Correlated rotations in benzylfluorene derivatives: Structure, conformation, and stereodynamics

Article abstract of DOI:10.1021/jo7026917

(Graph Presented) Fluorene derivatives, having substituted benzyl groups bonded to position 9, have been investigated by variable temperature NMR spectroscopy. Stereodynamic processes involving restricted rotation about the fluorenyl-CH₂ and ar

Full text of DOI:10.1021/jo7026917

Correlated Rotations in Benzylfluorene Derivatives: Structure,
Conformation, and Stereodynamics
Daniele Casarini,*,† Lodovico Lunazzi,‡ and Andrea Mazzanti*,‡
Department of Chemistry, UniVersity of Basilicata, Via N. Sauro 85, Potenza 85100, Italy and Department
of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4, Bologna 40136, Italy
casarini@unibas.it; mazzand@ms.fci.unibo.it
ReceiVed December 18, 2007
Fluorene derivatives, having substituted benzyl groups bonded to position 9, have been investigated by
variable temperature NMR spectroscopy. Stereodynamic processes involving restricted rotation about
the fluorenyl-CH2 and aryl-CH2 bonds have been observed, leading to conformers and enantiomeric
forms, and the corresponding barriers were determined by line shape simulation. These dynamic processes
are interpreted as being due to correlated rotation pathways, on the basis of DFT computations that
satisfactorily reproduce the experimental barriers. The structures of two such compounds were also
determined by single-crystal X-ray diffraction
Introduction
temperature NMR spectroscopy.5 All the compounds investi-
gated so far have an aryl group directly bonded to position 9 of
the fluorenyl moiety so that only one kind of bond rotation
process could be detected. Here we present a number of fluorene
derivatives bearing susbstituted benzyl moieties at position 9,
thus making possible the detection of two concomitant rotation
processes, as well as the identification of stereolabile isomers
(conformers) of different stabilities. For this purpose we
synthesized the compounds displayed in Chart 1, where the
isopropyl group was introduced for monitoring the possible
asymmetry of the conformers.
The study of fluorenyl derivatives has received considerable
attention owing to the circumstance that the fluorene motif
appears in a number of molecules with possible applications in
material science.1-4 The 9-arylfluorenyl derivatives also display
dynamic processes that have been investigated by variable
† University of Basilicata.
‡
University of Bologna.
(1) Grell, M.; Knoll, W.; Lupo, D.; Meisel, A.; Miteva, T.; Neher, D.;
Noyhofer, H.-G.; Scherf, U.; Uasuda, A. AdV. Mater. 1999, 11, 671-675.
(2) Rathore, R.; Abdelwahed, S. H.; Guzei, I. A. J. Am. Chem. Soc. 2003,
125, 8712-8713.
(3) Geng, Y.; Trajkovska, A.; Culligan, S. W.; Ou, J. J.; Chen, H. M.
P.; Katsis, D.; Chen, S. H. J. Am. Chem. Soc. 2003, 125, 14032-14038.
(4) Nakano, T.; Yade, T. J. Am. Chem. Soc. 2003, 125, 15474-15484.
(5) Siddall, T. H., III; Stewart, W. E. Chem. Commun. 1968, 1116.
Siddall, T. H., III; Stewart, W. E. Tetrahedron Lett. 1968, 9, 5011.
Chandross, E. A.; Sheley, C. F., Jr. J. Am. Chem. Soc. 1968, 90, 4345.
Rieker, A.; Kessler, H. Tetrahedron Lett. 1969, 10, 1227. Bartle, K. D.;
Bavin, P. M .G.; Jones, D. W.; L’Amie, D. Tetrahedron 1970, 26, 911.
Nakamura, M.; Oki, M. Tetrahedron Lett. 1974, 15, 505. Ford, W. T.;
Thompson, T. B.; Snoble, K. A.; Timko, J. M. J. Am. Chem. Soc. 1975,
97, 95. Albert, K.; Rieker, A. Chem. Ber. 1977, 110, 1804. Nakamura, M.;
Nakamura, N. Oki, M. Bull. Chem. Soc. Jpn. 1977, 50, 2986. Murata, S.;
Kanno, S.; Tanabe, Y.; Nakamura, M.; Oki, M. Bull. Chem. Soc. Jpn. 1982,
55, 1522. Tukada, H.; Iwamura, M.; Sugawara, T.; Iwamura, H. Org. Magn.
Res. 1982, 19, 78. Lam, Y.-L.; Koh, L.-L. Huang, H.-H.; Wang, L. J. Chem.
Soc., Perkin Trans. 2 1999, 1137.
