Suppressed β-effect of silicon in 3-silylated monocyclic β-lactams: The role of antiaromaticity

Article abstract of DOI:10.1021/ol902411r

[Chemical Equation Presented] The β-stabilizing effect of silicon substituent at C-3 on a C-4 cation and a radical In the 2-azetidinone systems is studied using NMR kinetics. While the β-effect Is virtually nonexistent in the case of a cation, a foiled β-effect (only a 3-fold rate enhancement) Is observed for a radical intermediate. From both the experimental and theoretical studies, It Is demonstrated that antiaromaticity Is playing the prime role In suppressing the β-stabilizing effect of silicon.

Full text of DOI:10.1021/ol902411r

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5722-5725
Suppressed ꢀ-Effect of Silicon in
3-Silylated Monocyclic ꢀ-Lactams: The
Role of Antiaromaticity
Subhendu Sekhar Bag,*,† Rajen Kundu,† Amit Basak,‡ and Zdenek Slanina§
Department of Chemistry, Indian Institute of Technology, Guwahati-781039, India,
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India,
and Institute for Molecular Science, Okazaki-444-8585, Japan, and Institute of
Chemistry, Academia Sinica, Taipei, Taiwan-ROC
ssbag75@iitg.ernet.in
Received October 22, 2009
ABSTRACT
The ꢀ-stabilizing effect of silicon substituent at C-3 on a C-4 cation and a radical in the 2-azetidinone systems is studied using NMR kinetics.
While the ꢀ-effect is virtually nonexistent in the case of a cation, a foiled ꢀ-effect (only a 3-fold rate enhancement) is observed for a radical
intermediate. From both the experimental and theoretical studies, it is demonstrated that antiaromaticity is playing the prime role in suppressing
the ꢀ-stabilizing effect of silicon.
A great deal of effort has been put forth to know the nature
of the intermediates, a radical or cation, involved in the
enzymatic conversion of proclavaminate to dihydroclavami-
nate in the biosynthesis of clavulanic acid (Scheme S2,
Supporting Information); however, a definitive answer is still
to be found.1 To offer some supportive light for the proposed
radical mechanism and to find out the real cause of
suppression of ꢀ-secondary isotope effects2 which failed to
settle the matter, we decided to use silicon-substituted
ꢀ-lactams for a model study. The presence of a ꢀ-trimeth-
ylsilyl group has been shown to enhance the rate of solvolysis
up to an order of 1012 as compared to a ꢀ-hydrogen which
has been known for a long time and is at the heart of
organosilicon chemistry.3,4 Such rate enhancement is due to
† Indian Institute of Technology, Guwahati-781039.
‡ Indian Institute of Technology, Kharagpur-721302.
§ Institute for Molecular Science and Institute of Chemistry, Academia
Sinica.
(1) (a) Krol, W. J.; Basak, A.; Salowe, S. P.; Townsend, C. A. J. Am.
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Chem. Soc. 1990, 112, 1654. (c) Zhang, Z.; Ren, J.; Stammers, D. K.;
Baldwin, J. E.; Harlos, K.; Schofield, C. J. Nat. Struct. Biol. 2000, 7, 127.
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10.1021/ol902411r  2009 American Chemical Society
Published on Web 11/16/2009

