Enantiomerization study of some α-nitroketones by dynamic high-resolution gas chromatography

Article abstract of DOI:10.1021/jo0267302

The kinetics of the reversible enantiomer interconversion of 3-nitrobutan-2-one (1), 3-nitropentan-2-one (2), and 2-nitropentan-3-one (3) have been studied by dynamic high-resolution gas chromatography (DHRGC) by using a β-cyclodextrin derivative chiral stationary phase; the process occurs via enolization of the keto forms. The DHRGC experiments involving the studied nitroketones and the chiral stationary phase show chromatographic profiles with a typical interconversion plateau in the temperature range between 130 and 160 °C. Computer simulation of the experimental chromatographic elution profiles was employed for the determination of rate constants and the corresponding enantiomerization barriers (k, ΔG^#(T), ΔH^#, and ΔS^#). The highly negative entropy of activation (ΔS^# values from -19 to -37 cal mol^-1 K^-1) points to a transition state (TS) with large charge separation. The obtained results for 1-3 show the dramatic effect of an α-nitrosubstituent on the rate of enolization of simple ketones, when compared with those for 3-chloro-2-butanone and 3-methyl-2-pentanone. To get some information on the separate contributions of the stationary liquid phase and the mobile gas phase on the studied process, some DFT ab initio calculations have been performed for the same compounds.

Full text of DOI:10.1021/jo0267302

En a n tiom er iza tion Stu d y of Som e r-Nitr ok eton es by Dyn a m ic
High -Resolu tion Ga s Ch r om a togr a p h y
Francesco Gasparrini,* Marco Pierini,* and Claudio Villani
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita`
“La Sapienza”, Piazzale A. Moro 5, 00185 Roma, Italy
Paolo De Maria and Antonella Fontana
Dipartimento di Scienze del Farmaco, Universita` “G. d’Annunzio”, Via dei Vestini 31, 66013 Chieti, Italy
Roberto Ballini
Dipartimento di Scienze Chimiche, Universita` degli Studi di Camerino, Via S. Agostino 1,
62032 Camerino, Italy
francesco.gasparrini@uniroma1.it; marco.pierini@uniroma1.it.
Received November 18, 2002
The kinetics of the reversible enantiomer interconversion of 3-nitrobutan-2-one (1), 3-nitropentan-
2-one (2), and 2-nitropentan-3-one (3) have been studied by dynamic high-resolution gas chroma-
tography (DHRGC) by using a â-cyclodextrin derivative chiral stationary phase; the process occurs
via enolization of the keto forms. The DHRGC experiments involving the studied nitroketones and
the chiral stationary phase show chromatographic profiles with a typical interconversion plateau
in the temperature range between 130 and 160 °C. Computer simulation of the experimental
chromatographic elution profiles was employed for the determination of rate constants and the
corresponding enantiomerization barriers (k, ∆G#(T), ∆H#, and ∆S#). The highly negative entropy
of activation (∆S# values from -19 to -37 cal mol-1 K-1) points to a transition state (TS) with
large charge separation. The obtained results for 1-3 show the dramatic effect of an R-nitro-
substituent on the rate of enolization of simple ketones, when compared with those for 3-chloro-
2-butanone and 3-methyl-2-pentanone. To get some information on the separate contributions of
the stationary liquid phase and the mobile gas phase on the studied process, some DFT ab initio
calculations have been performed for the same compounds.
1. In tr od u ction
(pKT ) 2.34) in aqueous solution at 25 °C by combining
the rate constants for ketonization of the enolate and the
R-Nitroketones containing an R-hydrogen atom are
very acidic carbon acids1,2 with pKa values close to those
of unsubstituted carboxylic acids. In aqueous solution
they are also characterized by a relatively high enol
content1,2 and by the possible presence of the R-ketoni-
tronic “aci” form at equilibrium.
