Conformational studies by dynamic NMR. 57.1 stereodynamics of syn-anti interconversion of disubstituted acyl durenes

Article abstract of DOI:10.1021/jo9604503

The orthogonal syn and anti isomers, originated by the restricted rotation about the Ar-C(O)Bu^t single bonds in 1,4-bis(2,2-dimethylpropanoyl)durene (2e), have been separated by preparative thin layer chromatography. In solution they reach an equilibrium where the syn-anti ratio depends upon the polarity of the solvent. This allowed us to assign the anti structure, which has a null dipole moment, to the least retained isomer. The free energy of activation (ΔG*) for the interconversion was found to be 22.5 kcal mol^-1, a value high enough for identifying these species as configurational isomers. When less hindered derivatives, also having two RCO (R = Prⁱ, Et, Me) substituents in the positions 1,4 of the durene moiety, were examined, the syn and anti forms could be detected only at low temperature by means of NMR spectroscopy. The corresponding interconversion barriers (ΔG* = 13.4, 11.7, 10.9 kcal mol^-1, respectively) are, in fact, much lower than for R = Bu^t, indicating that in these cases we are dealing with conformational rather than with configurational isomers.

Full text of DOI:10.1021/jo9604503

6240
J . Org. Chem. 1996, 61, 6240-6243
Con for m a tion a l Stu d ies by Dyn a m ic NMR. 57.1 Ster eod yn a m ics
of Syn -An ti In ter con ver sion of Disu bstitu ted Acyl Du r en es†
Daniele Casarini* and Lodovico Lunazzi
Department of Organic Chemistry “A. Mangini”, University of Bologna,
Risorgimento 4 Bologna 40136, Italy
Received March 5, 1996X
The orthogonal syn and anti isomers, originated by the restricted rotation about the Ar-C(O)But
single bonds in 1,4-bis(2,2-dimethylpropanoyl)durene (2e), have been separated by preparative thin
layer chromatography. In solution they reach an equilibrium where the syn-anti ratio depends
upon the polarity of the solvent. This allowed us to assign the anti structure, which has a null
dipole moment, to the least retained isomer. The free energy of activation (∆G*) for the
interconversion was found to be 22.5 kcal mol-1, a value high enough for identifying these species
as configurational isomers. When less hindered derivatives, also having two RCO (R ) Pri, Et,
Me) substituents in the positions 1,4 of the durene moiety, were examined, the syn and anti forms
could be detected only at low temperature by means of NMR spectroscopy. The corresponding
interconversion barriers (∆G* ) 13.4, 11.7, 10.9 kcal mol-1, respectively) are, in fact, much lower
than for R ) But, indicating that in these cases we are dealing with conformational rather than
with configurational isomers.
In tr od u ction
Recently we have shown how the barrier to rotation
about the Ar-C(O)R bond in derivatives of type 1 (R )
Me, Et, Pri, But) can be measured in a chiral environment
by dynamic NMR spectroscopy.1
Indeed a case has been reported where analogous
halogenated acyl derivatives (e.g. 2, R ) CCl3) displayed,
at room temperature, separated NMR signals for the
orthogonal syn and anti isomers.3 There, however, the
interconversion barrier was still too low (i.e. ∆G* ) 18.8
3
kcal mol-1
)
for allowing a physical separation to be
Such an experiment has been made possible by the
orthogonality of the Ar (Ar ) 2,4,6-trimethylphenyl) and
RCO planes1,2 which renders the otherwise enantiotopic
o-methyl groups diastereotopic in the presence of a chiral
environment at appropriate low temperatures. When R
is a tert-butyl group a barrier (∆G*) of 19.2 kcal mol-1
was measured.1 In these nonplanar ketones it is ex-
pected that substitution of the methyl group in the para
position of a derivative of type 1 with an electron-
withdrawing substituent would enhance the Ar-C(O)R
rotational barrier. Electron-withdrawing substituents
should in fact destabilize the planar rotational transition
state (where the phenyl-carbonyl conjugation delocalizes
a positive charge upon the aromatic ring) without sig-
nificantly affecting the orthogonal rotational ground
state, where such a kind of conjugation cannot occur. As
a consequence the introduction of an electron-withdraw-
ing carbonyl group in the place of the electron-releasing
methyl group in the para position of 1 (R ) tert-butyl)
should make the Ar-C(O)But rotational barrier signifi-
cantly higher. It is therefore conceivable that the sym-
metrically substituted 1,4-diacyl durene 2e, (R ) But)
constitutes a pair of syn,anti isomers which might pos-
sibly be amenable to a physical separation.
