Conformational studies by dynamic NMR. 74. Stereomutations of the conformational enantiomers in peri-substituted 1-acylnaphthalenes

Article abstract of DOI:10.1021/jo991853g

Naphthalenes bearing an acyl and a phenyl group in a peri relationship give rise to a pair of enantiomers in the temperature range where the rotations of the acyl group are slow. Such enantiomers were observed by means of low temperature NMR spectra in chiral environments. The barrier to rotation for the acyl substituents, that causes the interconversion of the enantiomers, was demonstrated to be lower than that for the phenyl group. In an appropriately synthesized derivative it was possible to measure the two barriers that were found equal to 10.4 and 15.9 kcal mol^-1, respectively. The barriers for the acyl group rotation increase regularly (from 9.5 to 13.2 kcal mol^-1) with the increasing dimension of the RCO groups (R = Me, Et, Pr(i), Bu(t)). When a bromine atom replaces the phenyl group, the enantiomerization barrier for the corresponding acyl derivatives increases significantly.

Full text of DOI:10.1021/jo991853g

3200
J . Org. Chem. 2000, 65, 3200-3206
Con for m a tion a l Stu d ies by Dyn a m ic NMR. 74.1 Ster eom u ta tion s of
th e Con for m a tion a l En a n tiom er s in P er i-Su bstitu ted
1-Acyln a p h th a len es
Lodovico Lunazzi,* Andrea Mazzanti,* and Anna Mun˜oz AÄ lvarez2
Department of Organic Chemistry “A.Mangini”, University of Bologna,
Risorgimento, 4, Bologna 40136, Italy
Received December 2, 1999
Naphthalenes bearing an acyl and a phenyl group in a peri relationship give rise to a pair of
enantiomers in the temperature range where the rotations of the acyl group are slow. Such
enantiomers were observed by means of low temperature NMR spectra in chiral environments.
The barrier to rotation for the acyl substituents, that causes the interconversion of the enantiomers,
was demonstrated to be lower than that for the phenyl group. In an appropriately synthesized
derivative it was possible to measure the two barriers that were found equal to 10.4 and 15.9 kcal
mol-1, respectively. The barriers for the acyl group rotation increase regularly (from 9.5 to 13.2
kcal mol-1) with the increasing dimension of the RCO groups (R ) Me, Et, Pri, But). When a bromine
atom replaces the phenyl group, the enantiomerization barrier for the corresponding acyl derivatives
increases significantly.
In tr od u ction
about the naphthyl-CO and that about the naphthyl-
aryl bonds are expected to be different, so that the
restriction of the two motions will be detectable in
different temperature ranges. With the purpose of study-
ing the dynamic processes in this type of derivatives, the
following 1,8-disubstituted naphthalene compounds 1-5
have been prepared and investigated by dynamic NMR
spectroscopy:
Naphthalenes bearing two aromatic substituents lack-
ing a local C2 symmetry axis in the peri positions 1 and
8 give rise to stereolabile diastereoisomers, owing to the
restricted naphthyl-aryl bond rotation.3-6 This is a
consequence of the planes of the aryl moieties being
orthogonal to that of naphthalene.3-7 The values of the
corresponding barriers depend on the steric and elec-
tronic effects of the substituents and cover a range of 14-
25 kcal mol-1 3-6
Likewise, the presence of two acyl
.
groups in the peri relationship originates analogous
stereolabile diastereoisomers since the same type of
orthogonal conformation is adopted; the corresponding
rotation barriers about the naphthyl-CO bond are, how-
ever, lower and cover a range of 6.7-14.6 kcal mol-1 8,9
.
In a naphthalene having one acyl and one aryl sub-
stituent in a peri relationship, there are two possible
stereogenic axes that might create either a pair of
stereolabile enantiomers or diastereoisomers, depending
on the symmetry of the aryl substituent. On the basis of
the previously mentioned values, the rotation barrier
Resu lts a n d Discu ssion
Molecular mechanic calculations (MMX force field)10
indicate that 1-acetyl-8-phenylnaphthalene (1) has the
planes of the acetyl and phenyl substituents parallel to
each other and orthogonal to the plane of the naphtha-
lene ring. As a consequence, 1 is expected to exist as a
pair of stereolabile enantiomers that can be labeled as
Ra and Sa (Scheme 1) or, alternatively, as M and P.
An experimental verification of this prediction can be
achieved by rendering slow in the NMR time scale the
rotation rates of both the MeCO and phenyl groups, since
in these conditions the ortho and meta carbons of the
phenyl ring would become diastereotopic. The 13C spec-
trum of 1 in CD2Cl2 shows how the signals of these
carbons broaden on cooling and eventually split, at -100
°C, into pairs of equally intense peaks, all the other
signals remaining sharp (Figure 1). Computer line shape
simulation yielded an activation energy for the corre-
sponding dynamic process of 9.5 kcal mol-1 (Table 1).
(1) For part 73, see: Casarini, D.; Lunazzi, L.; Mazzanti, A.; Simon,
G. J . Org. Chem. 2000, 65, 3207.
(2) On leave of absence from the Unitat de Qu´ımica Orga`nica,
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193
Bellaterra, Barcelona, Spain.
(3) Cosmo, R.; Sternhell, S. Aust. J . Chem. 1987, 40, 1107.
(4) (a) Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, J .
S. J . Am. Chem. Soc. 1992, 114, 5729. (b) Cozzi, F.; Cinquini, M.;
Annunziata, R.; Siegel, J . S. J . Am. Chem. Soc. 1993, 115, 5330. (c)
Cozzi, F.; Ponzini, F.; Cinquini, M.; Annunziata, R.; Cinquini, M.;
Siegel, J . S. Angew. Chem., Int.Ed. Eng. 1995, 34, 1019.
(5) Nagawa, Y.; Honda, K.; Nakanishi, H. Magn. Reson. Chem. 1996,
34, 78.