KH
EH
pKa ()5.15) of the keto form. Consequently the pKa
of the enol form turned out to be 2.81. These values can
be compared with the corresponding values4 for acetone
KH
EH
(pKT ) 8.33, pKa
) 19.27, pKa
) 10.94). This
comparison highlights the strong influence of an R-nitro
group on keto-enol tautomerism.
The synthetic procedures and vast preparative poten-
tial of these compounds have been extensively reviewed.3
However, kinetic and/or thermodynamic studies on the
keto-enol interconversion in water are scarce and “the
paucity of the data does not make it possible to examine
structural effects on the enol content of R-nitroketones
in detail”.1
Ab initio calculations5 suggest that the higher values
of KT ) [enol]/[ketone] observed for nitroketones depend
on the capability of the NO2 group to destabilize the keto
tautomer and to stabilize the enol tautomer through the
π- and σ-electron-withdrawing effects of the substituent
as well as the formation of an intramolecular H-bond in
the enol form (see Scheme 1). However, experimental
results6 indicate that the latter effect is of minor impor-
tance in the case of acyclic R-nitroketones.
We have recently measured2 the equilibrium constant
for the keto-enol tautomerism of 3-nitrobutan-2-one (1)
Even more scanty are the available data on the kinetics
and the thermodynamics of the keto-enol interconver-
sion in aprotic solvents and in the gas phase. The
* Address correspondence to this author. Phone: +39 06 49912776.
Fax: +39 06 49912780. E-mail: francesco.gasparrini@uniroma1.it.
(1) Toullec, J . In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley
& Sons: New York, 1990; p 323.
(2) Fontana, A.; De Maria, P.; Siani, G.; Pierini, M.; Cerritelli, S.;
Ballini, R. Eur. J . Org. Chem. 2000, 1641.
(3) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
33, 1. (b) Fischer, R. H.; Weitz, H. M. Synthesis 1980, 261. (c) Rosini,
G.; Ballini, R. Synthesis 1988, 833. (d) Ballini, R. Synlett 1999, 1009.
(4) Keefe, R.; Kresge, A. J . In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley & Sons: New York, 1990; p 399.
(5) Bouma, W.; Radom, L. Aust. J . Chem. 1978, 31, 1649.
(6) Simmons, T.; Love, R. F.; Kreuz, K. L. J . Org. Chem. 1966, 31,
2400.
10.1021/jo0267302 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/15/2003
J . Org. Chem. 2003, 68, 3173-3177
3173

Gasparrini et al.
SCHEME 1. Ta u tom er s of r-Nitr ok eton es
the determination of enantiomeric excess in scalemic
mixtures. Moreover the same technique has been used
in recent years to obtain kinetic data [k, ∆G#(T), ∆H#,
and ∆S#] for suitable enantiomerization processes moni-
tored at different temperatures.12-26 The latter procedure,
generally referred to as dynamic chromatography (DC),
to be applicable requires that the studied reversible R
h S interconversion occurs during the time scale of the
enantiomeric separation. If this is the case, characteristic
peak profiles are obtained.
SCHEME 2. En a n tiom er iza tion of r-Nitr ok eton es
via En ol a n d /or “Aci” Ta u tom er s
Peak-form analysis through the iterative comparison
of simulated and experimental chromatograms12-26 al-
lows the determination of the desired kinetic parameters
of enantiomerization. So far the most widely investigated
enantiomerizations by DC are conformational enanti-
omerizations. In fact configurational enantiomerizations
are usually characterized by ∆G# values which are too
high for the equilibration times to be compatible with the
times of the chromatographic separation. Noticeable
exceptions are some enantiomerizations of chiral species
which rapidly interconvert their configurations by pass-
ing through achiral tautomeric forms17,18,27 as, for ex-
ample, those of Scheme 2.