Results and Discussion
As shown in the NMR spectrum of Figure 1, the 1H doublet
signal for the isopropyl methyl groups of compound 1 broadens
below -120 °C and eventually splits into two signals of different
intensities (94:6) at -157 °C. Analogous splitting was also
observed for all the other three aliphatic signals. The major
interconverts into the minor conformer with a free energy of
activation of 6.0 kcal mol-1 (Table 1), this value deriving from
the rate constants used for the simulation of the spectrum of
Figure 1. Both the methyl signals of the major and of the minor
conformer appear as single signals at -157 °C, indicating that
the pairs of methyls on an isopropyl group are not diastereotopic
10.1021/jo7026917 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/08/2008
J. Org. Chem. 2008, 73, 2811-2818
2811

SCHEME 1. Schematic Representations and Corresponding
Newman Projections of the Two Most Stable Conformers of
Compound 1a
a See also Figure S-1 of the Supporting Information.
exist as a pair of conformational enantiomers (displayed in the
corresponding Newman projections on the top left of Scheme
1) that interconvert, however, with a barrier too low for NMR
detection (computed value 3.6 kcal mol-1). The corresponding
transition state has a Cs symmetry, thus the conformer A (anti),
involved in such a rapid interconversion, is perceived by NMR
as having, in practice, a dynamic Cs symmetry and, as such, is
schematized in Scheme 1. The same calculations6 also predict
that the rotation barrier about the fluorenyl-CH2 bond, required
to accomplish the A to B interconversion, is 5.5 kcal mol-1, a
FIGURE 1. Temperature dependence of the methyl signal (600 MHz
in CHF2Cl/CHFCl2) of compound 1 (left). On the right the spectral
simulation with the rate constants indicated.
TABLE 1. Experimental and DFT Computed Barriers (kcal
mol-1) of Compounds 1-5
compd
type of motion (see text)
experimental
computed
1
2
3
conformer interconversion
enantiomerization
homomerisation
enantiomerization
conformer interconversion
conformer interconversion
6.0a
7.4
5.5
7.0
11.7
7.4
4.7
4.65
11.7
7.9
4
5
5.3a
5.6a
value in agreement with the measured barrier (6.0 kcal mol-1
)
for the observed exchange of the two conformers. These
theoretical results thus explain the spectral appearance of
compound 1 as a function of temperature.
a The barriers refer to the interconversion of the major into the minor
conformer.
Contrary to the case of 1, the low-temperature NMR spectrum
of 2 indicates that only a single conformer is populated:7 this
conformer undergoes a dynamic process, because anisochronous
signals are observed at low temperature for the ortho methyl
groups and for the methylene hydrogens (Figure 2). The spectral
simulation was obtained by using a single rate constant, and
the barrier derived from the reported k values is 7.4 kcal mol-1
(Table 1): the same barrier was also obtained by monitoring
the 13C signal of the ortho quaternary carbons of the mesityl
moiety (Figure S-2 of the Supporting Information).
CHART 1
(6) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision D.01; Gaussian, Inc.: Wallingford, CT, 2004.
(the viscosity broadened spectrum at such low temperatures does
not allow one to observe the splitting due to the J coupling
with the isopropyl methine hydrogen). Due to the frozen rotation
about the fluorene-CH2 bond, the existence of two conformers
with different populations could be observed in the spectrum
at -157 °C: on the contrary, the rotation about the Ar-CH2
bond (Ar being the di-isopropylphenyl moiety) is still fast at
that temperature, thus explaining why the expected diastereotop-
icity of the isopropyl methyl groups was not detected.
DFT computations6 predict that in compound 1 the two lowest
energy minima, separated by 1.2 kcal mol-1, correspond to the
two conformers (labeled A and B) shown in Scheme 1.
Conformer A, where the aryl and the fluorenyl moieties are in
an anti relationship, has an energy lower than that of B, where
these moieties are in a syn relationship. Conformer A might
(7) The different behaviour is a consequence of the fact that compound
2 is more hindered than 1, having two methyl groups in the ortho positions
of the aryl substituent.
2812 J. Org. Chem., Vol. 73, No. 7, 2008

FIGURE 4. DFT computed transition states for the four possible
motions that might occur in compound 2. The energy values (in kcal
mol-1) are relative to the ground state of Figure 3.
group). This accounts for the anisochronous signals (labeled
HR and Hâ) observed for the two methylene hydrogens in the
-141 °C trace of the NMR spectrum in Figure 2. In this
spectrum the downfield signal at 3.45 ppm (labeled HR) appears
as a doublet since there is a large J coupling with only one
geminal hydrogen Hâ, whereas the upfield signal at 2.46 ppm
(labeled Hâ) appears as a triplet, because there is an additional
large coupling with the anti H9 proton. This allowed us to assign8
the two methylene hydrogens as shown in the Newman
projection at the top of Figure 3. Such an assignment is further
confirmed by the computed6 chemical shifts that predict the HR
signal to be downfield with respect to Hâ (3.68 and 2.62 ppm,
respectively): the separation of the computed chemical shifts
(1.06 ppm) is in even better agreement with the experiment (0.99
ppm), the deviation being only 0.07 ppm.