(6) (a) Zoltewicz, J . A.; Maier, N. M.; Fabian, W. M. F. Tetrahedron
1996, 52, 8703. (b) Zoltewicz, J . A.; Maier, N. M.; Fabian, W. M. F. J .
Org. Chem. 1996, 61, 7018.
(7) (a) Clough, R. L.; Roberts, J . D. J . Am. Chem. Soc. 1976, 98,
1018. (b) Clough, R. L.; Kung, W. J .; Marsh, R. E.; Roberts, J . D. J .
Org. Chem. 1976, 41, 3603.
(8) Staab, H. A.; Chi, C.-S.; Dabrowski, J . Tetrahedron 1982, 38,
3499.
(9) Casarini, D.; Lunazzi, L.; Foresti, E.; Macciantelli, D. J . Org.
Chem. 1994, 59, 4637.
(10) Computer package PCMODEL, Serena Software, Bloomington,
IN.
10.1021/jo991853g CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

Conformational Studies by Dynamic NMR
J . Org. Chem., Vol. 65, No. 10, 2000 3201
Ta ble 1. Ba r r ier s (∆G*) for th e En a n tiom er iza tion , Du e
to th e RCO Gr ou p Rota tion , in 1-8
∆G*
frequency
(MHz)
compd
(kcal mol-1
)
solvent
1
9.5
9.9
13C (75.5)
1H (300)
13C (75.5)
13C (75.5)
1H (300)
13C (75.5)
1H (300)
13C (75.5)
1H (400)
1H (300)
1H (300)
1H (400)
13C (75.5)
1H (300)
1H (400)
CD2Cl2
CD2Cl2 + CSA (70:1)a
CD3OD
10.1
10.4
10.4
11.3
11.3
13.2
14.3
10.4
[15.9]b
13.5
13.9
14.0
18.0
2
3
4
5
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2 + CSA (270:1)a
CD2Cl2
c
toluene-d8 + Yb(fod)3
CD2Cl2
6
7
CDCl3
CDCl3
8
toluene-d8 + CSA (315:1)a
a
The CSA (chiral auxiliary agent) is (R)-(-)-1-(9-anthryl)-2,2,2-
trifluoroethanol. The values in parentheses represent the molar
b
excess of CSA with respect to the compound. Barrier for the
rotation of the m-ethylphenyl group (see text). c Yb(fod)3 (see ref
16) has been added in trace amounts.
F igu r e 1. Portion of the 13C spectral region of 1 (75.5 MHz
in CD2Cl2) displaying a few aromatic signals at +25 °C (top)
and at -100 °C (bottom). The single lines for the pair of
ortho,ortho′ (o,o′) and meta,meta′ (m,m′) carbons are split at
low temperature, owing to the restricted rotation of both the
acetyl and phenyl groups.
Sch em e 1. MM Com p u ted Rep r esen ta tion of th e
Ra a n d Sa Ster eola bile En a n tiom er s of 1
F igu r e 2. Left: experimental 1H signal (300 MHz in CD2Cl2)
of the Me group of 1 in the presence of a 70:1 molar excess of
a chiral auxiliary agent (see text) as function of temperature.
Right: computer simulation obtained with the rate constants
(k in s-1) indicated.
generated by the restricted rotation about the stereogenic
naphthyl-CO axis, become, in fact, distinguishable in a
chiral environment. This result is independent of the
motion of the phenyl ring (topomerisation), so that the
barrier measured by monitoring the methyl signal cor-
responds to that of the enantiomerization process brought
about by the naphthyl-CO rotation. The rate constants
used to simulate the experimental spectra (Figure 2) yield
a ∆G* of 9.9 kcal mol-1, a value quite close to the one
measured in the achiral solvent. The difference (0.4 kcal
mol-1) between the barriers measured in the achiral and
chiral environments slightly exceed the experimental
errors ((0.15 kcal mol-1), and this might be attributed
Such a value corresponds to the lower of the two rotation
barriers about the naphthyl-CO and naphthyl-Ph bonds.
This experiment, however, does not allow one to decide
which of the two motions is responsible for the measured
activation energy.
To solve this dilemma, the spectrum of 1 was obtained
in the presence of a chiral auxiliary agent. When a molar
excess (Table 1) of an enantiomerically pure Pirkle’s
alcohol [1-(9-anthryl)-2,2,2-trifluoroethanol] is added to
a solution of 1, the 1H signal of the methyl group
broadens on cooling and splits into two lines below -70
°C (Figure 2). The two conformational enantiomers,

3202 J . Org. Chem., Vol. 65, No. 10, 2000
Lunazzi et al.
to a different temperature dependence of the free energies
of activation, due to not negligible ∆S* values. However,
in all these measurements we never found evidence of
an appreciable temperature dependence, in agreement
with what was reported in the majority of the conforma-
tional processes, so that the larger ∆G* is likely to be a
consequence of the increased polarity of the solution
containing the Pirkle’s alcohol.11 To check this point the
variable temperature 13C spectrum of 1 was reinvesti-
gated in CD3OD in order to mimic, somewhat, the
polarity due to the Pirkle’s alcohol. In this solvent the
∆G* value was found actually equal (10.1 kcal mol-1),
within the errors, to the one measured in the chiral
medium. This result thus proves that the MeCO rotation
has a barrier equal to or lower than that of the phenyl
group The proportion of the two methyl signals dis-
played in Figure 2 is not 50:50, as might have been
expected, but is about 59:41 at -82 °C and changes on
rising the temperature (near the coalescence it becomes
55:45). This means that of the two diastereomeric sol-
vates, due to the interaction of the R(-)-alcohol with one
of the two enantiomers of 1, one is more favored than
the other. By using the alcohol with the opposite config-
uration S (+), the same unequal intensity ratio was again
observed.
simulation yielded rate constants corresponding to a ∆G*
of 10.4 kcal mol-1, a value identical to that simulta-
neously determined from the appropriate phenyl carbon
signals of 2. Likewise in 3, the same value was obtained
for the barrier measured either monitoring the aniso-
chronous Me signals of the isopropyl or the appropriate
carbon signals of the phenyl group (11.3 kcal mol-1).
