Conformational studies by dynamic NMR. 85. Stereomutation of conformational atropisomers of o-tert-butylphenyl alkyl ketones

Full text of DOI:10.1021/jo010521k

J . Org. Chem. 2001, 66, 7879-7882
7879
Ch a r t 1
Con for m a tion a l Stu d ies by Dyn a m ic NMR.
85.1 Ster eom u ta tion of Con for m a tion a l
Atr op isom er s of o-ter t-Bu tylp h en yl Alk yl
Keton es
Rino Leardini, Lodovico Lunazzi,
Andrea Mazzanti,* and Daniele Nanni*
to the near orthogonality of hindered aryl ketones is
apparently offered by 2,4,6-trihydroxyphenyl acetophe-
none, where the hydrogen bonding seems to maintain the
MeCO and the aryl ring almost coplanar.18
When dealing with non-coplanar phenyl ketones, the
rotation barriers are sufficiently high for NMR detection
only when substituents are present in both the ortho
positions.7,9-11 So far, therefore, restricted rotation has
never been measured by NMR in phenyl ketones contain-
ing solely one ortho substituent,19 the only exception
being the peculiar situation encountered in the racemic
conformer of a phenyl bearing two i-PrCO groups in an
ortho relationship.12a
The latter finding thus suggests that it should be
possible to render NMR visible the Ar-CO bond rotation
if a sufficiently large group is purposely introduced in
one of the two ortho positions of a phenyl ketone. As a
consequence, we synthesized and investigated the fol-
lowing aryl alkyl ketones (1-3, as in Chart 1) where a
tert-butyl substituent is expected to severely hinder the
Ar-CO rotation process.
Department of Organic Chemistry “A. Mangini”, University
of Bologna, Viale Risorgimento, 4 Bologna 40136, Italy
lunazzi@ms.fci.unibo.it
Received May 22, 2001
Unhindered aryl ketones have the plane of the carbonyl
moiety essentially coplanar with that of the aryl ring,
owing to the conjugation occurring between the CdO and
the Ar moieties. The barrier for the rotation process about
the Ar-CO bond (π-barrier) can be measured by dynamic
NMR since at low temperature the ortho positions
become diastereotopic, yielding anisochronous 1H and 13C
signals.2,3 Conversely, hindered aromatic ketones (for
instance, those bearing ortho or ortho-like substituents)
have the plane of the carbonyl group significantly twisted
with respect to that of the aromatic ring, as shown by
the X-ray diffraction structures determined in the crys-
talline state.4-6 In these cases, the rotation barriers
(steric barriers) can be measured by dynamic NMR only
if prochiral probes are also available,7-12 or if pairs of
diastereoisomers are present at the equilibrium.13-15 In
favorable circumstances the barriers become NMR de-
tectable when the hindered ketone adopts a propeller-
like chiral conformation,16 or if the enantiotopic groups
in the molecule can be made diastereotopic by the
presence of an appropriate chiral agent.17 An exception
Molecular mechanics (MM) calculations20 predict that
the planes of the carbonyl and aryl groups of 1 are
orthogonal (dihedral angle ϑ ) 90°), so that the molecule
comprises two stereolabile atropisomers (conformational
enantiomers), indicated as 1 (P) and 1 (M) in Scheme 1.
The rotation about the Ar-CO bond interconverts these
antipodes (enantiomerization), and such a process might
occur, in principle, through two possible transition states.
The one (TS-2) where the benzyl group crosses the tert-
butyl substituent (ϑ ) 180°) entails a theoretical barrier
(16 kcal mol-1) much higher than that (8 kcal mol-1) due
to the transition state (TS-1), where the carbonyl moiety
crosses the tert-butyl substituent (ϑ ) 0°).21 The latter
pathway is therefore expected to be the route followed
by 1 to achieve the interconversion of the two enanti-
omers. As a consequence, the motion about the Ar-CO
bond would not be a complete 2π-rotation pathway: a
π-rotation (from ϑ ) 90° to ϑ ) -90°) is in fact sufficient
to accomplish this process.