1
FIGURE 2. Temperature dependence of the H (600 MHz in CHF2-
Cl/CHFCl2) spectral region from 3.9 to 1.2 ppm of 2 (left). On the
right the simulation obtained with the rate constants reported.
The existence of a single barrier for the rotation about two
different bonds suggests that these motions are probably
correlated. Four possible pathways, each with its own transition
state, should be in principle considered in order to explain the
exchange of the diastereotopic ortho methyl groups and of the
diastereotopic methylene hydrogens. All these pathways appear
to be correlated since the visual observation of the vibrational
modes, associated with the negative frequency of the transition
states, shows that both the aryl-CH2 and fluorenyl-CH2 bonds
are simultaneously involved. The corresponding computed
transitions states are reported in Figure 4.
(n° I) A possible pathway is that corresponding to the
correlated rotation about the mesityl-CH2 and the fluorenyl-
CH2 bonds,9 where the transition state (TS-1 of Figure 4) has
the fluorenyl and mesityl moieties in a syn relationship, with
one of the two ortho methyl groups eclipsing the C9-H9 bond
FIGURE 3. DFT computed (left) and X-ray structure (right) of
compound 2 (bottom). On the top is displayed the corresponding
Newman projection, where Ar is the mesityl moiety.
DFT computations predict that in the case of 2 the conformer
of type B (syn) of Scheme 1 does not correspond to an energy
minimum (actually corresponds to a transition state, as will be
subsequently discussed) and the only populated ground state is
that where the fluorenyl and the mesityl moieties are in an anti
relationship (analogous to the form A of Scheme 1). The results
of the calculations are confirmed by the X-ray diffraction that
shows how the experimental structure is essentially equal to
the computed one (Figure 3). In the corresponding Newman
projection the mesityl (Ar) appears in a gauche relationship with
respect to the H9 hydrogen of fluorene, thus indicating that 2
adopts an asymmetric, thus chiral, conformation (C1 point
(8) At -141 °C the H9 signal of the fluorenyl moiety (4.20 ppm) is
sufficiently sharp as to display a double doublet, with J values equal to 4.5
and to 11 Hz. The larger of these values, according to the Karplus
relationship (see Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870-2871), is
due to the coupling with Hâ, which is in an anti relationship to H9 (i.e.,
H9-C-C-Hâ dihedral angle ≈ 180°), whilst the smaller coupling is that
with HR (i.e., H9-C-C-HR dihedral angle ≈ 60°). The signal of HR thus
comprises the J ≈ 4.5 Hz and also the geminal coupling with Hâ (J ≈ -15
Hz). Owing to the quite broad line width of the methylene signals below
-140 °C, however, a doublet signal is observed, because only the effect of
major coupling is detectable. The signal of Hâ comprises the J ≈ 11 Hz
and also the geminal coupling with HR (J ≈ -15 Hz). The combination of
these two large couplings yields, in practice, a triplet signal since the
difference between these two values cannot be detected, owing to the quite
broad line width of the methylene signals below -140 °C.
J. Org. Chem, Vol. 73, No. 7, 2008 2813

of fluorene (i.e., dihedral angle C9-CH2-Cipso-Cortho ) 0°).
This enantiomerization process has a computed barrier of 11.0
kcal mol-1
.
(n° II) Another possible pathway9 is that where the transition
state (TS-2 of Figure 4) has the fluorenyl and mesityl moieties
in an anti relationship, with one of the two ortho methyl groups
eclipsing the C9-H9 bond of fluorene (i.e., dihedral angle C9-
CH2-Cipso-Cortho ) 0°). This enantiomerization process has a
computed barrier of 9.6 kcal mol-1
.
(n° III) The correlated motions can also occur according to
a pathway9 where the transition state (TS-3 of Figure 4) has
the fluorenyl and mesityl moieties in an anti relationship, with
the C9-H9 bond of fluorenyl orthogonal to the mesityl ring
(i.e., dihedral angle C9-CH2-Cipso-Cortho ) 90°) and with H9
pointing toward the mesityl moiety. This enantiomerization
process has a computed barrier of 8.5 kcal mol-1
.
(n° IV) The last possible pathway corresponds to a process9
where the transition state (TS-4 of Figure 4) has the fluorenyl
and mesityl moieties in a syn relationship, with the C9-H9 bond
also orthogonal to the mesityl ring (i.e., dihedral angle C9-
CH2-Cipso-Cortho ) 90°), but with H9 pointing away from the
mesityl moiety. The enantiomerization barrier computed for this
pathway has the lowest value (7.0 kcal mol-1, as in Table 1).