In these cases as, at a statistical level, only one-half
of the achiral tautomer originated from a given enanti-
omer is transformed into the other enantiomer, the rate
constants of tautomerization, kt, and enantiomerization,
k, are related by the equation kt ) 2k and the ∆G# values
for the reversible enantiomerization can be calculated
from k values according to the Eyring eq 1 with a
transmission factor γ of 0.5.17
collected information is derive mostly from qualitative
analysis of UV-vis, IR, and 1H NMR spectra recorded
in various organic solvents.3b,7-10 In general, there is clear
evidence of the presence of the enol form, while the
corresponding “aci” form is hardly detectable. R-Nitroke-
tones bearing on the R-carbon a R′′ substituent (as in
Scheme 1) are chiral species which can invert their con-
figurations on passing from the keto tautomer, KH, to
the achiral enol, EH, and/or “aci” tautomers (Scheme 2).
In this paper we have studied the enantiomerization
(i.e. the reversible enantiomer interconversion which
occurs via enolization of the keto form) of the following
R-nitroketones 1-3 at different temperatures by dy-
namic high-resolution gas chromatography (DHRGC)
using a chiral stationary phase (CSP) made of 6-O-[(tert-
butyldimethyl)silyl-2,3-di-O-acetyl-â-cyclodextrin].
In the investigated temperature range the obtained
chromatograms showed typical3b,11-13 plateaus between
the peaks of the separated enantiomers. Comparison of
the experimental chromatographic elution profiles with
the corresponding computer-simulated profiles has al-
lowed the determination of the apparent rate constants,
kapp, of enantiomerization. These rate constants are aver-
aged values that bring contributions from the process
occurring in the mobile gas phase (km) and in the station-
γkBT
∆G#(T) ) RT ln
(1)
hk
In eq 1 kB is the Boltzmann constant, T is temperature,
h is the Planck constant and R is the gas constant. In
the present DHRGC experiments the enantiomerization
of nitroketones 1-3 has been investigated in the tem-
perature range 130-160 °C by using 30% 6-O-[(tert-
butyldimethyl)silyl]-2,3-di-O-acetyl-â-cyclodextrine in OV-
1701 w/w as the CSP. Under the adopted experimental
conditions the enantiomers of nitroketones 1-3 are
effectively discriminated by the column, with enantiose-
lectivity values (R) in the range 1.10-1.93. The obtained
chromatograms also showed typical interconversion be-
s
ary liquid phase (k1 and k-1s) according to Scheme 3.
The detailed kinetic analysis which underlies this
model has been previously reported.12
The enthalpy, ∆H#, and entropy, ∆S#, components of
the standard free energy of activation, ∆G#, have been
separated by plotting ∆G#/T against 1/T.
Finally some DFT ab initio calculations have been
performed to test if enantiomerization in the mobile gas
phase can possibly occur by an intramolecular mecha-
nism with a four-membered transition state. This mech-
anism of enolization is generally considered as very
unlikely for simple ketones either in the gas phase, as
suggest by ab initio calculations,11 or in protic solvents.1,4
(13) Mannschreck, A.; Zinner, H.; Pustet, N. Chimia 1989, 43, 165.
(14) Trapp, O.; Schurig, V. J . Am. Chem. Soc. 2000, 122, 1424.
(15) Schurig, V.; Bu¨rkle, W. J . Am. Chem. Soc. 1982, 104, 7573.
(16) Veciana, J .; Crespo, M. I. Angew. Chem., Int. Engl. Ed. 1991,
30, 74.
(17) Trapp, O.; Schoetz, G.; Schurig, V. J . Pharm. Biomed. Anal.
2002, 27, 497.
(18) Cabrera, K.; J ung, M.; Fluck, M.; Schurig, V. J . Chromatogr.
A 1996, 731, 315.
2. Resu lts a n d Discu ssion
(19) Gasparrini, F.; Lunazzi, L.; Misiti, D.; Villani, C. Acc. Chem.
Res. 1995, 28, 163.