(1) Part 84. Garcia, Ma. B.; Grilli, S.; Lunazzi, L.; Mazzanti, A.;
Orelli, L. R. J . Org. Chem. 2001, 66, 6679.
(2) (a) Klinck, R. E.; Marr, D. H.; Stothers, J . B. Chem. Commun.
1967, 409. (b) Klinck, R. E.; Stothers, J . B Can. J . Chem. 1976, 54,
3267.
(3) (a) Drakenberg, T.; Sommer, J . M.; J ost, R. Org. Magn. Reson.
1976, 8, 579. (b) Drakenberg, T.; Sommer, J . M.; J ost, R. J . Chem.
Soc., Perkin Trans. 2 1980, 363.
(4) Sgarabotto, P.; Uguzzoli, F.; Casarini, D.; Lunazzi, L. J . Cryst.
Spectrosc. Res. 1990, 20, 506.
(5) Casarini, D.; Lunazzi, L.; Foresti, E.; Macciantelli, D. J . Org.
Chem. 1994, 59, 4637.
(6) Casarini, D.; Lunazzi, L.; Mazzanti, A.; Foresti, E. J . Org. Chem.
1998, 63, 4991.
(7) Nakamura, N.; Oki, M. Bull. Chem. Soc. J pn. 1972, 45, 2565.
(8) (a) Anderson, J . E.; Cooksey, C. J . Chem. Comm. 1975, 942. (b)
Anderson, J . E.; Barkel, D. I. D. J . Chem. Soc., Perkin Trans. 2 1984,
1053.
(9) Dahlberg, E.; Nilsson, B.; Olson, K., Martinson, P. Acta Chem.
Scand. 1975, B20, 30.
Even allowing for the approximations involved in the
MM approach, the lower of the two enantiomerization
(10) Ito, Y.; Umehara, Y.; Nakamura, K.; Yamada, Y.; Matsuura,
T.; Imashiro, F. J . Org. Chem. 1981, 46, 4359.
(11) (a) Bonini, B. F.; Grossi, L.; Lunazzi, L.; Macciantelli, D. J . Org.
Chem. 1986, 51, 517. (b) Casarini, D.; Lunazzi, L.; Verbeck, R.
Tetrahedron 1996, 52, 2471.
(12) (a) Casarini, D.; Lunazzi, L.; Mazzanti, A. J . Org. Chem. 1997,
62, 7592. (b) Lunazzi, L.; Mazzanti, A.; Mun˜oz Alvarez, A. J . Org.
Chem. 2000, 65, 3520.
(13) Pinkus, A. G.; Kalyanam, N. Chem. Commun. 1978, 201.
(14) Staab, H. A.; Chi, C. S.; Dabrowski, J . Tetrahedron 1982, 38,
3499.
(15) (a) Casarini, D.; Lunazzi, L.; Pasquali, F.; Gasparrini, F.;
Villani, C. J . Am. Chem. Soc. 1992, 114, 6521. (b) Casarini, D.; Lunazzi,
L. J . Org. Chem. 1996, 61, 6240.
(17) (a) Holik, M.; Mannschreck, A. Org. Magn. Reson. 1979, 12,
28. (b) Kiefl, C. Eur. J . Org. Chem. 2000, 3279.
(18) Antypas, W. G., J r.; Siukola, L. V. M.; Kleier, D. A. J . Org.
Chem. 1981, 46, 1172.
(19) Contrary to aryl ketones, aryl aldehydes bearing a single
substituent in the ortho (or ortho-like) position maintain a quasi-
coplanar conformation, thus exhibiting pairs of rotamers of different
stability. See: Drakenberg, T.; J ost, R.; Sommer, J . M. J . Chem. Soc.,
Perkin Trans. 2 1975, 1682. Lunazzi, L.; Ticca, A.; Macciantelli, D.;
Spunta, G. J . Chem. Soc., Perkin Trans 2. 1976, 1121. Drakenberg,
T.; Sandstro¨m, J .; Seita, J . Org. Magn. Reson. 1978, 11, 246. See also
ref 12a.
