11486 J. Am. Chem. Soc., Vol. 118, No. 46, 1996
Guthrie and Guo
2,6-heptanedione (judged by HPLC): 1H NMR (200 MHz, CDCl3) δ
(TMS) 1.78-1.92 (2H, quintet) CCH2C, 2.14 (6H,s) CH3CO, 2.45-
2.52 (4H,t) CH2CO.
ratio for 4a. However in the intermolecular analog, the rate
constants for aldol addition of the enolate of acetone to acetone
or acetaldehyde are similar, which suggests that in fact the
observed rate constant may reflect at least partially rate-limiting
C-C bond formation. Furthermore, the observed rate constant
leads to a value of the intrinsic barrier, G˜ , consistent with the
other intrinsic barriers calculated. If the rate-determining step
were in fact deprotonation, then by using the average G˜ value
for aldol addition one would calculate a rate constant only 5-fold
faster than the value we have used. Recently Koch et al.52
reported a study of the aldol cyclization of 7-aryl-5-oxoheptanal,
including an evaluation of the rate constant for carbon-carbon
bond formation from the enolate. From their data we can
calculate a rate constant for this step of 1.6 × 105 s-1, which is
similar to the value of 7 × 104 s-1 calculated for the
corresponding step for 5-oxohexanal using the observed rate
constant and the estimated rate constant for deprotonation.
Estimation of ∆Gf(aq). For some time we have been
concerned with the problem of estimating ∆G°f and Keq from
molecular structure.2,31 The systems discussed in this work
provide an incentive and opportunity to apply these techniques
to multifunctional compounds. Although estimation by group
additivity31,53 or molecular mechanics32,49,54,55 is straightforward
and generally reliable for monofunctional compounds, the
problem is much more difficult for molecules with more than
one potentially interacting functional group. It is clear that there
are important effects on solvation of molecules from such
interactions.38,56 We tried various approaches and discovered
that errors of over 3 kcal/mol were all too likely unless the
following guidelines were employed:
2,5-Hexanedione Bis(2,4-dinitrophenylhydrazone) (Bis-DNPH).
DNP solution (150 mL) was prepared by a standard method.58 To this
DNP solution was added 10 mL of 2,5-hexanedione (0.8 mL) solution
in 95% EtOH. A yellow precipitate appeared immediately, and the
reaction mixture was allowed to stand for another 1 h at room
temperature; 3.25g (100%) of yellow solid was obtained after filtration.
Recrystallization from pyridine gave pure bis-DNPH (judged by
HPLC): MS, m/e 474 (M+, 5%); mp 259 °C, UV (CHCl3) λmax 367
nm (4.64). Literature:59 mp 260 °C,60 UV (CHCl3) λmax 362 nm (4.64).
3-Hydroxy-3-methylcyclopentanone was synthesized following a
literature procedure61 used for the preparation of 3-hydroxy-3-phenyl-
cyclohexanone, as follows: An ethereal solution (250 mL) of meth-
ylmagnesium iodide from methyl iodide (11.4 mL, 0.18 mol) and
magnesium turnings (4.5 g, 0.18 mol) was prepared in the pot of a
Soxhlet extractor. The extraction thimble was charged with 1,3-
cyclopentanedione (3.0 g, 30.6 mmol) and the extraction process
continued under nitrogen for 24 h. The reaction mixture was cooled
in an ice bath and quenched by solid ammonium chloride (19.3 g, 0.36
mol) and then water (10 mL). The ether layer was separated, the residue
was extracted by ether (4 × 150 mL), and the combined ether extracts
were dried over anhydrous MgSO4. Column chromatography (silica
gel 60, 0.063-0.2 mm, from Chemica Alta Ltd., eluting with 4:1 ethyl
acetate-petroleum ether) gave 71 mg (2.0%) of 3-hydroxy-3-methyl-
cyclopentanone (ketol-1): 1H NMR (300 MHz, CDCl3) δ 1.51 (s, 3
H), 1.73 (s, 1 H), 1.84-2.50 (m, 6 H); MS, m/z 114 (M+, 30%), 96
(100%). Literature62 data for ketol-1: 1H NMR (CDCl3) δ 1.50 (s, 3
H), 1.90-2.60 (m, 7 H); MS, m/z 114 (M+, 27%), 96 (100%).