attained, at least at room temperature.
Thus we have here undertaken the synthesis of deriva-
tives of type 2 in order to isolate the pair of syn and anti
isomers in the case of 2e, to assign the corresponding
structures, to measure the interconversion barrier, and
to determine the dependence of such a barrier on the
steric hindrance by comparing the ∆G* value of 2e with
those of 2d , 2c, 2b (R ) Pri, Et, Me, respectively).
Resu lts a n d Discu ssion
Preparative thin layer chromatographic separation of
2e afforded two isomeric compounds, each exhibiting a
1
two line H NMR spectrum, with a 3:2 relative intensity,
as expected for six and four equivalent methyl groups.
These isomers have the structures displayed in Scheme
1, as obtained by molecular mechanics calculations.4
The two NMR signals (300 MHz in CDCl3) of the least
retained isomer were found at 1.214 ppm (tert-butyl) and
2.053 ppm (aryl bonded methyl groups), whereas the
most retained isomer had the corresponding signals at
1.209 and 2.044 ppm, respectively (Table 1). Each
isomer, on standing in a CDCl3 solution, slowly develops
the pair of NMR signals for the other isomer (Figure 1)
until an equilibrium is reached whereby the upfield pair
of signals become 36% and the downfield 64%, at 21 °C.
† This work is dedicated to the memory of Professor Carlo Zauli,
1931-1994.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Part 56: Casarini, D.; Lunazzi, L.; Verbeek, R. Tetrahedron 1996,
52, 2471.
(3) Pinkus, A. G.; Kalyanam, N. J . Chem. Soc., Chem. Commun.
1978, 201.
(2) Bear, C. A.; Macdonald, A. L.; Trotter, J . Acta Crystallogr. 1973,
B29, 2716.
(4) The MMX force field (as implemented in the program PC Model,
Serena Software, Bloomington, IN) has been employed.
S0022-3263(96)00450-1 CCC: $12.00 © 1996 American Chemical Society

Syn-Anti Interconversion of Disubstituted Acyl Durenes
J . Org. Chem., Vol. 61, No. 18, 1996 6241
Sch em e 1. MM-Com p u ted Str u ctu r es of th e Syn
a n d An ti Isom er s of 2e: th e Ca r bon yl Bon d s Ar e
P r esen ted a s Bla ck for Con ven ien ce
Ta ble 1. Rela tive P r op or tion of th e An ti a n d Syn
Isom er s of 2e in Solven ts of Low a n d High P ola r ity. Th e
1H Sh ifts (300 MHz) for th e Tw o Isom er s Ar e Also
Rep or ted
dielectric percent of shift (ppm) shift (ppm)
solvent
CDCl3
constant (ꢀ) isomers
of methyl-Ar of tert-butyl
low (4.8)
low (2.6)
low (2.4)
anti: 64
syn :36
anti: 68
syn :32
anti: 60
syn :40
anti: 47
syn :53
anti: 48
syn :52
anti: 50
syn :50
2.053
2.044
1.983
1.972
2.055
2.043
2.072
2.058
2.268
2.255
1.995
1.984
1.214
1.209
1.158
1.133
1.209
1.201
1.204
1.193
1.420
1.400
1.147
1.136
CS2
C2Cl4
acetone-d6 high (25.0)
CD3OD high (32.6)
DMSO-d6 high (46.5)
F igu r e 1. Top: 1H signals (300 MHz) of the aryl-bonded
methyl groups (left) and of the tert-butyl groups (right) of the
most retained isomer (syn) of 2e (2.044 and 1.209 ppm,
respectively) taken about 20 min after being dissolved in
CDCl3. The weaker signals (starred) of the least retained
isomer (anti) begin to appear at lower field. Bottom: 1H signals
(300 MHz) of the same groups of the least retained isomer
(anti) of 2e (2.053 and 1.214 ppm, respectively) taken about
20 min after being dissolved in CDCl3. The weaker signals
(arrowed) of the most retained isomer (syn) begin to appear
at higher field.