When any of these four pathways is rapid, a dynamic
symmetry is created (this will make the CH2 hydrogens
enantiotopic); as a consequence they must all be frozen in order
to account for the asymmetric chiral conformation corresponding
to the -141 °C NMR spectrum of Figure 2. The barrier
experimentally measured should be therefore the one corre-
sponding to the fastest rate, i.e., pathway n° IV which has the
transition state (TS-4 of Figure 4) with the lowest energy. This
is further confirmed by the observation that the experimental
barrier (7.4 kcal mol-1) has a value which is very close to the
lowest (7.0 kcal mol-1) of the four computed barriers.
1
FIGURE 5. Temperature dependence (left) of the H methyl signals
of compound 3 (600 MHz in CHF2Cl/CHFCl2). The simulation,
obtained with the rate constants k1, is shown on the right.
become diastereotopic11 when the pathway n° II (homomeri-
sation) is frozen. Owing to the larger steric hindrance of the
isopropyl with respect to the methyl groups, the computed
barrier for this process is expected to be higher in 3 with respect
to 2. Indeed the computed energy value (11.7 kcal mol-1) for
the corresponding transition state (see TS-2 in Figure S-3 of
the Supporting Information) not only is higher than that for the
analogous situation of 2 but also is coincident with the
experimental value, thus making quite reliable the assignment
of the pathway n° II as the route responsible for the observed
dynamic process reported in Figure 5 for compound 3.
On further lowering the temperature below -55 °C, a second
process begins to take place, which was better monitored by
looking to the 13C spectrum of the CH carbons of the ortho
isopropyl groups (Figure 6). From the rate constants k2, a barrier
of 7.9 kcal mol-1 is obtained (Table 1).
The variable temperature spectrum of compound 3 shows how
1
the H methyl signal of the ortho isopropyl groups broadens
and splits into two equally intense signals below -35 °C,
whereas the methyl signal of the para isopropyl group does
not10 (Figure 5). The experimental barrier (11.7 kcal mol-1
)
determined from the rate constants (k1) employed for the
simulation should correspond to the transition state TS-2, i.e.,
the transition state involved in the faster of the two pathways
(indicated as n° I and II in the case of 2) that can make
isochronous the signals of the diastereotopic methyl groups.
Contrary to the case of 2 this pathway is NMR visible in 3
because the prochiral methyls of the ortho isopropyl groups
(9) These processes bear some analogy with those indicated as ring-flip
pathways by Mislow et al. See: Gust, D.; Mislow, K. J. Am. Chem. Soc.
1972, 95, 1535-1547. Mislow, K. Acc. Chem. Res. 1976, 9, 26-33.
Iwamura, H.; Mislow, K. Acc. Chem. Res. 1988, 21, 175-182. Mislow, K.
Chemtracts: Org. Chem. 1989, 2, 151. Glaser, R. In Acyclic Organonitrogen
Stereodynamics; Lambert, J. B., Takeuchi, Y., Eds; VCH: New York, 1992;
Chapter 4. Rappoport, Z.; Biali, S. E. Acc. Chem. Res. 1997, 30, 307-314.
Lindner, A. B.; Grynszpan, F.; Biali, S. E. J. Org. Chem. 1993, 58, 6662-
6670. Grilli, S.; Lunazzi, L.; Mazzanti, A.; Casarini, D.; Femoni, C. J. Org.
Chem. 2001, 66, 488-495. Grilli, S.; Lunazzi, L.; Mazzanti, A.; Mazzanti,
G. J. Org. Chem. 2001, 66, 748-754. Grilli, S.; Lunazzi, L.; Mazzanti, A.
J. Org. Chem. 2001, 66, 4444-4446. Grilli, S.; Lunazzi, L.; Mazzanti, A.
J. Org. Chem. 2001, 66, 5853-5858.
(10) The doublet due to the coupling with the isopropyl CH hydrogen is
not visible anymore at low temperature in the case of the methyl signal of
the ortho isopropyl groups because the corresponding line width is
broadened by a second motion (see Figure 6) which begins to affect the
spectrum. This broadening does not occur for the methyl signal of the para
isopropyl group because the latter is not affected by the mentioned second
motion.
This second barrier must be related to the lowest of the four
transition states having Cs symmetry. In the case of 3, this
pathway corresponds to the same type of process indicated as
n° IV in the case of 2. The computed energy of the correspond-
ing transition state (7.4 kcal mol-1, as in TS-4 of Figure S-3 of
the Supporting Information) matches satisfactorily the experi-
mental barrier of 7.9 kcal mol-1
.
1
In the H spectrum of 4 the signals of H9, CH2, and CH3
remain essentially unchanged down to -130 °C but broaden
(11) Mislow, K.; Raban, M. Top. Stereochem. 1967, 1, 1. Jennings, W.