the stabilization of the developing carbocation ꢀ-to silicon
primarily via hyperconjugation of a C-Si σ-bond with the
unfilled p-orbital of the ꢀ-carbon atom.5
Thus, this model study may shed some light on the nature
of intermediates involved in the oxygen insertion at C-4 in
actual enzymatic reaction.1
However, in small cyclic systems, such as 2-azetidinone,
the hyperconjugative stabilization of a cation or a radical at
C-4 by ꢀ-silicon at C-3 might be difficult, and hence
stabilization might be expected to be less and expressed to
different extents.2a,b,6 Previously, Fedor and others7 have
shown that the formation of an acylimine intermediate via
the E1cB mechanism is the rate-determining step in mono-
cyclic ꢀ-lactams. Therefore, the generated acylimine inter-
mediate can be thought to be stabilized by a silicon
substituent (Scheme 1a; structure II), and hence a rate
Therefore, we have synthesized the ꢀ-lactams 1-3 fol-
lowing literature procedures,9 with some modifications, for
studying the kinetics of reactions passing through a cationic
intermediate (Scheme S1, Supporting Information). The
ꢀ-lactams 4-6 served as substrates for studying the radical
reactions. With all the substrates in hand, we proceeded to
find out the reactivity of 1-3 (Scheme 1b) toward nucleo-
philic displacement of the phenylsulfonyl group. The kinetics
was followed by treating various ꢀ-lactams with thiophenol
and DMAP as base in CDCl3 under identical conditions of
1
concentration and temperature and recording the H NMR
at different times. We observed that all the three substrates
reacted at nearly equal rates, and their reactions essentially
followed first-order kinetics as revealed in the plot (Figure
1a; Table 1, entries 1-3). Thus, the presence of the ꢀ-silyl
Scheme 1. (a) Presentation of Acylimine Formation and (b)
Nucleophilic Substitution and Reduction of Different ꢀ-Lactams
Figure 1. Reaction kinetics of (a) nucleophilic displacement of 1-3
with thiophenol and (b) reduction of 4-6 by Bu3SnH.
enhancement is expected as the transition state leading to
the intermediate will have partial positive character at C-4.
The same argument holds for the reactions going through a
radical at C-4.8
Since silicon has a strong ꢀ-effect, we thought that it would
be worthwhile to study the effect of a silicon substituent at
C-3 on reactions involving a cation (partial) or a radical at
C-4 in monocyclic ꢀ-lactams. The specific question we
wanted to address was: could silicon at C-3 stabilize a cation
or a radical at C-4 in ꢀ-lactams? The difference between
the two effects might be large and hence easily determinable,
e.g., by NMR. As ꢀ-lactams occur relatively rarely in nature,
it is not surprising that the biological activity of these
compounds should be attributed to their chemical reactivity.
Table 1. Rate Constants for Reactions of 1-3 with Thiophenol
at 60 °C and Reduction of 4-6 with n-Bu3SnH at 80 °C
rate constants
(kobs) (min-1
rate constants
(kobs) (min-1
entry
)
entry
)
1
2
3
8.89 × 10-3
8.17 × 10-3
7.41 × 10-3
4
5
6
1.39 × 10-3
4.31 × 10-3
4.60 × 10-3
substituent has practically no influence on the kinetics of
the reaction which reflects its inability to stabilize the
acylimine intermediate. To our knowledge, this is the first
example of a ꢀ-lactam system where the ꢀ-effect of silicon
is virtually nonexistent.
When the ꢀ-lactams 4-6 (Scheme 1b) were treated with
tri-n-butyltinhydride keeping identical conditions of temper-
ature and concentrations, rate enhancement of about 3-fold,
independent of the concentration of tinhydride, was observed
for both the silyl-substituted derivatives. Thus, the reaction
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Org. Lett., Vol. 11, No. 24, 2009
5723