Similarly the 13C spectrum of 2e at the equilibrium
displays, in CDCl3, six lines for each isomer, those upfield
corresponding to the least stable isomer (Table 2).
Analysis of the kinetic process afforded a first order
rate constant for the transformation of the more into the
less stable isomer (k ) 5.8 × 10-5 s-1, in CDCl3 at 21
°C), hence a ∆G* value of 22.5 kcal mol-1 (a transmission
1
coefficient of /2 was used to account for the fact that
Ta ble 2. 13C Ch em ica l Sh ifts (p p m ) of th e An ti a n d Syn
Isom er s of 2e a t th e Equ ilibr iu m in CDCl3 a t 75.5 MHz
rotation of either of the two ButCO groups allows to
achieve the interconversion).5 Such a value confirms the
prediction of a substantial increase of the rotational
Μe(2,3,5,6) Me(But) C(But) C(2,3,5,6) C(1,4)
CO
barrier in 2e with respect to the value (19.2 kcal mol-1
)
anti (64%)
syn (36%)
17.97
17.79
28.03
27.79
45.24
42.78
128.81
128.76
141.98 219.68
141.54 218.48
measured for Ar-C(O)But (Ar ) 2,4,6-trimethylphenyl).1
When each of the two isomers of 2e is allowed to reach
the equilibrium in acetone-d6, rather than in CDCl3, the
ratio of the two isomers is reversed: the most retained
one (which also in acetone displays upfield NMR signals)
becomes now 53% (the free energy of activation for the
interconversion, on the contrary, remains essentially the
same). This suggests that the most retained isomer
should have the syn structure which, contrary to the anti,
must exhibit a substantial dipole moment. Its stability,
in fact, increases in acetone (a polar solvent) with respect
to the case of a less polar solvent such as chloroform. This
was further confirmed by investigations in two additional
nonpolar solvents (CS2 and C2Cl4) where a ratio similar
to that of CDCl3 was observed (Table 1). Conversely in
other polar solvents (CD3OD and DMSO-d6) the ratio
became approximately 50:50 (Table 1).
The assignement of the anti structure to the most
stable species in non polar solvents also agrees with the
MM theoretical calculations4 for an isolated molecule of
2e: the anti is predicted to have an energy 1.7 kcal mol-1
lower than the syn (the computed dipole moments being,
respectively, 0.0 and 4.5 Debye).
Less hindered compounds, like 2d , 2c, 2b (R ) Pri, Et,
Me, respectively), display separated NMR signals for the
syn and anti species only at temperatures much lower
than ambient (they could only be detected by low tem-
perature NMR spectroscopy), in that the corresponding
interconversion rates are much faster. Thus in these
cases we are dealing with a pair of syn,anti conforma-
tional isomers rather than with a pair of configurational
isomers. For instance in the case of 2d (R ) Pri) only at
-55 °C the aryl-bonded methyl groups display a pair of
1H signals (ratio ∼2:1 for the downfield and upfield lines,
respectively) in nonpolar solvents such as CD2Cl2 and
(5) Sandstro¨m, J . Dynamic NMR spectroscopy; Academic Press:
London, 1982.