1-Phenyl-1,5-hexanedione was synthesized by published proce-
dures.63 The product from the reaction was found to be pure (judged
by HPLC), and the structure was confirmed by NMR: 1H NMR (300
MHz, CDCl3) δ 2.05 (quintet, 2 H, CH2CH2CH2), 2.19 (s, 3 H, CH3),
2.60 (t, 2 H, CH2COCH3), 3.05 (t, 2 H, CH2COPh), 7.4-8.0 (m, 5 H,
aromatic H); UV (H2O) λmax 246 nm (log ꢀ ) 3.96).
In disproportionation reactions all important interactions
between functional groups must be matched in both starting
materials and products. If an interaction perturbs ∆Gt, it will
3-Hydroxy-3-phenylcyclohexanone (ketol-3) and 3-phenyl-2-
cyclohexen-1-one (enone-3) were prepared following Woods’s pro-
cedure,61 by reaction of phenylmagnesium bromide with cyclohexadi-
enone.
Recrystallization from ether gave pure 3-hydroxy-3-phenylcyclo-
hexanone (judged by HPLC): 1H NMR (300 MHz, CDCl3) δ 1.94-
2.12 (m, 2 H), 2.16-2.30 [m and s(OH), 3 H], 2.36-2.58 (m, 2 H),
2.60-3.00 (AB system, 2 H, CH2 at C-2), 7.3-7.6 (m, 5 H, aromatic
H); 13C NMR (75 MHz, CDCl3) δ 21.8 (C-5), 38.0 and 41.0 (C-4 and
C-6), 49.0 (C-3), 55.0 (C-2), 124.0, 127.8, 128.2 and 147.0 (aromatic
C), 210 (C-1) (1H-1H and 1H-13C COSY experiments were also carried
out for ketol-3, which confirmed the structure assignments); UV (H2O)
257 nm (2.66).
surely perturb ∆Gdisproportionation
.
A molecular mechanics calculation can only be as good as
the parameters involved in itsif they are not solidly based, the
results will be unreliable. This applied to calculations involving
enones. The published parameters are based on few compounds
and must be regarded as preliminary.
Conclusions
1. Marcus theory can be applied to intramolecular aldol
additions, leading to essentially the same intrinsic barrier as for
intermolecular aldol additions.
2. It appears that effective molarities for rates of reaction
can be calculated by thermodynamic estimation combined with
Marcus theory, once appropriate parameters have been evalu-
ated.
Recrystallization from petroleum ether (35-60 °C) gave pure
3-phenyl-2-cyclohexen-1-one (judged by HPLC): 1H NMR (300 MHz,
CDCl3) δ 2.2 (quintet, 2 H, CH2 at C-5), 2.5 (t, 2 H, CH2 at C-6), 2.8
(t, 2 H, CH2 at C-4), 6.45 (s, 1 H, olefinic H), 7.4-7.6 (m, 5 H, aromatic
H); UV (H2O) 289 nm (4.31).
Experimental Section
1-Methylcyclopentene. A solution of cyclopentanone (20.0 g, 0.238
mol) in ether (100 mL) was added to an ethereal solution of
methylmagnesium iodide (3 M, 95 mL) under nitrogen within 30 min.
The reaction mixture was stirred at room temperature for another 3 h,
and then the reaction was quenched by the addition of hydrochloric
acid (3 M, 100 mL). The ether layer was separated, and the aqueous
layer was extracted by ether (3 × 100 mL). The combined ether
(57) Mecheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland,
L. A.; Sciamanna, W. J. Org. Chem. 1975, 40, 675.
(58) Shriner, R. L.; Fuson, R. C.; Curtin, D. Y. The Systematic
Identification of Organic Compounds, 4th ed.; Wiley: New York, 1956.
(59) Jones, L. A.; Hancock, C. K.; Seligman, R. B. J. Org. Chem. 1961,
26, 228.
Materials. 2,5-Hexanedione (98%), 3-methyl-2-cyclopenten-1-one
(97%), and 3-methyl-2-cyclohexen-1-one (98%) were obtained from
Aldrich; diacetone alcohol (97%) was from BDH and 2,4-dinitrophe-
nylhydrazine (DNP) from Eastman. 2-Cyclohexen-1-one (enone-4,
98%) was from Aldrich and diacetone alcohol (97%) from BDH. All
compounds were used as supplied but were checked by H NMR and
HPLC before being used in this work.
2,6-Heptanedione was synthesized from formaldehyde and diketene
by published procedures.57 Recrystallization from n-hexane gave pure
1
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