again essentially followed pseudo-first-order kinetics (Figure
1b; Table 1, entries 4-6). Since the rates of tin hydride
mediated reactions depend primarily upon the stability of
the radical intermediates10 unlike in the case of cations, the
ꢀ-silicon substituent is able to stabilize to some extent the
radical at C-4 which is manifested in the observation of rate
enhancement by 3-fold. The magnitude of ꢀ-stabilization
was, however, much less than expected (calculated ꢀ-stabi-
lization energy was ∼3.2 kJ/mol vs 12.3 kJ/mol reported
for 2-trimethylsilyl-2-methyl propyl radical6).
From the above results, it is clear that while the ꢀ-effect
of silicon is absent in the case of a cationic intermediate the
effect is considerably suppressed in the case of a radical
intermediate. Three possible factors, (a) the antiaromaticity,
(b) involvement of N-lone pair, and (c) the dihedral angle,
might be considered, all of which could potentially suppress
the ꢀ-effect. It is indeed true that the dihedral angle11 plays
a dominant role in controlling the magnitude of the ꢀ-effect.
The optimized structure (Figure 2a) of the ꢀ-lactam contain-
Therefore, with the N-lone pair effect also failing to
satisfactorily explain our observation, one has to invoke the
role of antiaromaticity in these systems, which is in our view
mainly responsible for suppression of ꢀ-effect. Although the
suppression of the ꢀ-effect of silicon is beyond any doubt,
the subtle difference in its extent in the radical and the
cationic regime is not clear; the geometry of the radical and
cation at C-4 might be playing an important role which
accounts for the difference in percent antiaromatic destabi-
lization and thus can explain the suppressed ꢀ-effect to a
different extent.
To ascertain the relative reactivities of the ꢀ-lactams with
and without ꢀ-silyl groups at C-3, we carried out theoretical
calculations at the ROMP2)FC/6-31G**//B3LYP/3-21G*
level12 using Gaussian 98. Thus, the result showed no significant
change in charge distribution, especially at C-4 which is ꢀ to
silicon for both silylated and nonsilylated systems with a cation
or a radical generated at C-4. Although charge distribution in
the ground state is not an accurate method for predicting the
reactivity, development of any extra charge at C-4 indicated
the absence of any ꢀ-effect of silicon in these systems. The
results are in good agreement with our experimental findings.
The computational results also showed no significant change
in energetics whether silicon is present in the ꢀ-position or not.
Computation on cyclobutylamine systems as our ꢀ-lactam
model also showed no change in energetics. Although the
numbers refer to the thermodynamic changes, it is unlikely that
there would be a substantial change in kinetic barrier (Table
S4, Supporting Information).
The isodesmic calculation on the radical reaction using
B3LYP/3-21G* (using Gaussian 03)13 optimized geometries
pointed out strongly repressed ꢀ-silyl effect (stabilization
energies were only 3.36 kJ/mol for N-unprotected and 4.52
kJ/mol for N-protected ꢀ-lactam) supporting our experimental
results (Scheme S4, Supporting Information). Therefore, the
ꢀ-silyl effect has essentially been faded away because of the
Figure 2. (a) Calculated dihedral angle of the ꢀ-silyl cation. (b)
Kinetics of radical displacement of N-substituted ꢀ-lactams.
ing an empty p-orbital indicated that the concerned dihedral
angle was ∼32°, which suggests that the ꢀ-effect should still
be substantial at this dihedral angle, of the order of ∼104.11
Thus, the dihedral angle could not alone explain the
suppression of the ꢀ-effect.
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.;
Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
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J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
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C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
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Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.5;
Gaussian, Inc.: Pittsburgh, PA, 1998.
The involvement of the N-lone pair in stabilization of the
cation or radical should be of the same order, if at all, in all
the cases since we were dealing with similar systems.
Moreover, even where such stabilization is weak, we still
observed considerable suppression of the ꢀ-effect as revealed
in the radical-mediated reaction shown in Figure 2b (stabi-
lization is only about 3.3 kJ/mol). It is interesting to note
that our results on the ꢀ-effect of silicon followed the same
trend as the reported suppressed ꢀ-secondary deuterium
isotope effects2a in ꢀ-lactam systems for a cationic or a
radical intermediate. The absence of any downfield shift of
NH in 1-3 in the presence of excess thiophenol points out
again no additional participation of N-lone pair with the
carbonyl.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; 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.;
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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 C.02; Gaussian, Inc.: Wallingford, CT, 2004.
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5724
Org. Lett., Vol. 11, No. 24, 2009