6242 J . Org. Chem., Vol. 61, No. 18, 1996
Casarini and Lunazzi
Ta ble 3. In ter con ver sion Ba r r ier (∆G* in k ca l m ol-1
)
a n d An ti/Syn Ra tio a t th e Equ ilibr iu m for Com p ou n d s
2b-e a t Ap p r op r ia te Tem p er a tu r es
compd
∆G*
Anti:Syn
temp (°C)
solvent
2b (RdMe)
2c (RdEt)
2d (RdPri)
2e (RdBut)
10.9
11.7
13.4
22.5
22.5
67:33
63:37
68:32
64:36
47:53
-85
-65
-55
+21
+30
CHF2Cl
CD2Cl2
CD2Cl2
CDCl3
acetone-d6
CDCl3. In agreement with the observations made in the
case of 2e the conformers ratio of 2d becomes about 1:1
in polar solvents (e.g. CD3OD and acetone-d6, at -55 °C).
A further support is thus offered to the proposed assign-
ment of the anti structure to the more stable conformer
in nonpolar solvents. The barrier for the interconversion
(∆G* ) 13.4 kcal mol-1, Table 3) was determined by
complete line shape analysis of the two 13C signals of the
isopropyl methyl groups, which exhibit a sufficiently
large chemical shift difference (12.5 Hz at 300 MHz).
For the less hindered derivatives 2c (R ) Et)6 and 2b
(R ) Me),7 the barriers (Table 3) were found even lower
(11.7 and 10.9 kcal mol-1, respectively): as an example
the temperature dependence of the acetyl methyl 1H
signals of 2b is reported in Figure 2, accompanied by the
appropriate line shape simulation.
F igu r e 2. Experimental (left) 1H signals (300 MHz in CHF2Cl)
of the methyl groups of the acetyl moieties of 2b as function
of temperature. On the right the computer simulation, ob-
tained with the rate constants (k in s-1) indicated, are also
displayed.
The differences between the ∆G* values of 2e (R ) But)
and 2d (R ) Pri) is much larger (i.e. 9.1 kcal mol-1) than
the difference between the values of 2d and 2c (i.e. 1.7
kcal mol-1) as well as between that of 2c and 2b (i.e. 0.8
kcal mol-1). This somehow reflects the much larger steric
hindrance of the tert-butyl group with respect to the other
alkyl groups. The same trend had been also found in acyl
mesityl ketones (i.e. derivatives of type 1): for R ) But,
Pri, Et, Me their ∆G* values are, in fact, 19.2, 9.1, 7.2,
6.1, respectively.1 The barriers observed here for com-
pounds of type 2 are, as an average, 4.2 kcal mol-1 larger
than those of the corresponding acyl mesityl ketones, 1.
This seems too large an enhancement to be solely
explained by the electron-withdrawing properties of the
second RCO moiety in position 4.8 An additional contri-
bution to this enhancement should be also attributable
to the reciprocal buttressing effect of the aryl-bonded
methyl groups in derivatives 2. For example, the pair
of methyl groups in positions 2,6 would be pushed closer
to the RCO moiety in position 1 by the presence of the
second pair of methyl groups in positions 3,5 (the same
would obviously occur for the methyl groups in positions
3,5 with respect to the acyl substituents in position 4).
As a consequence the aryl-bonded methyl groups in
derivatives of type 2 can exert a greater steric hindrance
upon the RCO moieties, further enhancing the corre-
sponding Ar-C(O)R rotational barriers. Such an inter-
pretation seems, apparently, supported also by molecular
mechanics calculations.4 In the case of 2e, for instance,
the computed geometry suggests a Me(2)-C(2)-C(1)
angle of 121° whereas in the tert-butyl mesityl ketone
(1, R ) But) the same angle is computed to be slightly
wider (i.e. 123°). The buttressing effect might be indeed
responsible for such a difference.