(20) MMX force field, as implemented in the PC Model 88.0
computer program, Serena Software, Bloomington, IN.
(21) Calculations20 indicate that the rotation barrier of the tert-butyl
(16) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Casazini, D.; Femoni, C.
J . Org. Chem. 2001, 66, 488.
group is as low as 0.5 kcal mol-1
.
10.1021/jo010521k CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/23/2001

7880 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
F igu r e 2. 13C spectra (75.5 MHz) of the methyl region of 3 at
-30 and -145 °C. At the latter temperature, the signal of the
three tert-butyl methyl groups remains a singlet whereas that
of the two methyl groups splits into a pair of lines.
F igu r e 1. Left: experimental 1H signal (400 MHz) of the
methylene hydrogens of 1 as a function of temperature.
Right: computer simulations obtained with the rate constants
indicated.
Ta ble 1. Exp er im en ta l ∆Gq Va lu es,a MM-Com p u ted
Rela tive En er gies (E),a a n d Dih ed r a l An gles (θ)b for th e
Gr ou n d (GS) a n d Low er Rota tion Tr a n sition Sta te (TS-1)
of 1-3
Sch em e 1
compd
1
2(RM)
2(RP)
3
θ (deg)
90
-75
65
75
-73c
53c
∆Gq (expt)
E (GS)
5.5
0
not measurable
0
0
6.7
0
0.4
0.55c
E (TS-1)
8.1
8.2
9.9
a
b
In kcal mol-1
.
Dihedral angles between the CdO and aryl
ring planes in the ground state. c Results from ab initio computa-
tion.22
two enantiotopic methyl groups. At -145 °C, these
methyls become diastereotopic, so that the corresponding
signal splits into a pair of equally intense lines, display-
ing a chemical shift difference as large as 7.5 ppm (Figure
2). The related enantiomerization barrier (6.7 ( 0.2 kcal
mol-1) was found to be higher than that of 1, due to the
increased steric effect: a result also predicted by MM
calculations, as reported in Table 1.
Derivative 2 bears a configurationally stable chiral
center, so that two stereolabile diastereoisomers of dif-
ferent stability (Chart 2) are expected to be observable
when the rotation about the stereogenic Ar-CO axis is
blocked, each diastereoisomer comprising two enantio-
meric forms (i.e., the pair RM, SP and the pair RP, SM).
Since derivative 2 has steric requirements intermedi-
ate between those of 1 and 3, the barrier for the
interconversion of 2 RM into 2 RP cannot be lower than
that of 1: indeed, MM computations predict this barrier
to be essentially equal to that for the enantiomerization
of 1 (Table 1). Although the Ar-CO rotation of 2 should
be consequently frozen at about the same temperature,
yet the 13C spectrum displays signals due to a single
species, even at -160 °C. Unless all the 13C lines of the
barriers predicted for 1 should be amenable to an
experimental observation by NMR spectroscopy. The
spectrum of 1, taken at 400 MHz, actually shows how
the single line of the methylene hydrogens broadens
considerably below -140 °C, eventually exhibiting (at
-162 °C) the typical pattern (∆ν ) 70 Hz, J ) -17 Hz)
of an AB system (Figure 1). This is because the slow Ar-
CO bond rotation makes diastereotopic the two otherwise
enantiotopic methylene hydrogens. Line shape simulation
(Figure 1) provided the rate constants, hence, the ∆Gq
value (5.5 ( 0.15 kcal mol-1), for the corresponding
enantiomerization process.
