta-generalized gradient
equilibrium associated with which carbonyl oxygen is proto-
nated; in order to lose carbon monoxide, there must be a proton
11
12
approximation functional and the 6-31+G(d) basis set.
Aqueous free energies for each minimum and maximum were
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
1
3
then recomputed by using the IEFPCM solvation model with
default united-atom radii. To assess the maximum effects of
polar solvation, the continuum model for water was chosen as
a matter of convenience. The choice of solvent modeled has
only a small effect on relative energies. For example, the com-
puted free energy difference between 5′f and 5′e was 4.0 kcal/
mol in water and 4.6 kcal/mol in THF while the computed free
energy difference between 7′f and 7′e was 17.3 kcal/mol in water
and 15.4 kcal/mol in THF. Analytical vibrational frequencies
were computed in order to assign the nature of all stationary
points as either minima or transition state (TS) structures and
also to compute thermal contributions to 298 K isomer enthal-
M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision D.01; Gaussian, Inc.: Pittsburgh, PA, 2004.
1
4
pies.
(16) (a) For the anionic reaction pathways for 5′ and 7′, reactant structures
Solvation free energies were summed with gas-phase enthal-
pies to generate composite free energies in aqueous solution
and TS structures corresponding to loss of carbon monoxide could be
located, but no intermediate structures could be found. Attempts to generate,
for example, intermediates associated with ring opening of the lactam
following attack of the carboxylate on the amide carbonyl led smoothly
back to reactants. Thus, lactam ring opening is computed to occur with
concerted loss of carbon monoxide [e.g., see TS in brackets for 5′(anion)
to 9′(anion)]
(gas-phase thermal contributions to free energies had no
significant influence on relative isomer energetics, but were
judged to be of limited utility based on the sensitivity of
computed entropies to low-frequency vibrations in the quantum-
1
4
mechanical harmonic-oscillator approximation ). A pruned
75 302) integration grid containing 75 radial shells and 302
(
angular points per shell (approximately 7 000 points for each
atom) was used on each atom. Density functional calculations
were carried out by using the Gaussian 03 suite of electronic
structure programs.15
.
However, the computed activation free energies for the reactions of each
of 5′ and 7′ are in excess of 45 kcal/mol, suggesting that the anionic reaction
does not play a significant role in the observed decarbonylations. (b) In the
cases of neutral 5′ and 7′, bicyclic anhydrides formed by ring opening of
the lactam together with proton transfer from the carboxylic acid to the
1,3-thiazolidine were identified as stable intermediates having free energies
of 4.2 and 18.4 kcal/mol relative to precursors 5′ and 7′, respectively.
Decarbonylation TS structures that produce zwitterionic thiazolinium
carboxylate products could be located. Again, however, the computed free
energies of activation were too high to be experimentally relevant: 53.7
and 59.4 kcal/mol for 5′ and 7′, respectively.
(
11) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. Online First [doi
10.1007/s00214-007-0310-x)].
12) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986; p 82.
13) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117-
29.
14) Cramer, C. J. Essentials of Computational Chemistry: Theories and
Models, 2nd ed.; John Wiley & Sons: Chichester, UK, 2004; pp 334-
66.
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3026 J. Org. Chem., Vol. 73, No. 8, 2008