(20) Gasparrini, F.; Misiti, D.; Pierini, M.; Villani, C. Tetrahedron:
Asymmetry 1997, 8, 2069.
Enantioselective chromatographic methods based on
CSPs represent the most commonly used technique for
(7) Feuer, H.; Pivawer, P. M. J . Org. Chem. 1966, 31, 3152.
(8) Zajac, W. W., J r.; Ozbal, H. J . Org. Chem. 1980, 45, 4154.
(9) Schwarzenbach, G.; Zimmerman, M.; Prelog, V. Helv. Chim. Acta
1951, 34, 1954.
(10) Rhoads, S. J .; Gilbert, J . C.; Decora, A. W.; Garland, T. R.;
Spangler, R. J .; Urbigkit, M. J . Tetrahedron 1963, 19, 1625.
(11) Lee, D.; Kim, C. K.; Lee, B. S.; Lee, I. J . Comput. Chem. 1997,
18, 56.
(21) Wolf, C.; Pirkle, W. H.; Welch, C. J .; Hochmuth, D. H.; Ko¨nig,
W. A.; Chee, G.-L.; Charlton, J . L. J . Org. Chem. 1997, 62, 5208.
(22) Oxelbark, J .; Allenmark, S. J . Org. Chem. 1999, 64, 1483.
(23) Schoetz, G.; Trapp, O.; Schurig, V. Anal. Chem. 2000, 72, 2758.
(24) Trapp, O.; Schoetz, G.; Schurig, V. Chirality 2001, 13, 403.
(25) J ung, M.; Schurig, V. J . Am. Chem. Soc. 1992, 114, 529.
(26) J ung, H.; Fluck, M.; Schurig, V. Chirality 1994, 6, 510.
(27) Galli, B.; Gasparrini, F.; Lanzotti, V.; Misiti, D.; Riccio, R.;
Villani, C.; Guan-Fu, H.; Zhong-Wu, M.; Wan-Fe, Y. Tetrahedron, 1999,
55, 11385.
(12) Bu¨rkle, W.; Karfunkel, H.; Schurig, V. J . Chromatogr. 1984,
288, 1.
3174 J . Org. Chem., Vol. 68, No. 8, 2003

Enantiomerization Study of Some R-Nitroketones
F IGURE 1. Selected dynamic high-resolution gas chromatograms of ketones 1-3 (simulated chromatograms, dotted lines).
SCHEME 3. Equ ilibr ia Occu r r in g d u r in g Ch r om a togr a p h y, Wh er e k Rep r esen ts Ra te Con sta n ts a n d KD
Rep r esen ts Distr ibu tion Con sta n ts
tween the peaks of the separated enantiomers. The
process of reversible enantiomerization becomes progres-
sively faster with increasing temperature and the peak
interference increases accordingly. Peak-form analysis
through the iterative comparison of simulated and ex-
perimental chromatograms (see Figure 1 and Experi-
mental Section) was performed in terms of the discon-
tinuous plate model.28,29 The obtained kapp values are
reported in Table 1.
For ketone 1, the independence of enantioselectivity
(and the associated ∆G# values) on the adopted gas
chromatographic experimental conditions has been as-
J . Org. Chem, Vol. 68, No. 8, 2003 3175

Gasparrini et al.