B. Chem. ReV. 1975, 75, 307. Eliel, E. L. J. Chem. Educ. 1980, 57, 52.
Casarini, D.; Lunazzi, L.; Macciantelli, D. J. Chem. Soc., Perkin Trans 2
1992, 1363.
2814 J. Org. Chem., Vol. 73, No. 7, 2008

FIGURE 6. Temperature dependence (left) of the 13C NMR CH signal
of the ortho isopropyl groups (150.8 MHz in CHF2Cl/CHFCl2) of
compound 3. On the right is shown the simulation obtained with the
rate constants (k2) employed.
considerably on further cooling and eventually split, at -173 °C,
into two (H9 and CH3) and three (CH2) signals, with a 70:30
intensity ratio (Figure 7). This proves that two conformers have
been detected, as a consequence of the restricted rotation about
the tolyl-CH2 and fluorenyl-CH2 bonds. The barrier for
interconverting the more into the less populated conformer is
5.3 kcal mol-1, as determined by the line shape simulation
(Figure S-4 of the Supporting Information). The spectrum of
the major conformer displays two anisochronous lines (labeled
HR and Hâ in Figure 7) due to the diastereotopicity of the
methylene hydrogens (the line width is too broad at this low
temperature to display the splitting due to the geminal coupling),
whereas a single line is observed for the CH2 hydrogens of the
minor form.
FIGURE 7. 1H NMR spectrum (600 MHz in CHF2Cl/CHFCl2) of the
aliphatic region of 4 at two different temperatures. The arrows (red for
the major and blue for the minor conformer) represent the DFT
calculated shifts (all moved upfield by 0.16 ppm).
SCHEME 2. Schematic Representations of the Equilibrium
between the Enantiomers of the Two Most Stable
Conformers and X-ray Structure of Compound 4
DFT computations predict indeed the existence of two energy
minima, corresponding to two ground states, separated by an
energy difference of 0.13 kcal mol-1, both having the aryl and
fluorenyl moieties in an anti relationship. As shown in Scheme
2 one conformer (labeled C) has the Me group pointing toward
H9 of the fluorene ring, whereas the other (labeled D) points
away from it. The interconversion of the conformers C and D
can take place Via a correlated rotation about the tolyl-CH2
and fluorenyl-CH2 bonds. In the corresponding transition state,
the tolyl ring is othogonal to the C9-CH2 bond (i.e., dihedral
angle C9-CH2-Cipso-Cortho ≈ 90°), with a DFT computed
energy (4.7 kcal mol-1) which is in fair agreement with the
barrier (5.3 kcal mol-1, as in Table 1) measured for the
conformer interconversion (see Figure S-5 of the Supporting
Information). This process thus corresponds to the pathway of
type n° III mentioned above.
interconverting D with its enantiomer D′, has a transition state
where the methyl crosses over the CH2 hydrogens (dihedral
angle C9-CH2-Cipso-Cortho ≈ 180°). According to DFT
computations this torsion process is expected to be very fast,
having a predicted barrier of only 3.9 kcal mol-1, which is a
value too small to be detected in an NMR experiment (See
Figure S-5 of the Supporting Information). This fast motion
generates a dynamic plane of symmetry (a situation similar to
that occurring in conformer A of compound 1 reported in
To the more populated conformer the enantiomeric structures
C and C′ of Scheme 2 should be assigned, because here the
two CH2 hydrogens (R and â) must be diastereotopic, thus
accounting for the observed anisochronous lines at -173 °C
(Figure 7). The less populated conformer must have the structure
D, since in this conformer the small amplitude torsion process,
J. Org. Chem, Vol. 73, No. 7, 2008 2815

Scheme 1), which makes the methylene hydrogens R and â of
the minor conformer equivalent (enantiotopic), as experimentally
observed.
The computed ground state energy for conformer D is 0.13
kcal mol-1 lower than that of C, in apparent contradiction with
the assignment above. When such small energy differences are
involved, the approximations of the calculations make the results
not very reliable. In these cases a more satisfactory approach is
that based on the computed values of chemical shifts, if the
latter are significantly different. DFT calculations indicate that
the upfield methyl signal, which is the less intense in the
experimental spectrum (Figure 7), is that of conformer D,12
confirming that the latter should be the less populated one. Also,
the computed separation for the signals of the diastereotopic
methylene hydrogens (HR and Hâ) of conformer C is 1.55 ppm,
in agreement with the 1.47 ppm separation observed for the
corresponding signals of the major conformer (Figure 7). In
addition, the average value of the computed methylene shifts
of conformer D lies in between the two signals of conformer
C.13 Since in the experimental spectrum (Figure 7) the intensity
of the single CH2 signal is lower than that of the pair of
anisochronous CH2 signals, the assignment of C as the more
stable, and D as the less stable, conformer in solution is further
supported.