Molecular mechanics calculations indicate that the
rotation of the MeCO group in 1 may have two possible
transition states, since either the methyl group or the
oxygen atom can be directed toward the phenyl ring The
corresponding calculated barriers are, respectively, 21.1
and 12.3 kcal mol-1 so that it is the lowest one that must
correspond to the actual enantiomerization process. It is
gratifying to observe that such a computed barrier is also
the one closer to the experimental measurement (9.5 kcal
mol-1).
The enantiomerization barriers for 1-4, measured in
the same solvent (i.e., in CD2Cl2), increase regularly from
9.5 to 13.2 kcal mol-1 (Table 1) reflecting the increasing
steric requirements of the Me, Et, Pri, and But substit-
uents. The effect, however, is smaller than observed in
other molecules with the same substituents,12 and this
seems to support the theoretical prediction that the
transition state is the one having the oxygen atom
directed toward the phenyl group in position 8. The alkyl
moieties, in fact, cross over position 2, where their
passage is not hindered to a large extent, due to the small
dimensions of the hydrogen atom bonded to this carbon.
Although we have demonstrated that the phenyl rota-
tion has a ∆G* value equal to or higher than for the RCO
rotation, its value has not yet been experimentally
determined. The value calculated for the phenyl-naphthyl
rotation (27.9 kcal mol-1) is predicted to be higher than
for the MeCO rotation, and suggests that the correspond-
ing rate should be sufficiently slow as to become detect-
able even at ambient temperature. On the basis of these
calculations we envisaged that introduction of an ethyl
group in the meta position of the phenyl ring of 1 would
cause the resulting derivative 5 to display, in addition
to a pair of stereolabile diastereoisomers, two sufficiently
stable enantiomers (atropisomers) which should be de-
tectable at ambient temperature even in the presence of
a fast MeCO rotation. In fact, the high barrier predicted
for the rotation of the aryl group (here the m-ethylphenyl
substituent) would deprive derivative 5 of any element
of symmetry (Scheme 2).
When the methyl groups of 1 (R ) Me) is replaced by
the tert-butyl group to yield derivative 4 (R ) But) the
o-and m-phenyl carbons display anisochronous 13C sig-
nals at higher temperatures (-50 °C, rather than -100
°C). Accordingly, the free energy of activation for the
observed dynamic process was found larger (∆G* ) 13.2
kcal mol-1) than in 1, owing to the hindrance of the bulky
1
tert-butyl group. The H spectrum of 4, obtained in the
presence of the mentioned Pirkle’s alcohol, displays two
1H tert-butyl methyl signals at low temperature (∆ν )
0.019 ppm at -60 °C). As in the case of 1 the enantiomers
yield two diastereomeric solvates displaying signals with
a different proportion (58:42 at -60 °C). On warming,
these lines coalesce yielding a ∆G* of 14.3 kcal mol-1 for
the related enantiomerization process. As observed for
1, the presence the polar alcohol again makes this barrier
slightly higher, but its value remains nonetheless close
to that measured in the achiral solution (Table 1). This
finding further confirms that the barrier for the acyl
group rotation (corresponding to the enantiomerization
process) is equal to or lower than that for the phenyl
group rotation (topomerisation). Even when the former
barrier has increased, still it does not overtake the value
of the latter.
In derivative 2, the methylene hydrogens of the ethyl
group provide a probe for the direct determination of the
enantiomerization barrier due to EtCO rotation, which
can be thus measured in exactly the same conditions as
those derived by monitoring the ortho and meta 13C
signals of the phenyl ring. Independently of the rotation
of the phenyl group, the signal of the CH2 hydrogens
becomes anisochronous when the rotation about the
naphthyl-CO bond is rendered slow at low temperature.
The single CH2 line, obtained by decoupling at the
frequency of the methyl triplet, splits in fact into an AB-
type spectrum (J ) -19 Hz) when, at -85 °C, the two
geminal hydrogens become diastereotopic, the corre-
sponding shift separation being 0.14 ppm. Line shape
Both the 1H and 13C NMR spectra are expected to
indicate, in principle, the presence of two unequally
populated conformational diastereoisomers by displaying
two sets of signals of different intensity at low temper-
ature. On the other hand the existence of the enantiomers
at ambient temperature would be inferred by the 1H
spectrum displaying anisochronous methylene signals.
Compound 5 does not have any element of symmetry if
the aryl group, orthogonal to the naphthalene ring, is
essentially locked at ambient temperature, even in the
presence of a fast rotation of the MeCO group. However
the 1H spectrum of 5 does not reveal the predicted
diastereotopicity of the methylene hydrogens in a number
of solvents (CDCl3, CD3NO2, pyridine-d5, CD2Cl2), owing
(12) (a) Casarini, D.; Lunazzi, L.; Verbeek, R. Tetrahedron 1996,
52, 2471. (b) Casarini, D.; Lunazzi, L. J . Org. Chem. 1996, 61, 175. (c)
J ennings, W. B.; Kochanewycz, M. J . K.; Lunazzi, L. J . Chem. Soc.,
Perkin Trans. 2 1997, 2271. (d) Casarini, D.; Lunazzi, L.; Mazzanti,
A.; Foresti, E. J . Org. Chem. 1998, 63, 4991.
(11) Casarini, D.; Davalli, S.; Lunazzi, L.; Macciantelli, D. J . Org.
Chem. 1989, 54, 4616.