In derivative 3, the dynamic process was more conve-
niently followed by monitoring the 13C NMR signal of the

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7881
cautiously hydrolyzed with an aqueous 10% ammonium chloride
solution. The organic phase was separated and the aqueous layer
extracted twice with diethyl ether. The combined organic phases
were dried, the solvent removed under vacuum, and the residue
chromatographed to give the title compound (9.5 g, 75%): oil;
IR νmax (neat, cm-1) 3434 (OH); MS m/z 164 (M+ - 90, 100), 91
(36), 57 (50); 1H NMR (200 MHz) δ 1.27 (9 H, s, t-Bu), 2.04 (1 H,
bs, OH), 2.86 (2 H, d, J ) 6.3 Hz, CH2), 5.38 (1 H, t, J ) 6.3 Hz,
Ch a r t 2
CH), 6.99-7.17 (7 H, m, Ar-H), 7.20 (1 H, dd, J 1 ) 7.4 Hz, J 2
)
1.9 Hz, Ar-H), 7.54 (1 H, dd, J 1 ) 7.4 Hz, J 2 ) 1.9 Hz, Ar-H);
13C NMR (50 MHz) δ 32.06, 35.26 (q), 45.45 (CH2), 71.07 (CH),
125.43, 126.34, 127.25, 128.20, 128.33, 129.28, 138.86 (q), 142.95
(q), 146.10 (q) (2 aromatic CH overlapped). Anal. Calcd for
C18H22O: C, 84.99; H, 8.72. Found: C, 85.30; H, 8.70.
1-(2-ter t-Bu tylp h en yl)-2-p h en yleth a n on e (1). Following
the literature,24 concentrated sulfuric acid (2.4 mL) was cau-
tiously added, at 0 °C, to a solution of CrO3 (2.86 g, 29 mmol) in
water (20 mL). The resulting mixture was added dropwise to a
stirred solution of the above alcohol (5.6 g, 22 mmol) in acetone
(10 mL). The reaction course was monitored by TLC; after a few
hours, an approximately 1:1 ketone/alcohol ratio was obtained
that did not change by prolonging the reaction time. After 12 h,
the mixture was diluted with water and extracted with diethyl
ether. The organic phase was dried, the solvent removed under
vacuum, and the residue chromatographed to give, together with
some unreacted starting alcohol (45%), the title ketone (2.8 g,
50%): oil; IR νmax (neat, cm-1) 1703 (CO); MS m/z 252 (M+, 1),
237 (3), 161 (100), 91 (45); 1H NMR (200 MHz) δ 1.35 (9 H, s,
t-Bu), 4.14 (2 H, s, CH2), 7.11 (1 H, dd, J 1 ) 7.1 Hz, J 2 ) 2.0 Hz,
Ar-H), 7.15 (1 H, dd, J 1 ) 6.5 Hz, J 2 ) 1.2 Hz, Ar-H), 7.20-7.38
(6 H, m, Ar-H), 7.47 (1 H, bd, J ) 7.1 Hz, Ar-H); 13C NMR (50
MHz) δ 32.46, 36.60 (q), 51.88 (CH2), 125.84, 126.92, 127.60,
127.87, 129.09, 129.81, 130.46, 134.45 (q), 142.10 (q), 147.62 (q),
207.24 (q). Anal. Calcd for C18H20O: C, 85.67; H, 7.99. Found:
C, 85.82; H, 7.96.
Met h yla t ion of 1-(2-ter t-Bu t ylp h en yl)-2-p h en ylet h a -
n on e. According to the literature,25 in a three-necked round-
bottomed flask sodium hydride (60% dispersion in mineral oil,
0.64 g, 16 mmol) was suspended under stirring at 10 °C in
anhydrous DMF (20 mL) under nitrogen. Methyl iodide (2.8 g,
20 mmol) was added, followed by dropwise addition of a solution
of the above ketone (3.68 g, 15 mmol) in anhydrous DMF (10
mL). After 5 h, the mixture was carefully hydrolyzed with water
and extracted with diethyl ether. The organic phase was dried
and the solvent removed to give an oily residue that was purified
twice by column chromatography and finally by preparative TLC
to yield 1-(2-tert-butylphenyl)-2,2-dimethyl-2-phenylethanone 3
(1.03, 25%) [oil; IR νmax (neat, cm-1) 1690 (CO); MS m/z 280 (M+,
<1), 265 (3), 161 (100), 91 (44); 1H NMR (200 MHz) δ 1.42 (9 H,
s, t-Bu), 1.62 (6 H, s, CMe2), 6.43 (1 H, dd, J 1 ) 7.7 Hz, J 2 ) 1.4
Hz, Ar-H), 6.86 (1 H, bt, J ) 7.5 Hz, Ar-H), 7.16-7.60 (7 H, m,
Ar-H); 13C NMR (50 MHz) δ 28.18, 33.07, 36.63 (q), 52.32 (q),
125.18, 126.68, 127.48, 128.50, 129.33, 129.53, 140.16 (q), 145.41
(q), 148.53 (q), 213.26 (q) (two aromatic CH overlapped). Anal.