TABLE 1. Ch r om a togr a p h ic a n d Kin etic Resu lts Obta in ed by DHRGC of Keton es 1-3
compd 1 (column 25 m)
compd 1 (column 50 m)
compd 2 (column 50 m)
compd 3 (column 50 m)
b,c
b,c
b,c
b,c
kapp
∆G#
(kcal/mol)
kapp
∆G#
(kcal/mol)
kapp
∆G#
(kcal/mol)
kapp
∆G#
(kcal/mol)
T (° C)
Ra
(min-1
)
Ra
(min-1
)
Ra
(min-1
)
Ra
(min-1
)
130
135
140
145
150
155
160
1.92
1.87
1.87
1.63
1.61
1.55
1.34
0.038
0.051
0.092
0.114
0.162
0.199
0.250
29.19d
29.32d
29.31f
29.39f
29.46f
29.64f
28.8e
28.2e
1.93
1.81
1.78
1.69
1.64
1.54
0.087
0.099
0.121
0.149
0.199
0.261
28.89f
29.14f
29.34f
29.53f
29.64f
29.76f
1.18
1.15
1.12
1.12
1.10
1.10
0.165
0.230
0.271
0.351
0.408
0.454
28.37f
28.45f
28.67f
28.81f
29.03f
29.28f
1.70
1.56
1.46
0.101
0.178
0.358
29.13f
29.3f
29.49f
29.80
f
a
b
d
R: chromatographic enantioselectivity factor. kapp: apparent rate constant. c Values (0.001 min-1
.
Values (0.02 kcal mol-1
.
e Extrapolated value. f Values (0.01 kcal mol-1
.
TABLE 2. Eyr in g Activa tion P a r a m eter s for th e
respect to 3-nitrobutan-2-one 1 produces a significant
decrease in the enthalpy and entropy of activation (see
Table 2). This is in agreement with the higher confor-
mational freedom of ketones 2 and 3 than that of ketone
1. However, the conformational freedom is largely lost
in the TS of the R h S interconversion, as ∆S# values
for the three ketones are highly negative.
En a n tiom er iza tion of Keton es 1-3
compd
∆H# (kcal mol-1
)
∆S# (cal mol-1 K-1
)
1a
1b
2b
3b
21.7 ( 2.0
21.7 ( 0.5
14.8 ( 0.3
13.4 ( 0.3
-18 ( 5
-19 ( 2
-35 ( 1
-37 ( 1
a
b
An even more negative ∆S# value (about -59 cal mol-1
K-1) has been recently reported in a study of the
stereointegrity of thalidomide17 and was attributed to an
enantiomerization mechanism involving charge separa-
tion in the TS of the keto-enol tautomerization. Interest-
ingly, the higher enantiomerization barrier of thalido-
mide (∆G# ) 36.8 kcal mol-1 at 200 °C) is due to an
entropy effect as the enthalpy of activation (∆H# ) 10.0
kcal mol-1) is lower than those of compounds 1-3. It is
now well-established7,20,23 that rate constants measured
by DHRGC depend on the particular CSP used. The
chiral stationary phase leads to different values for the
Column length: 25 m. Column length: 50 m.
CHART 1
forward (ks ) and backward (ks-1) reactions. In addition,
1
the enantiomerization barrier in the stationary phase can
be higher or lower than that in the mobile phase. Either
the chiral selector or the inert matrix in which it is
dispersed can be responsible for this effect.
certained at 140, 150, and 160 °C by means of two
capillary columns of different length (25 and 50 m)
containing the same CSP. As one can see from the values
of R, ∆G# (Table 1), ∆H#, and ∆S# (Table 2), the differ-
ences of the results obtained by the two columns are quite
small, pointing to a negligible effect of the column
geometry on thermodynamic (R) and kinetic (∆G#) data.
On the other hand, it is very significant that the chro-
matogram obtained at 130 °C for racemic chloroketone
4 (Chart 1) does not show any evidence of a plateau
between the resolved peaks of the two enantiomers (R )
1.39). This fact clearly indicates that replacement of the
(polar) chloro substituent of compound 4 with the nitro
group (compound 1) strongly promotes the R h S
interconversion of the enantiomers at this temperature.
The values of the Gibbs free energy of activation, ∆G#,
for enantiomer interconversions of compounds 1-3 at the
different temperatures are similar, being equal to 29.0
( 0.8 kcal mol-1. However, an Eyring plot of ∆G#/T vs
1/T shows that the presence of an additional methyl
group in the isomeric nitropentanones 2 and 3 with
To approach this problem, the concept of the retention
increment has been put forward.25 Application14 of this
concept to the enantiomerization barrier of Troger’s base
(one example of configurational enantiomerization) has
revealed only marginal differences between the effects
of the chiral selector and the inert matrix on the stereo-
inversion process. Moreover, the small differences ob-
served are mainly entropic in origin (about 6% for ∆S#).