Not even at -140 °C (in CHF2Cl, at 300 MHz) was it
possible to detect dynamic NMR features leading to
observable conformers in the case of 2a (R ) H). This is
because 2a , contrary to 2b-e, adopts a planar conforma-
tion, according to theoretical calculations and lanthanide
induced shift (LIS) measurements carried out on a
similar derivative (mesitylaldehyde).9 Also, the com-
puted Ar-C(O)H (Ar ) 2,4,6-trimethylphenyl) rotational
barrier is predicted10 to be too low for NMR detection,
contrary to the case of less hindered benzaldehydes.11
Con clu sion s
Durene derivatives containing a pair of RCO groups
in positions 1,4 display syn,anti conformers due to
restricted rotation about the Ar-C(O)R single bonds, the
corresponding dihedral angles being essentially orthogo-
nal.1,2 The free energy of activation (∆G*) for the
interconversion increases with the increasing bulkiness
of the alkyl groups (R) of the acyl moiety, eventually
reaching, for R ) tert-butyl, a value high enough as to
transform the stereolabile conformers into configuration-
ally stable isomers. Although isolation of one of the two
enantiomers arising from restricted motions in aryl
ketones had been reported,12,13 this represents a quite
(6) The low temperature 1H spectrum of 2c does not display, even
at 300 MHz, separate signals for the syn and anti conformers: only
an unresolved shoulder was observed for the triplet of the methyl group
of the EtCO moiety. This accidental coincidence outlines how the
chemical shift of the aryl-bonded methyl groups cannot be used for
conformational assignment. A meaningful line shape analysis could
only be obtained by monitoring the 13C lines of the CO moiety which,
in CD2Cl2 at -65 °C, display a relatively large separation (33 Hz at
75.5 MHz).
(7) The position of the lines due to the aryl-bonded methyl groups
is reversed in 2b with respect to 2d , 2e in that the signal of the more
stable (anti) conformer appears upfield (by 0.005 ppm) rather than
downfield. This confirms once more how the relative chemical shifts
of these groups do not follow a pattern which can be related to the
structure in a simple manner.
(9) Abraham, R. J .; Angiolini, S.; Edgar, M.; Sancassan, F. J . Chem.
Soc., Perkin Trans 2 1995, 1973.
(10) Andersson, S.; Carter, R. E.; Drakenberg, T. Acta Chem. Scand.
1984, B38, 579.
(11) Lunazzi, L.; Ticca, A.; Macciantelli, D.; Spunta, G. J . Chem.
Soc., Perkin Trans 2 1976, 1121.
(8) J ennings, W. B.; Saket, B. M. J . Chem. Soc., Perkin Trans. 2
1985, 1005.

Syn-Anti Interconversion of Disubstituted Acyl Durenes
J . Org. Chem., Vol. 61, No. 18, 1996 6243
GC-MS showed a 306 m/e peak and the complete disappear-
ance of the starting material. The mixture was cooled to room
temperature and 10 mL of distilled water was added. The
organic layer was separated, washed (4 × 20 mL), and dried
over Na2SO4, and the solvent was removed by distillation at
reduced pressure. The crude product (0.8 g) was directly used
in the next reaction.
unusual case of isolable syn and anti isomers, due to
restricted rotation about the Ar-CO single bond.
Exp er im en ta l Section
Ma ter ia ls. 1-(2,3,5,6-Tetr a m eth yl-4-p r op ion ylp h en yl)-
p r op a n -1-on e (2c) was obtained with the same method
reported for 2b.14 1H NMR (CDCl3) δ 1.12 (t, 3 H, Me), 2.0 (s,
6 H, Me), 2.63 (q, 2 H, CH2). 13C NMR (CDCl3) δ 7.2 (Me),
16.0 (Me, Ar), 38.3 (CH2), 128.8 (CH, Ar), 143.3 (quat, Ar),
212.2 (quat, CO). Anal. Calcd for C16H22O2: C, 78.01; H, 9.00.
Found: C, 78.05; H, 9.03.