Conformational Studies by Dynamic NMR
J . Org. Chem., Vol. 65, No. 10, 2000 3203
Sch em e 2. Sch em a tic Rep r esen ta tion of th e F ou r
Obser ved Con for m a tion a l Ster eoisom er s
(Dia ster eoisom er s a n d En a n tiom er s) of 5a
that agrees with the previous assignment based on the
energy values: the more polar conformer 5b has in fact
increased its proportion in a more polar solvent. A proof
that such a variation depends indeed on the polarity of
the solution and is not a consequence of a shift inversion
in the different solvents employed, is offered by the
spectrum obtained in a 1:1 mixture of CD2Cl2 and CF2Br2
at -90 °C. Here the observed ratio becomes 50:50,
because the low dielectric constant of CF2Br2 (ꢀ ≈ 3) has
reduced the polarity of the CD2Cl2 solution, making the
situation intermediate between that of the solutions in
toluene-d8 and in CD2Cl2.
An independent approach to support the structural
identification of the diastereoisomers 5a and 5b was
carried out by means of the Lanthanide Induced Shift
(LIS) effect.15 Addition of a given amount of Yb(fod)3
16
to a toluene-d8 solution of 5 (kept at -95 °C) shifted
downfield the 13C methyl signal of the ethyl group
markedly more in the case of the major (from 16.78 to
17.43 ppm) than in that of the minor conformer (from
17.72 to 18.15). As a consequence the separation of the
two 13C signals was reduced from 95 to 73 Hz (at 100.6
MHz) by the effect of Yb(fod)3. Since in a derivative like
5 the paramagnetic Yb atom essentially interacts with
the carbonyl group,15,17 this effect requires that the
distance of the ethyl group from the carbonyl moiety is
shorter in the major than in the minor diastereoisomer.
Consequently the major diastereoisomer must have the
ethyl and carbonyl groups in a syn relationship, thus
confirming its identification with structure 5a . A similar
result was observed in the proton spectrum where the
downfield LIS displacement of the methyl triplet of the
ethyl group was larger for the major than in the minor
conformer. On the other hand the effect on the 1H methyl
signal of the MeCO moiety was found to be opposite, since
in the minor diastereoisomer this line was displaced more
than in the major one. The distances of the acetyl methyl
group from the Yb atom are obviously the same in both
cases, but the structure of 5a (having the ethyl and the
CO groups in a syn relationship) is more hindered, thus
making the interaction of the Yb(fod)3 with the carbonyl
moiety less efficient15,17 than in the case of 5b. This
accounts for the slightly larger LIS effect observed for
the MeCO signal of the latter conformer and confirms,
therefore, the structural assignment.18
a
The MM computed energies (E) are in kcal mol-1; the
computed dipole moments (µ) are in debye.
to accidental shift degeneracy at any temperature be-
tween -40° to +30 °C. Only the spectrum in toluene-d8
does show that each quartet line is further split (0.005
ppm at +25 °C and 0.01 ppm at -20 °C).13 The aniso-
chronicity observed at ambient temperature, even if very
small, proves that the barrier for the naphthyl-aryl
rotation must be higher than that for the naphthyl-CO
rotation.
At about -90 °C in toluene-d8 all the 1H aliphatic
signals of 5 display two groups of lines having unequal
intensity. For instance, the methyl line of the acetyl
moiety splits into two, with the line upfield (1.64 ppm)
more intense than its downfield (1.79 ppm) partner (ratio
65:35), an indication that, as conceivable, the two con-
formational diastereoisomers have a different stability.
The interconversion of these two diastereoisomers has a
∆G* value (10.4 kcal mol-1, Table 1) that is similar to
that determined for the enantiomerization process of the
unsubstituted derivative 1, since in both cases it is the
result of the same naphthyl-CO rotation process (the
slightly larger value reflects the hindrance of the m-
ethylphenyl with respect to the unsubstituted phenyl
group).
Molecular mechanics calculations predict that the
diastereoisomer with the ethyl substituent syn to the
oxygen atom (5a in Scheme 2) is 0.14 kcal mol-1 more
stable than that having these two moieties in an anti
relationship (5b in Scheme 2). Such an energy difference
for the isolated molecule entails a 60:40 ratio at -90 °C,14
a value quite close to that (65:35) experimentally deter-
mined in an inert solvent like toluene. These calculations
also predict that the less stable conformer 5b has a dipole
moment (2.95 D) larger than that (2.70 D) of the more
stable conformer 5a . The NMR spectrum of 5 was thus
taken in CD2Cl2 at -90 °C, where the dielectric constant
(ꢀ ) 16) is quite higher than that of toluene at the same
temperature (ꢀ ) 2.7). In CD2Cl2 the conformer ratio is
reversed in that the highfield MeCO signal appeared less
intense than its low field partner (ratio 43:57), a result
As predicted, two conformational diastereoisomers
were detected for 5 (i.e. 5a and 5b) at low temperature,
each of them being actually a racemic mixture of two
conformational enantiomers (Scheme 2). This was ascer-
1
tained by obtaining the H spectrum of 5 at -100 °C in
the presence of a 40:1 molar excess of the same R(-)
Pirkle’s alcohol mentioned above. Most of the lines
(15) (a) von Ammon, R.; Fischer, R. D. Angew. Chem., Int. Ed. Engl.
1972, 11, 675. (b) Cockerill, A. F.; Davies, G. L. O.; Harden, R. C.;
Rackham, D. M. Chem. Rev. 1973, 73, 553. (c) Reuben, J . Prog. NMR
Spectrosc. 1973, 9, 1. (d) Hofer, O. Top. Stereochem. 1976, 9, 111. (e)
Peters, J . A. Prog. NMR Spectrosc. 1996, 28, 283.
(16) The term (fod) stays for 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-
4,6-octanedioanate.15b
(17) Cipiciani, A.; Linda, P.; Macciantelli, D.; Lunazzi, L. J . Chem.
Soc., Perkin Trans. 2 1979, 1045.