Calcd for C20H24O: C, 85.67; H, 8.63. Found: C, 85.89; H, 8.59],
1-(2-tert-butylphenyl)-2-methyl-2-phenylethanone 2 (0.66, 17%)
[oil; IR νmax (neat, cm-1) 1697 (CO); MS m/z 251 (M+ - 15, 3),
161 (100), 91 (55); 1H NMR (200 MHz) δ 1.32 (9 H, s, t-Bu), 1.62
(3 H, d, J ) 7.0 Hz, CHMe), 4.30 (1 H, q, J ) 7.0 Hz, CHMe),
6.62 (1 H, dd, J 1 ) 7.8 Hz, J 2 ) 1.4 Hz, Ar-H), 6.96 (1 H, ddd, J 1
) J 2 ) 7.2 Hz, J 3 ) 1.0 Hz, Ar-H), 7.19-7.35 (6 H, m, Ar-H),
7.45 (1 H, dd, J 1 ) 8.2 Hz, J 2 ) 1.0 Hz, Ar-H); 13C NMR (50
MHz) δ 19.90, 32.71, 36.56 (q), 55.04, 125.43, 127.82, 128.01,
128.99, 129.37, 129.60, 140.99 (q), 141.74 (q), 147.73 (q), 210.74
(q) (two aromatic CH overlapped). Anal. Calcd for C19H22O: C,
85.67; H, 8.32. Found: C, 85.92; H, 8.30], and the starting ketone
(0.56 g, 15%). Some fractions of the first column contained minor
amounts of 1-(tert-butyl)-2-[1-methoxy-2-phenylethenyl]benzene
[1H NMR (300 MHz) δ 1.44 (9 H, s, t-Bu), 3.40 (3 H, s, MeO),
5.50 (1 H, s, CdCH), 7.10-7.40 (6 H, m, Ar-H), 7.49-7.59 (1 H,
m, Ar-H), 7.63-7.73 (2 H, m, Ar-H)] and 1-(tert-butyl)-2-[1-
methoxy-2-phenyl-1-propenyl]benzene [1H NMR (300 MHz) δ
1.44 (9 H, s, t-Bu), 1.73 (3 H, s, CdCMe), 3.19 (3 H, s, OMe),
two diastereoisomers happen to be accidentally coinci-
dent, we must conclude that only one of the two diaste-
reoisomers is appreciably populated. Actually an acci-
dental coincidence is not very plausible since, for instance,
the lines of the five quaternary carbons of 2 have a width
of only 2 or 3 Hz at -160 °C. Had two diastereoisomers
been present in comparable amount, it is unlikely that
not even one of these sharp lines would display the
expected splitting.
It has also to be considered that the poor solubility at
such low temperatures makes, in practice, invisible the
13C spectrum of a minor species having a population
lower than 10-15%. The MM calculations estimate that
diastereoisomer 2 RM is 0.4 kcal mol-1 more stable than
2 RP (Table 1), thus entailing a 85:15 ratio at -160 °C.
Likewise, ab initio calculations22 predict an energy dif-
ference of 0.55 kcal mol-1, which corresponds to a RM
population of 92% at that temperature. If we consider
the differences likely to come about between the situation
computed for the isolated molecule and the experimental
situation occurring in solution, it is quite plausible that
the actual population of the major diastereoisomer is
definitely larger than 90%. This would account for the
NMR detection of only one of the two diastereoisomers,
to which the RM structure should be therefore assigned.