1-[4-(2,2-D im e t h y lp r o p a n o y l)-2,3,5,6-t e t r a m e t h y l-
p h en yl]-2,2-d im eth ylp r op a n -1-on e (2e). In a three-necked
flask was suspended 1.3 g (10 mmol) of pyridinium chloro-
chromate in 15 mL of dry CH2Cl2; 0.8 g (2.6 mmol) of 3 in 2.5
mL of dry CH2Cl2 was added in one portion, and the mixture
vigorously stirred at room temperature. After stirring for 2 h
the reaction was completed and a GC-MS showed only a 302
m/e peak. A 25 mL volume of Et2O was then added, and a
black gum precipitate was observed. The mixture was filtered
off, and the solvent removed at reduced pressure. The crude
product (0.5 g) was purified by chromatography using as a
solvent n-hexane/Et2O 97:3. From the column was obtained
220 mg of a syn/anti isomer mixture (∼60/40) and a fraction
of 70 mg of a white, crystalline solid of pure anti isomer. Thin
layer chromatography of the mixture allowed to isolate both
1-(4-Isob u t yr yl-2,3,5,6-t et r a m et h ylp h en yl)-2-m et h yl-
p r op a n -1-on e (2d ). 1H NMR (CDCl3) δ 1.18 (d, 6 H, Me),
2.1 (s, 6 H, Me), 2.9 (m, H, CH). 13C NMR (CDCl3) δ 16.6 (Me),
17.4 (Me), 42.5 (CH), 129.1 (CH, Ar), 142.1 (quat, Ar), 214.5
(quat, CO). Anal. Calcd for C18H26O2: C, 78.78; H, 9.56.
Found: C, 78.75; H, 9.53.
Compounds 2d and 2e were synthesized by reacting 2a 15
with the appropriate Grignard or lithium alkyl derivatives,
followed by oxidation16 of the intermediate diol 3 to a diketone.
The preparation is reported for the di-tert-butyl derivative 2e
and its intermediate 3.
1
the syn and the anti isomers. The corresponding H and 13C
spectra are reported in Tables 1 and 2. Anal. Calcd for
C20H30O2: C, 79.42; H, 10.00. Found: C, 79.37; H, 9.9.
NMR Mea su r em en ts. The spectra at variable tempera-
ture were obtained at 300 MHz, the temperatures having been
calibrated by means of the shift of methanol. The errors are
believed not to exceed (2 °C. The line shape analyses were
carried out by means of a PC program based upon the Bloch
equations.5
1-[4-(1-Hyd r oxy-2,2-d im eth ylp r op yl)-2,3,5,6-tetr a m eth -
ylp h en yl]-2,2-d im eth ylp r op a n -1-ol (3). To a solution of 0.5
g (2.6 mmol) of 2a in 30 mL of dry Et2O, kept at -20 °C under
N2, was added 3.0 mL (1.24 mmol) of tert-butyllithium (1.5M)
in pentane (Acros). The temperature was allowed to reach 20
°C, and the mixture was subsequently refluxed. After 8 h a
(12) Narayanan, K. V.; Selvaraian, R.; Swaminathan, S. J . Chem.
Soc (C) 1968, 540. See also: Finocchiaro, P.; Gust, D.; Mislow, K. J .
Am. Chem. Soc. 1972, 96, 3198.
(13) Pinkus, A. G.; Riggs, I., J r.; Broughton, S. M. J . Am. Chem.
Soc. 1968, 90, 5043. The enantiomer isolated here was, however, quite
short lived having a lifetime of 6.2 min at 20.5 °C.
(14) (a) Pinkus, A. G.; Klyanam, N. Org. Prep. Proc. Int. 1978, 10,
255. (b) Andreou, A. D.; Bulbulian, R. V.; Gore, P. H. Tetrahedron 1980,
36, 2101.
Ack n ow led gm en t. Financial support from the Min-
istry of the University and Scientific Research (MURST)
and from the National Research Council (CNR), Rome,
is acknowledged. This work was carried out in the
frame of the “Progetto di Finanziamento Triennale,
Ateneo di Bologna”.
(15) Yakubov, A. P.; Tsyganov, D. V.; Belen’kii, L. I; Krayushkin,
M. M. Tetrahedron 1993, 49, 3397.
(16) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982, 245.
J O9604503