The structure of compound 4, obtained by single-crystal X-ray
diffraction, resembles quite closely (Scheme 2) that of the less
populated conformer D. It is not unusual to encounter differences
between the conformations in solids and in solution, which
depend on the fact that crystals privilege the conformation which
fits better the crystal cell.14,15 This feature further indicates that
the energies of the two conformers are quite similar and that
their relative populations are strongly dependent on the environ-
ment.16
FIGURE 8. 1H NMR spectrum (600 MHz in CHF2Cl/CHFCl2) of the
aliphatic region of 5 at two different temperatures. The arrows (red for
the major and blue for the minor conformer) represent the DFT
calculated shifts (all moved upfield by 0.34 ppm).
Analogous results, as should be expected, were obtained in
the case of the similar compound 5, which has an isopropyl
replacing the ortho methyl group. The H NMR of the signal
of the aliphatic hydrogens (with the exception of that of H9)
split, at -162 °C, into two groups of lines, with a 70:30 intensity
ratio (Figure 8). Again the methylene of the major conformer
yields two anisochronous lines, due to the diastereotopicity of
the corresponding hydrogens (the line width is too broad at this
low temperature to display the splitting due to the geminal
coupling). On the contrary, the methylene hydrogens of the
minor conformer display a single line. Thus to the major form
should be assigned the asymmetric structure (C1 point group)
of the same type C displayed in Scheme 2 for 4, and to the
minor that of type D, where the fast torsion process makes the
methylene signals equivalent (isochronous) owing to the men-
tioned Cs dynamic symmetry. This assignment is further
confirmed by the trend of the DFT computed chemical shifts
reported in Figure 8.17
1
The line shape simulation (Figure S-6 of the Supporting
Information) of the aliphatic signals yields a barrier for the
interconversion equal to 5.6 kcal mol-1. As in the case of 4
this process can be attributed to the correlated motion of type
n° III, since the corresponding computed transition state
(analgous to TS-3 of Figure 4 and of Figure S-3 of the
Supporting Information) has an energy of 4.65 kcal mol-1 (Table
1), quite close to the experimental value. In the present case it
has been also possible to observe experimentally a further
consequence of the restricted rotations involving both the aryl-
CH2 and the fluorenyl-CH2 bonds. As expected on the basis
of the correlated rotation processes, in fact, the 13C spectrum
of 5 at -162 °C shows that the major conformer displays two
anisochronous signals (Figure S-7 of the Supporting Informa-
tion) for the quaternary carbons in positions 10 and 11 of the
(12) The computed difference between the methyl shifts of conformers
C and D is 0.77 ppm, which agrees well with the experimental separation
of 0.83 ppm.
(13) The two CH2 shifts of conformer D (3.70 and 2.58 ppm) must be
averaged, owing to the mentioned fast torsion process which creates the
dynamic Cs symmetry for this conformer. Computations predict that this
averaged shift lies in between the pair of CH2 signals of C and that the
upfield signal of the latter is separated by that of D by 0.79 ppm, in fair
agreement with the 0.69 ppm separation experimentally observed (Figure
7).
(14) Johansen, J. T.; Vallee, B. L. Proc. Natl. Acad. Sci. U.S.A. 1971,
68, 2532-2535. Kessler, H. Fresenius Z. Anal. Chem. 1987, 327, 66-67.
Burke, L. P.; DeBellis, A. D.; Fuhrer, H.; Meier, H.; Pastor, S. D.; Rihs,
G.; Rist, G.; Rodebaugh, R. K.; Shum, S. P. J. Am. Chem. Soc. 1997, 119,
8313-8323. Paulus, E. F.; Kurz, M.; Matter, H.; Ve´rtesy, L. J. Am. Chem.
Soc. 1998, 120, 8209-8221. Perry, N. B.; Blunt, J. W.; Munro, M. H. Magn.
Reson. Chem. 2005, 27, 624-627.
(15) A situation where it has been unambiguously demonstrated that the
X-ray diffraction structure in the solids is that of the minor conformer present
in solution has been reported in: Lunazzi, L.; Mazzanti, A.; Minzoni, M.;
Anderson, J. E. Org. Lett. 2005, 7, 1291-1294.
(17) The isopropyl methyl signals of 5 should be anisochronous in the
-162 °C spectrum of the major conformer, but the corresponding shift
difference is smaller than the line width (about 85 Hz at this temperature).
This is confirmed by the computed shift separation, which is predicted to
be only 0.04 ppm (i.e., 24 Hz at 600 MHz).
(16) A recent example where the type of conformer observed in the
crystal depends on the crystallisation solvent was reported in: Coluccini,
C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2003, 68, 7266-
7273.