Exp er im en ta l Section
Gen er a l P r oced u r es a n d Ma ter ia l. Mass spectra (MS)
were performed by electron impact with a beam energy of 70
eV: relative intensities are given in parentheses. Column
chromatography was carried out on silica gel (63-200, 60 Å) by
gradual elution with light petroleum (40-70 °C)/diethyl ether
mixtures (from 0 up to 100% diethyl ether). Preparative TLC
chromatography was performed on 1 mm thick aluminum oxide
plates. 2-tert-Butylbenzaldehyde was prepared according to a
known procedure.23
1-(2-ter t-Bu tylph en yl)-2-ph en yleth an ol. A solution of 2-tert-
butylbenzaldehyde (8.0 g, 50 mmol) in dry diethyl ether (25 mL)
was added dropwise to a stirred solution of benzylmagnesium
chloride, obtained by treatment of benzyl chloride (6.85 g, 50
mmol) with magnesium turnings (1.35 g, 50 mmol) in dry diethyl
ether (150 mL). The resulting mixture was stirred for 3 h and
(22) Calculations carried out at the RHF 6-31G* level using the
J aguar 3.5-42 version, as implemented in the computer package Titan,
Wavefunction Inc., Irvine, CA.
(23) Meyers, A. I.; Himmelsbach, R. J .; Reuman, M. J . Org. Chem.
1983, 48, 4053.
(24) Teitei, T. Aust. J . Chem. 1983, 33, 605.
(25) Leardini, R.; Lucarini, M.; Pedulli, G. F.; Valgimigli, L. J . Org.
Chem. 1999, 64, 3726.

7882 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
7.15-7.27 (3 H, m, Ar-H), 7.29-7.41 (3 H, m, Ar-H), 7.46-7.59
(3 H, m, Ar-H)].
responding dependence of the solvent signal was measured. The
appropriate ratio with the line width of the compound was then
taken into account. We also checked that errors as large as 50%
on this value affected the activation energy by less than 0.05
kcal mol-1 in the temperature range investigated.27
NMR Mea su r em en ts. 1H and 13C NMR spectra were re-
corded in deuteriochloroform using tetramethylsilane or deute-
riochloroform, respectively, as internal standards. The assign-
ment of the 13C signals was carried out by DEPT sequences. The
samples for the low-temperature measurements were prepared
by connecting to a vacuum line the NMR tubes containing the
desired compounds dissolved in some C6D6 (for locking purpose)
and condensing therein the gaseous solvents CHF2Cl and
CHFCl2 (in a 4:1 proportion) by means of liquid nitrogen. The
tubes were subsequently sealed in vacuo and introduced into
the precooled probes of the 300 or 400 MHz spectrometers. The
temperatures were calibrated by substituting the sample with
a precision Cu/Ni thermocouple before the measurements. Total
line shape simulations were achieved by using a PC version of
the DNMR-6 program.26 Since at the low temperatures required
to observe the exchange process the intrinsic line width of the
compounds was significantly temperature dependent, the cor-
Ack n ow led gm en t. Thanks are due to the I.Co-
.C.E.A. Institute of CNR (Bologna) for access to the 400
MHz spectrometer. Financial support has been received
from MURST (national project “Stereoselection in Or-
ganic Synthesis”) and from the University of Bologna
(Funds for selected research topics 1999-2001).
Su p p or tin g In for m a tion Ava ila ble: MMX computed20
Z-matrixes for compounds 1-3 and ab initio computed22
Z-matrixes for compounds 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O010521K
(26) PC version of the QCPE program no. 633, Indiana University,
Bloomington, IN.
(27) Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org. Chem. 2000, 65,
3653.