(18) The LIS effect observed for the MeCO line indicates that in
the more stable 5a conformer the equilibrium with Yb(fod)3 is shifted
toward the CdO‚‚‚Yb dimer less than in 5b. Despite the consequent
lower efficiency, the LIS effect experienced by the ethyl methyl signal
is larger in 5a than in 5b, because in the diastereoisomer syn the Cd
O is closer to the Et group than in the diastereoisomer anti (the
computed average distances between the carbonyl oxygen atom and
the ethyl methyl hydrogens are 3.65 Å in 5a and 5.52 Å in 5b).
(13) Such a small shift difference (1.5 Hz at 300 MHz) makes the
intensity of the outer lines of the AB portion of the ABX3 spectrum
too low to be observed, thus preventing the measurement of the
geminal J AB coupling constant.
(14) This results from the equation ln(N1/N2) ) -∆G°/RT, with ∆G°
assumed to be independent of temperature.

3204 J . Org. Chem., Vol. 65, No. 10, 2000
Lunazzi et al.
F igu r e 4. Left: temperature dependence of the methylene
signal of 5 (decoupled at the frequency of the corresponding
methyl triplet) in the presence of Yb(fod)3 in toluene-d8 at 400
MHz. Right: computer simulation obtained with the rate
constants (k in s-1) indicated.
F igu r e 3. Top: spectrum of the methyl hydrogens of the ethyl
moiety of 5 at -100 °C (300 MHz in CD2Cl2) showing two
overlapping triplets (in a 57:43 ratio), due to the conforma-
tional diastereoisomers 5a and 5b. Bottom: the same spectrum
at -100 °C in the presence of a 40:1 molar excess of a chiral
auxiliary agent (see text), displaying four methyl triplets due
to the conformational enantiomers 5a ′, 5a ′′, 5b′, 5b′′ (Scheme
2). In the same spectral region also appears, now, one of the
four methylene quartets signals.
than the computed value, this barrier is nonetheless
higher, as theoretically predicted, than that for the
exchange of the conformational diastereoisomers due to
the MeCO rotation and is similar to other barriers
reported for analogous situations.3-6
displayed an additional splitting in this chiral environ-
ment: in particular both the overlapping methyl triplets
of the ethyl moiety (indicated as 5a and 5b in Figure 3,
top) were further split into two, yielding four triplets as
a whole. Two of them (labeled 5a ′ and 5a ”) correspond
to the pair of enantiomers of conformer 5a and have,
accordingly, an intensity higher (ratio 57:43) than that
of the other two (5b′ and 5b”), corresponding to the pair
of enantiomers of 5b (Figure 3, bottom).
The shift separation of the diastereotopic methylene
hydrogens of 5, previously observed at ambient temper-
ature in toluene-d8 (0.005 ppm), is indicative, as men-
tioned, of an aryl rotation barrier higher than that of
MeCO, but is definitely too small to allow a meaningful
measurement of the corresponding free energy of activa-
tion. Addition of even a small amount of Yb(fod)3 allowed,
however, to increase significantly this separation so that,
when decoupled at the frequency of the methyl triplet,
the methylene hydrogens of 5 displays an AB-type
spectrum with a J ) -14 Hz and a ∆ν ) 30 Hz (at 400
MHz) as shown in Figure 4. In such a way an experi-
mental ∆G* value of 15.9 kcal mol-1 could be obtained
for the enantiomerization process brought about by the
aryl-naphthyl rotation (Table 1). Although quite lower
The large difference (5.5 kcal mol-1) between the
barrier for the MeCO and for the m-ethyl phenyl group
rotation measured in 5 indicates that within the time
required for the phenyl ring to complete a single rotation,
the acetyl group makes a number of rotations exceeding
105. Thus, during the motion of the MeCO group, the
phenyl stays essentially locked in the plane orthogonal
to the naphthalene ring, so that it is perceived by the
acetyl group as a flat substituent, with relatively small
steric effects. Similar differences between the two rota-
tion rates are logically expected to occur also for the other
acyl substituents. This prediction can be checked by
replacing, for instance, the phenyl ring of 2 with a
spherical substituent, like a bromine atom, as in 6.
Obviously bromine displays the same steric effects in
any direction, contrary to the phenyl group whose effects,

Conformational Studies by Dynamic NMR
J . Org. Chem., Vol. 65, No. 10, 2000 3205
Exp er im en ta l Section
Ma ter ia ls. 8-Br om o-1-n a p h th oyl ch lor id e was prepared
as described in the literature.22
1-Br om o-3-eth ylben zen e. To a solution of 1,3 dibromo-
benzene (50 mmol in 125 mL of dry THF) kept under N2 at
-78 °C was added dropwise a solution of n-BuLi (52 mmol,
1.6 M in hexane). After 10 min, the reaction was quenched
with Et-I (75 mmol in 10 mL of dry THF), and the mixture
was allowed to warm to room temperature. After addition of
aqueous NH4Cl, the product was extracted (Et2O) and dried
(Na2SO4), and Et2O and THF were distilled off with an
adiabatic still column (15 cm height). The crude was purified
using the same column at reduced pressure (bp 80° at 13
mm): final yield 65%; 1H NMR (CDCl3, 200 MHz) δ 1.25 (3H,
t, J ) 7.5 Hz), 2.65 (2H, q, J ) 7.5 Hz), 7.10-7.22 (2H, m),
7.30-7.40 (2H, m); 13C NMR (CDCl3, 50.3 MHz) δ 15.2 (CH3),
24.4 (CH2), 122.3 (quat), 126.4 (CH), 128.6 (CH), 129.7 (CH),
130.8 (CH), 146.4 (quat).