antiaromatic character of the cations or radicals that would
necessarily come along with ꢀ-silyl stabilization.
z, perpendicular to the xy-plane.14 The shape of the plots (NICS
vs z) clearly indicates that the ꢀ-lactam cation is strongly
antiaromatic in character (Figure 3a).14 However, the shape is
quite different in the case of the ꢀ-lactam radical (4rad., Figure
3b)sthe out-of-plane shielding decays rapidly as the distance
between the probe and the ring plane increases which is
characteristic of a nonaromatic compound.14 This indicated that
the electronic structure of the radical is neither aromatic nor
antiaromatic and that the π-character of the C3-C4 bond is
not yet very developed in the transition structure. Thus, from
the NICS study it is concluded that percent antiaromaticity and
hence the destabilization is much less in the case of a radical
compared to that of a cation supporting our observed suppressed
ꢀ-silyl effect to a different extent.
To account for the antiaromatic origin of the subtle
difference in the extent of ꢀ-effect of silicon in the radical
and cationic regime, we studied the magnetic properties of
an acylimine and the other cationic and radical intermediates
by calculating the NICS (nucleus independent chemical shift)
at different points along the z-axis, magnetic exaltations (Λ),
and antiaromatic destabilization energies (ASE) at different
levels of theory using the Gaussian 03 program package.13
The result (GIAO-B3LYP/6-31+G*//B3LYP/6-311+G**)
showed that except the radical intermediate, 4rad. (Figure 3b),
The antiaromatic destabilization energy (ASE) based on
the hydrogenation reaction calculated at the B3LYP/6-
311+G** level13 also indicated the higher destabilization
of the cation compared to the radical intermediate (Table
2).15 It is also clear from the % antiaromaticity (y %) that
the radicals are much less antiaromatic or rather nonaromatic,
while the cations are strongly antiaromatic (Table 2).15 The
calculated values of magnetic exaltations (Λ)16 at the CSGT-
SCF level also indicated similar findings (Table 2). Therefore,
all the theoretical magnetic criteria are conclusive to the
relatively greater antiaromatic character of the cation com-
pared to the radical intermediates supporting their reactivity
to different extents.
Figure 3. Plot of NICS values (osotropic, out-of-plane, and in-
plane components) as a function of distance (z, Å).
In conclusion, we have shown that the ꢀ-radicals are better
stabilized (with a strong suppression) by silicon in our system
compared to the ꢀ-cation. Thus, this model study supports the
preferable formation of a radical over a cationic intermediate
in the conversion of proclavaminate to clavaminate in the actual
enzymatic pathway. From both the experimental and theoreti-
cal studies, it was demonstrated that antiaromaticity is playing
the prime role by ruling out several other possible factors in
suppressing the ꢀ-stabilization effect of silicon and hence
in controlling the reactivity at C-4 of monocyclic ꢀ-lactam
systems. The subtle difference in suppressed ꢀ-silicon effect
between the cationic and radical regime was also clearly
explained by considering their antiaromatic destabilization
and % antiaromaticity to different extents. To the best of
our knowledge, this is the first example where there is no
ꢀ-effect of silicon in ꢀ-lactam systems.
all other ꢀ-lactams-7, 7aze. (Figure S26, Supporting Informa-
tion), and 1cat. (Figure 3a) exhibited positive NICS values
at all the points calculated indicating their strong antiaromatic
character. The ꢀ-silyl unsubstituted and substituted ꢀ-lactam
radicals, 4rad. (Figure 3b, Table 2) and 5rad. (Table 2), respec-
Table 2. DFT Calculated NICS(0), Magnetic Exaltation (Λ),
ASE, and y % of Various ꢀ-Lactams
Acknowledgment. Support has been provided by DST
(SR/SI/OC-69/2008), Govt. of India, and IIT Guwahati.
Supporting Information Available: Synthetic Schemes
1
S1 and S2, experimental procedure, kinetic equation, H/13C
a NICS (ppm) at center. b Λ (ppm cgs).15 c ASE ) antiaromatic
destabilization energy (kJ/mol). d y % ) % antiaromaticity/aromaticity.
NMR spectra, and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL902411R
tively, showed a much less (-) ve isotropic chemical shift at
the ring center indicating their nonaromatic character.14
For a better understanding and comparing the antiaromatic
characters between the radicals and cations, we have plotted
isotropic chemical shifts of respective NICS probes (bq’s) and
their in-plane and out-of-plane components against the distance,
(14) (a) Wiest, O. J. Phys. Chem. A 1999, 103, 7907. (b) Stanger, A. J.
Org. Chem. 2006, 71, 883.
(15) Mucsi, Z.; Viskolcz, B.; Csizmadia, I. G. J. Phys. Chem. A 2007,
111, 1123.
(16) Proft, F. De.; Schleyer, P. v. R.; Lenthe, J. H. v.; Stahl, F.; Geerlings,
P. Chem.sEur. J. 2002, 8, 3402.
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