2816 J. Org. Chem., Vol. 73, No. 7, 2008

SCHEME 3. Reaction Scheme for the Preparation of 1-5
v/v) to give the intermediate alkenes (yield 62-70%). Spectroscopic
data of the alkenes are reported in the Supporting Information.
In a 150 mL reaction bottle of the Parr apparatus was fitted a
solution of the appropriate alkene (about 4 mmol in 10 mL of THF
and 60 mL of MeOH), and then 100 mg of catalyst Pd/C 5% were
added and the suspension was shaken under H2 pressure (≈ 2 bar)
at room temperature. After 2 h the reaction was completed. The
catalyst was filtered off. and the solvent evaporated to give the
desired benzylfluorenes 1-5 almost in a quantitative yield.
Analytically pure samples were obtained by semipreparative
HPLC using C18 or C8 columns (5 µm, 250 mm × 10 mm, 5
mL/min, ACN/H2O 70:30 v/v or 80:20 v/v). Crystals suitable for
X-ray diffraction were obtained for 2 and 4 by slow evaporation
of the solvent (hexane in both cases).
9-(3,5-Diisopropylbenzyl)-9H-fluorene (1). 1H NMR (600 MHz,
CDCl3, 25 °C, TMS): δ 1.23 (12H, d, J ) 6.9 Hz), 2.86 (2H, m,
J ) 6.9 Hz), 3.09 (2H, d, J ) 7.9 Hz), 4.22 (1H, t, J ) 7.9 Hz),
6.88 (2H, d, J ) 1.6 Hz), 6.95 (1H, br t, J ) 1.6 Hz), 7.19 (2H, d,
J ) 7.5 Hz), 7.22 (2H, dt, J ) 7.5, 1.0 Hz),7.34 (2H, t, J ) 7.1
Hz), 7.73 (2H, d, J ) 7.7 Hz). 13C NMR (150.8 MHz, CDCl3, 25
°C, TMS) δ 24.1 (4CH3), 34.1 (2CH), 40.3 (CH2), 48.9 (CH), 119.7
(2CH), 122.8 (CH), 125.0 (2CH), 125.1 (2CH), 126.5 (2CH), 127.0
(2CH), 139.3 (Cq), 140.8 (2Cq), 146.9 (2Cq), 148.7 (2Cq). HRMS-
(EI): m/z calcd for C26H28, 340.21910; found, 340.2192.
9-(2,4,6-Trimethylbenzyl)-9H-fluorene (2). Mp 94-96 °C. 1H
NMR (600 MHz, CDCl3, 25 °C, TMS): δ 2.19 (6H, s), 2.37 (3H,
s), 3.07 (2H, d, J ) 8.7 Hz), 4.22 (1H, t, J ) 8.7 Hz), 6.94 (2H,
s), 7.09 (2H, d, J ) 7.7 Hz), 7.22 (2H, dt, J ) 7.4, 1.1 Hz), 7.38
(2H, t, J ) 7.5 Hz), 7.80 (2H, d, J ) 7.6 Hz). 13C NMR (150.8
MHz, CDCl3, 25 °C, TMS): δ 20.3 (2CH3), 20.9 (CH3), 33.8 (CH2),
46.2 (CH), 119.8 (2CH), 124.8 (2CH), 126.6 (2CH), 127.0 (2CH),
129.1 (2CH), 133.6 (Cq), 135.6 (Cq), 137.0 (2Cq), 140.7 (2Cq),
147.1 (2Cq). HRMS(EI): m/z calcd for C23H22, 298.17215; found,
298.1721.
fluorenyl moiety (the minor conformer still displays a single
line for this pair of carbons, due to the dynamic Cs symmetry
generated by the small amplitude torsion previously discussed).
Summary. The stereodynamic processes occurring in fluo-
renes derivatives, having a number of substituted benzyl groups
bonded to position 9, were monitored by variable temperature
NMR spectroscopy. Depending on the type of benzyl substit-
uents, conformers of different stabilities (like in 1, 4, 5) and
enantiomeric forms (like in 2, 3) were observed at very low
temperatures. The structures of two such conformers (compound
2 and 4) were also determined by single-crystal X-ray diffraction
and were found to agree with the predictions of DFT calcula-
tions. The interconversion processes were interpreted as being
due to correlated rotation pathways, as suggested by DFT
calculations that indicated the appropriate transition states
reproducing the experimental barriers in a satisfactory manner.