3-Eth ylp h en ylbor on ic Acid .23 To a solution of 1-bromo-
3-ethylbenzene (15 mmol in 40 mL of dry THF) kept under N2
at -78 ° was added dropwise a solution of n-BuLi (16 mmol,
1.6 M in hexane). After 10 min, the solution was added
dropwise to a solution of B(O-i-Pr)3 (30 mmol in 10 mL of dry
THF) kept at -78 °C. The resulting solution was stirred for
10 min at -78 °C and then allowed to warm to room
temperature. After addition of 50 mL of 1 M HCl, the product
was extracted (Et2O), dried (Na2SO4), and concentrated at
reduced pressure. The crude was purified by crystallization
(H2O). The resulting filtrate was washed with pentane to
remove traces of the starting product: final yield 84%; 1H NMR
(DMSO-d6, 300 MHz), δ 1.18 (3H, t, J ) 7.6 Hz), 2.60 (2H, q,
J ) 7.6 Hz), 7.20-7.26 (2H, m), 7.50-7.65 (2H, m), 7.93 (2H,
broad s); 13C NMR (DMSO-d6, 75.5 MHz), δ 15.7 (CH3), 28.2
(CH2), 127.3 (CH), 129.4 (CH), 131.4 (CH), 133.5 (CH), 141.4
(quat).
1-(8-Br om o-1-n a p h th yl)-1-eth a n on e. To a suspension of
CuI (5.5 mmol in 10 mL of dry THF) kept at -78 °C under N2
was added dropwise a solution of MeLi (12 mmol, 1.5 M in
Et2O). The temperature was raised to -40 °C for 5 min and
then lowered again to -78 °C. A solution of 8-bromo-1-
naphthoyl chloride (5 mmol in 5 mL of dry THF) was
subsequently added, and the resulting brown-yellow solution
was stirred at -78 °C for about 1 h. The reaction was quenched
at -78 °C with 10 mL of aqueous NH4Cl. After ambient
temperature was reached, the crude was extracted (Et2O),
dried (Na2SO4), and concentrated at reduced pressure. The
resulting compound was purified on silica gel (eluent petro-
leum ether/Et2O 3:1 v/v): final yield after purification 60%;
1H NMR (CDCl3, 200 MHz) δ 2.72 (3H, s), 7.30-7.52 (3H, m),
7.80-7.91 (3H, m); 13C NMR (CDCl3, 50.3 MHz) δ 33.9 (CH3),
119.2 (quat), 125.5 (CH), 125.8 (CH), 126.8 (CH), 128.5 (quat),
128.6 (CH), 130.7 (CH), 132.7 (CH), 135.7 (quat), 141.3 (quat),
205.4 (CO). Anal. Calcd for C12H9BrO: C, 57.86; H, 3.64; Br,
32.08. Found: C, 57.92; H, 3.69; Br, 32.15.
1-(8-Br om o-1-n a p h th yl)-1-p r op a n on e (6). To a solution
of lithium diisopropylamine (LDA), prepared by adding n-BuLi
(1.4 mmol, 1.6M in hexane) to a solution of diisopropylamine
(1.4 mmol in 4 mL of dry THF) kept at 0 °C was added
dropwise at -78 °C a solution of 1-(8-bromo-1-naphthyl)-1-
ethanone (1 mmol in 3 mL of dry THF). The solution was
stirred at -78 °C for 1 h, and a solution of MeI (10 mmol in 2
mL of THF) was subsequently added. The system was allowed
to warm to room temperature and quenched with aqueous
NH4Cl. The product was extracted (Et2O), dried (Na2SO4), and
concentrated at reduced pressure. The crude was purified on
preparative TLC (eluent: petroleum ether/Et2O 2:1 v/v): final
yield after purification 65%; 1H NMR (CD2Cl2, 400 MHz) δ 1.26
(3H, t, J ) 6.9 Hz), 2.95 (2H, broad s), 7.32-7.37 (2H, m),
7.46-7.50 (1H, m), 7.81-7.90 (3H, m). 13C NMR (CD2Cl2, 100.6
MHz) δ 9.0 (CH3), 40.3 (CH2), 119.8 (quat), 126.3 (CH), 126.8
(CH), 127.5 (CH), 129.4 (quat), 129.5 (CH), 131.1 (CH), 133.4
F igu r e 5. Left: temperature dependence of the methylene
signal of 6 in CD2Cl2 at 400 MHz (except the trace at +70 °C,
in CCl4) showing how, on cooling, the quartet signal de-
coalesces into an AB-type spectrum, each line of which is also
split into a quartet (ABX3 spectrum). Right: computer simula-
tion obtained with the rate constants (k in s-1) indicated.
as mentioned, may vary significantly depending on its
orientation with respect to the acyl moiety. For this
reason, although the radius of bromine (1.86 ( 0.04 Å)19
is much shorter than the average dimension (4.33 Å) of
a rotating phenyl ring displaying a dynamic cylindrical
symmetry (measured as distance between two meta
hydrogen atoms), the effective radius of phenyl is actually
smaller (1.62 Å)19 than that of bromine. Accordingly, the
steric hindrance experienced by the EtCO moiety in the
resulting bromine derivative 6 should be larger than in
2. As shown in Figure 5, the methylene hydrogens of 6
become indeed diastereotopic at a higher temperature,
because the enantiomerization barrier, consequent to the
EtCO rotation, has actually increased by about 3.1 kcal
mol-1 with respect to 2, reaching a value of 13.5 kcal
mol-1 (Table 1).
Likewise the isopropyl derivative 7 and the tert-butyl
derivative 8 yield barriers higher than those of the
corresponding derivatives 3 and 4 (Table 1).20 It is thus
established that a spherical substitutent, like bromine,
has a larger steric effect than the “flat” phenyl substitu-
ent and the average difference for the three pairs of
examined molecules21 is ∆∆G* ) 3.2 ( 0.5 kcal mol-1
.
The very same ∆∆G* difference between a bromine and
a phenyl substituent had been also reported for another
class of compounds.19
(19) Bott, G.; Field, L. D.; Sternhell, S. J . Am. Chem. Soc. 1980,
102, 5618.