A similar effect of the stationary phase on the enanti-
omerization of our nitroketones should result in small
deviations from the activation parameters reported in
Table 2, and this small effect can probably be neglected
when relative activation parameters for ketones 1-3 are
compared. The residence time of the enantiomers in the
gas phase is usually low when the retention factors are
relatively high. Thus the contribution of the gas phase
to the overall rate of enantiomerization has commonly
been neglected.12,17,26 However, in consideration of the low
retention factors (1.5-11.0) observed in the present work,
this contribution might in principle be appreciable for
ketones 1-3 and the measured rate constant, kapp, strictly
would be an averaged value that brings contribution from
the process occurring in both phases. Nevertheless, the
gas phase is virtually apolar while the liquid phase is
semipolar due to the presence of the modified cyclodextrin
and polysiloxane OV-1701 moieties. It is well-known that
(28) (a) Martin, A. J . P.; Synge, R. L. M. Biochem. J . 1941, 35, 1358.
(b) Craig, L. C. J . Biol. Chem. 1944, 155, 519. (c) Kallen, J .;
Heilbronner, E. Helv. Chim. Acta 1960, 43, 489. (d) Basset, D. W.;
Habgood, H. W. J . Phys. Chem. 1960, 64, 769.
(29) M. J ung, Program Simul, No. 620, Quantum Chemistry Pro-
gram Exchange (QCPE). QCPE Bull. 1992, 3, 12.
3176 J . Org. Chem., Vol. 68, No. 8, 2003

Enantiomerization Study of Some R-Nitroketones
SCHEME 4. Keto-En oliza tion Mech a n ism via
Hyd r ogen [1,3] Sigm a tr op ic Sh ift
SCHEME 5. Ba se- a n d Acid -Ca ta lyzed
Mech a n ism s of En oliza tion
TABLE 3. Ab In itio Activa tion En er gy Ba r r ier s for
En oliza tion of Keton es 1-5 via Hyd r ogen [1,3]
Sigm a tr op ic Sh ift.
racemization via enolization of 1-3 (Scheme 5) with base
[a] and/or acid [b] catalysis in the DHRGC conditions.
In Scheme 5, B and BH+ can be a basic or acid group
of the stationary phase or a second molecule of ketone
(or its conjugate base).31 It is noteworthy that the
mechanism of Scheme 5 is in agreement with the highly
negative ∆S# values observed in the DHRGC experiments
and with a TS with large charge separation.14,17,32,33
compd
∆E# (kcal mol-1
)
1
2
3
4
5
50.1
50.7
50.1
59.7
62.3
keto-enol tautomerizations are subject to general acid-
base catalysis30 and that they occur in preference in protic
media. Consequently the apolar mobile gas phase is likely
not to give a significant contribution to the observed
kinetic process.
3. Exp er im en ta l Section
Ma ter ia ls. 1, 2, and 3 were synthesized and purified
following described procedures;34 3-chlorobutan-2-one 4 and
3-methylpentan-2-one 5 were commercial samples.
Ga s Ch r om a togr a p h y. The measurements were per-
formed on a gas chromatograph equipped with a flame-
ionization detector. Two commercial fused silica capillary
columns (25 m × 0.25 mm i.d. and 50 m × 0.25 mm i.d.) coated
with 0.25 µm OV-1701 containing 30% 6-O-[(tert-butyldim-
ethyl)silyl-2,3-di-O-acetyl-â-cyclodextrin] were used. Helium
was used as a carrier gas.