(20) To observe two signals for the pair of enantiomers of 8, the
measurement had to be carried out in the presence of a chiral solvating
agent (see Table 1), so that the comparison has to be made with the
barrier of 4 obtained in the same conditions (i.e., 14.3 kcal mol-1).
(21) The three differences are 3.1, 2.7 and 3.7 kcal mol-1, respec-
tively, for the ethyl derivatives 6 and 2, for the isopropyl derivatives
7 and 3 and for the tert-butyl derivatives 8 and 4 (see Table 1).
(22) Bailey, R. J .; Card, P. J .; Shechter, H. J . Am. Chem. Soc. 1983,
105, 6103.

3206 J . Org. Chem., Vol. 65, No. 10, 2000
Lunazzi et al.
(CH), 136.5 (quat), 141.9 (quat), 208.8 (CO). Anal. Calcd for
(quat) 140.8 (quat), 143.5 (quat), 207.7 (CO). Anal. Calcd for
C19H16O: C, 87.66; H, 6.19. Found: C, 87.74; H, 6.23.
C
13H11BrO: C, 59.34; H, 4.21; Br, 30.37. Found: C, 59.41; H,
4.15, Br, 30.28.
2-Meth yl-1-(8-p h en yl-1-n a p h th yl)-1-p r op a n on e (3): 1H
NMR (CD2Cl2, 300 MHz) δ 0.40 (6H, d, J ) 6.8 Hz), 2.64 (1H,
septet, J ) 6.8 Hz), 7.32-7.40 (6H, m), 7.45-7.61 (3H,
m),7.88-8.00 (3H, m); 13C NMR (CD2Cl2, 75.5 MHz) δ 18.9
(CH3), 42.7 (CH2), 125.8 (CH), 126.7 (CH), 128.1 (quat), 128.3
(CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 131.28 (CH), 131.35
(CH), 131.8 (CH), 135.1 (quat), 139.4 (quat), 139.5 (quat), 142.0
(quat), 213.3 (CO). Anal. Calcd for C20H18O: C, 87.56; H, 6.61.
Found: C, 87.53; H, 6.67.
1-(8-Br om o-1-n a p h th yl)-2-m eth yl-1-p r op a n on e (7). To
a solution of LDA, prepared by adding (at 0 °C) n-BuLi (0.7
mmol, 1.6 M in hexane) to diisopropylamine (0.7 mmol
dissolved in 2 mL of dry THF) was added dropwise at -78 °C
a solution of 1-(8-bromo-1-naphthyl)-1-propanone (0.5 mmol
in 2 mL of THF). The system was then stirred at -78 °C for
1 h, and a solution of MeI (5 mmol in 1 mL of THF) was
subsequently added. The system was allowed to warm to room
temperature and quenched with aqueous NH4Cl. The product
was extracted (Et2O), dried (Na2SO4), and concentrated at
reduced pressure. The crude was purified on preparative TLC
(eluent: petroleum ether/Et2O 2:1 v/v): final yield after
2,2-Dim e t h yl-1-(8-p h e n yl-1-n a p h t h yl)-1-p r op a n on e
(4): 1H NMR (CDCl3, 300 MHz) δ 0.72 (9H, s), 7.23(1H, dd, J
) 7.0, 1.4 Hz), 7.30-7.55 (8H, m), 7.88 (1H, dd, J ) 8.2, 1.3
Hz), 7.95 (1H, dd, J ) 8.2, 1.3 Hz); 13C NMR (CDCl3, 75.5 MHz)
δ 27.3 (CH3), 45.4 (quat), 124.4 (CH), 125.6 (CH), 125.9 (CH),
127.5 (CH), 127.9 (CH), 128.1 (quat), 128.2 (CH), 130.1 (CH),
130.7 (CH), 134.3 (quat), 139.6 (quat), 140.0 (quat), 140.6
(quat), 215.2 (CO). Note: the signal of a CH is extremely broad,
its chemical shift can be calculated as 132.5 ppm by the
spectrum at -40 °C. Anal. Calcd for C21H20O: C, 87.46; H,
6.99. Found: C, 87.50; H, 6.95.
1-[8-(3-Eth ylp h en yl)-1-n a p h th yl]-1-p r op a n on e (5): 1H
NMR (CDCl3, 300 MHz) δ 1.25 (3H, t, J ) 7.7 Hz), 1.82 (3H,
s) 2.66 (2H, q, J ) 7.7 Hz), 7.15-7.37 (4H, m), 7.43-7.60 (4H,
m), 7.85-7.96 (2H, m); 13C NMR (CDCl3, 75.5 MHz) δ 15.2
(CH3), 28.8 (CH2), 30.5 (CH3), 124.8 (CH), 126.0 (CH), 126.7
(CH), 127.0 (CH), 127.1 (CH), 128.1 (CH), 128.2 (quat), 128.7
(CH), 129.6 (CH), 130.0 (CH), 131.3 (CH), 134.8 (quat), 139.7
(quat), 141.2 (quat), 142.5 (quat), 144.2 (quat), 207.7 (CO).
Anal. Calcd for C20H18O: C, 87.56; H, 6.61. Found: C, 87.54;
H, 6.56.
1
purification 52%; H NMR (CDCl3, 300 MHz) δ 1.23 (6H, b b
s), 3.24 (1H, sept., J ) 6.9 Hz), 7.30-7.38 (2H, m), 7.44-7.52
(1H, m), 7.80-7.91 (3H, m). 13C NMR (CDCl3, 75.5 MHz) δ
19.9 (CH3, b s), 44.2 (CH), 119.3 (quat), 125.4 (CH), 126.7 (CH),
127.4 (CH), 128.7 (CH), 129.0 (quat), 130.6 (CH), 132.5 (CH),
135.7 (quat), 139.6 (quat), 212.3 (CO). Anal. Calcd for C14H13
-
BrO: C, 60.67; H, 4.73; Br, 28.83. Found: C, 60.71; H, 4.66,
Br, 28.75.
1-(8-Br om o-1-n a p h th yl)-2,2-d im eth yl-1-p r op a n on e (8).
To a suspension of CuCN (4.5 mmol in 10 mL of dry THF)
kept at -78 °C under N2 was added dropwise a solution of
t-BuLi (9 mmol, 1.5 M in pentane). The temperature was
raised to -40 °C for 5 min and then lowered again to -78 °C.
A solution of 8-bromo-1-naphthoyl chloride (4 mmol in 5 mL
of dry THF) was subsequently added, and the resulting brown-
yellow solution was stirred at -78 °C for about 1 h. The
reaction was quenched at -78 °C by adding 10 mL of aqueous
NH4Cl. The mixture was then allowed to warm to room
temperature, and the crude was extracted (Et2O), dried
(Na2SO4), and concentrated at reduced pressure. The product
was purified on silica gel (eluent: petroleum ether/Et2O 1:1
NMR Mea su r em en ts. The NMR spectra were obtained
with either a 300 MHz or a 400 MHz spectrometer. All the
13C signals were identified by DEPT sequence. The tempera-
tures within the probes of the two instruments were calibrated
by substituting the samples with a Ni/Cu thermocouple before
the experiments. In the spectra obtained in the presence of
chiral solvating agents, the shift separation (∆ν) is tempera-
ture dependent. By means of an empirical equation this
separation was related to the temperature in the range where
the rotation rate is undoubtedly negligible. The ∆ν values were
subsequently extrapolated in the temperature range where a
significant exchange rate occurred, allowing one to obtain
reliable line shape simulations (use was made of PC version
of the DNMR 6 Program25). To observe sufficiently separate
1H NMR signals for the enantiomers, a very large molar excess
(up to 300:1) of the chiral solvating agent (CSA) was needed.
Thus in these experiments the concentration of the substrate
had to be quite small (typically 10-3 M) in order to have, in
any case, a concentration of CSA lower than the saturation
point. Otherwise the DNMR spectra were acquired using a
10-2 M solution for 1H and 10-1 for 13C NMR, respectively.
1
v/v): final yield after purification 64%; H NMR (CDCl3, 200
MHz), δ 1.30 (9H, s), 7.22-7.31 (3H, m), 7.38-7.48 (1H, m),
7.72-7.85 (3H, m); 13C NMR (CDCl3, 50.3 MHz), δ 28.0 (CH3,),
46.4 (quat), 118.9 (quat), 125.0 (CH), 125.8 (CH), 126.4 (CH),
128.7 (CH), 129.1 (quat), 129.8 (CH), 132.3 (CH), 135.2 (quat),
139.2 (quat), 216.0 (CO). Anal. Calcd for C14H13BrO: C, 60.67;
H, 4.73; Br, 28.83. Found: C, 60.71; H, 4.66, Br, 28.75.
Compounds 1-4 were prepared according to the following
general procedure.24 To a solution of 1-(8-bromo-1-naphthyl)-
1-ethanone (0.5 mmol in 3 mL of benzene) were added K2CO3
(1 mmol, 2 M solution in H2O), phenylboronic acid (0.6 mmol
in 1 mL of ethanol), and Pd(PPh3)4 (0.05 mmol) at room
temperature. The mixture was gently refluxed for 2-4 h until
the starting bromo ketone disappeared (TLC). The reflux was
then stopped and the product extracted (Et2O), dried (Na2SO4),
and concentrated to reduced pressure. The crude was purified
on preparative TLC (eluent: petroleum ether/Et2O 4:1 v/v).
Final yields were 60% for 1, 45% for 2, 50% for 3, and 30% for
4. Compound 5 was obtained with the same procedure, using
3-ethyl-phenylboronic acid instead of phenylboronic acid.
1-(8-P h en yl-1-n a p h th yl)-1-eth a n on e (1): 1H NMR (CD2-
Cl2, 300 MHz) δ 1.91 (3H, s), 7.34-7.63 (9H, m), 7.89-8.01
(2H, m). 13C NMR (CD2Cl2, 75.5 MHz) δ 31.0 (CH3), 125.6 (CH),
125.6 (CH), 126.8 (CH), 127.4 (CH), 128.2 (CH), 128.9 (CH),
129.1 (quat), 129.3 (CH), 130.5 (CH), 130.9 (CH), 132.0 (CH),
135.7 (quat), 140.4 (quat), 142.0 (quat), 143.8 (quat), 204.1
(CO). Anal. Calcd for C18H14O: C, 87.77; H, 5.73. Found: C,
87.86; H, 5.67.
1-(8-P h en yl-1-n a p h t h yl)-1-p r op a n on e (2): 1H NMR
(CD2Cl2, 300 MHz) δ 0.51 (3H, t, J ) 7.1 Hz),2.39 (2H, q, J )
7.1 Hz), 7.30-7.60 (8H, m), 7.88-8.00 (3H, m). 13C NMR
(CD2Cl2, 75.5 MHz) δ 8.1 (CH3), 37.6 (CH2), 125.7 (CH), 126.7
(CH), 127.3 (CH), 128.1 (CH), 128.9 (quat), 129.0 (CH), 129.3
(CH), 130.6 (CH), 131.1 (CH), 131.7 (CH), 134.9 (quat), 139.5
Ack n ow led gm en t. Thanks are due to Prof. D.
Casarini, University of Basilicata, for helpful comments,
to Mr. F. Fratepietro and Dr. S. Grilli for skillful
technical assistance, and to I.Co.C.E.A. Institute of
CNR, Bologna, for the use of the 400 MHz spectrometer.
Financial support has been received from MURST
(national project “Stereoselection in Organic Synthesis”)
and from the University of Bologna (Progetto triennale
d’Ateneo 1997-99).
J O991853G
(23) Thompson, W. J .; Gaudino, J . J . Org. Chem. 1984, 49, 5237.
(24) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(25) QCPE program no. 633, Indiana University, Bloomington, IN.