Com p u ter Sim u la tion . The calculations were performed
on a personal computer. Use was made of the program Auto-
DHPLC-y2k (Auto-Dynamic HPLC), which is an improved
version for PC of the program SIMUL29 implemented with a
novel control on peaks asymmetry and a Simplex algorithm
for automatic fitting of experimental data.
Ab initio calculations suggest that the enolization of
simple carbonyl compounds via direct hydrogen transfer
(i.e. [1,3] sigmatropic shift, Scheme 4) in the gas phase
is unlikely to occur at ordinary experimental tempera-
tures, as the corresponding activation barrier is >70 kcal
mol-1 11
To check if this is a difficult process for nitroke-
.
tones too, ab initio calculations of structures and energies
for compounds 1-5 and the corresponding transition
states for the intramolecular enolization have been
carried out.
The ab initio DFT (nonlocal density functional of the
Becke and Perdew model) calculations have been per-
formed on compounds 1-5 with the 6-31G** basis set.
The choice of the DFT approach was dictated by the
necessity of taking into account the electronic correlation
effects, more pronounced in the TS than in the keto
form,11 and of keeping the calculation times reasonably
low. The obtained ∆E# values of Table 3 suggest that,
even for nitroketones 1-3, the intramolecular hydrogen
transfer is a very unlikely mechanism for the “spontane-
ous” enolization reaction under the experimental condi-
tions adopted for the DHRGC measurements.
However, it is apparent that the nitro-substituent in
compounds 1-3 lowers ∆E# by some 11 kcal mol-1 with
respect to the methyl group in compound 5. This is in
agreement with the strong π-acceptor effect (σR ) 0.15)
of the NO2 group (for a detailed discussion of electronic
effects on ∆E# of enolization of simple ketones see ref 11).
It is also interesting to note that while the fluoro-
substituent increases11 (with respect to CH3) the activa-
tion barrier to enolization, the chloro-substituent (4)
slightly decreases the same barrier, and this can probably
be accounted for by the reduced π-donor effect of Cl (σR-
Cl: -0.18) relative to F (σRF: -0.31).
Ab in itio Ca lcu la tion s. Molecular Mechanics and DFT ab
initio methods as implemented in the Titan 1.0.1 package were
used throughout this work. Preliminary conformational searches
on ketones 1-5 were carried out with the MMFF Force Field.
All the rotatable bonds were explored. Low-energy structures
found within 3 kcal mol-1 and their TS on enolization pathway
were optimized at the SCF level with the 6-31G** basis set.
Lowest energy structures of 1-5 and their TS were identified
as minima or first-order saddle points by calculating harmonic
vibrational frequencies at the DFT BP/6-31G** level.
Ack n ow led gm en t. We thank MIUR, Italy for fi-
nancial support (Faculty Research Projects and Contract
2001033797_004).
Su p p or tin g In for m a tion Ava ila ble: Calculated struc-
tures of ketones 1-5 and their transition states in PDB format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0267302
(31) Preliminary kinetic measurements carried out on the keto-
enol interconversion of 2-nitro-cyclohexanone in aprotic apolar solvents,
such as cyclohexane or carbon tetrachloride, show quite clearly that a
basic catalyst (e.g. triethylamine) is necessary for the tautomerization
to take place. On the contrary, acid species (e.g. trifluoroacetic acid)
apparently inhibit the tautomerization process.
(32) Huisgen, R.; Mader, H. J . Am. Chem. Soc. 1971, 93, 1779.
(33) Yankee, E. W.; Badea, F. D.; Howe, N. E.; Cram, D. J . J . Am.
Chem. Soc. 1973, 95, 4210.
In conclusion the experimental kinetic results and the
above calculations point to a stepwise mechanism of
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Ballini, R.; Sorrenti, P.; Petrini, M. Synthesis 1984, 607. (c) Ballini,
R.; Bosica, G.; Parrini, M. Tetrahedron Lett. 1998, 39, 7963.
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London, UK, 1973.
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