1
9-(2,4,6-Triisopropylbenzyl)-9H-fluorene (3). H NMR (600
MHz, CDCl3, 25 °C, TMS): δ 1.13 (12H, d, J ) 6.9 Hz), 1.32
(6H, d, J ) 6.9 Hz), 2.94 (1H, m, J ) 6.9 Hz), 3.01 (2H, m, J )
6.9 Hz), 3.14 (2H, d, J ) 8.8 Hz), 4.13 (1H, t, J ) 8.8 Hz), 7.02
(2H, d, J ) 7.6 Hz), 7.05 (2H, s), 7.19 (2H, dt, J ) 7.5, 0.9 Hz),
7.35 (2H, t, J ) 7.5 Hz), 7.78 (2H, d, J ) 7.5 Hz). 13C NMR
(150.8 MHz, CDCl3, 25 °C, TMS): δ 24.1 (4CH3, broad), 24.2
(2CH3), 29.5 (2CH), 31.4 (CH2), 34.2 (CH), 48.1 (CH), 119.8
(2CH), 120.8 (2CH), 125.0 (2CH), 126.5 (2CH), 127.0 (2CH), 130.7
(Cq), 140.6 (2Cq), 146.9 (2Cq), 147.1 (Cq), 147.4 (2Cq). HRMS-
(EI): m/z calcd for C29H34, 382.26605; found, 382.2662.
9-(2-Methylbenzyl)-9H-fluorene (4).20 Mp 72-73 °C. 1H NMR
(600 MHz, CDCl3, 25 °C, TMS): δ 2.26 (3H, s), 3.04 (2H, d, J )
8.3 Hz), 4.19 (1H, t, J ) 8.3 Hz), 7.10 (2H, d, J ) 7.6 Hz), 7.19
(2H, t, J ) 8.2 Hz), 7.22 (3H, br s), 7.26 (1H, br m), 7.35 (2H, t,
J ) 7.4 Hz), 7.75(2H, d, J ) 7.6 Hz). 13C NMR (150.8 MHz,
CDCl3, 25 °C, TMS): δ 19.7 (CH3), 37.7 (CH2), 47.6 (CH), 119.8
(2CH), 124.8 (2CH), 125.9 (CH), 126.6 (CH), 126.7 (2CH), 127.1
(2CH), 130.4 (CH), 130.4 (CH), 136.7 (Cq), 138.4 (Cq), 140.7
(2Cq), 147.0 (2Cq). HRMS(EI): m/z calcd for C21H18, 270.14085;
found, 270.1409.
9-(2-Isopropylbenzyl)-9H-fluorene (5). Mp 88-89 °C. 1H NMR
(600 MHz, CDCl3, 25 °C, TMS): δ 1.20 (6H, d, J ) 6.9 Hz), 3.11
(2H, d, J ) 8.3 Hz), 3.15 (1H, m, J ) 6.9 Hz), 4.20 (1H, t, J ) 8.3
Hz), 7.09 (2H, d, J ) 7.5 Hz), 7.22 (3H, dt, J ) 6.9, 1.0 Hz),
7.26(1H, m), 8.0 (1H, m), 7.33 (1H, dt, J ) 7.4, 1.5 Hz), 7.37
(3H, t, J ) 7.4 Hz), 7.79 (2H, d, J ) 7.9 Hz). 13C NMR (150.8
MHz, CDCl3, 25 °C, TMS): δ 23.9 (2CH3), 28.8 (CH), 37.0 (CH2),
48.6 (CH), 119.8 (2CH), 124.9 (2CH), 125,4 (CH), 125.5 (CH),
126.6 (2CH), 127.0 (2CH), 127.1 (CH), 130.8 (CH), 136.8 (Cq),
140.7 (Cq), 146.9 (2Cq), 147.3 (Cq). HRMS(EI): m/z calcd for
C23H22, 298.17215; found, 298.1722.
Experimental Section
Materials: 2-Methyl-benzaldehyde and 2,4,6-trimethylben-
zaldehyde were commercially available. 1-Bromo-3,5-diisopro-
pylbenzene was prepared according to the literature.18
2-Isopropylbenzaldehyde, 3,5-diisopropylbenzaldehyde, and
2,4,6-triisopropylbenzaldehyde19 were prepared following known
procedures (see the Supporting Information for details). Compounds
1-5 were achieved by reacting 9-fluorene with the requested
aromatic aldehydes and reducing the intermediate alkenes, as
reported in Scheme 3.
General Procedure for 1-5: To a stirred solution of N,N-
diisopropylamine (1.1 mL, 8 mmol in 30 mL of anhydrous THF)
kept at -10 °C under nitrogen, 5.5 mL (8.5 mmol, 1.6 M solution)
of n-BuLi were slowly added. The mixture was allowed to react at
-10 °C for 30 min and then slowly transferred by a double-tipped
needle into a solution of 9-fluorene (1.0 g, 6 mmol in 25 mL of
anhydrous THF) kept at -15 °C. The resulting yellow solution was
stirred at -15 °C for additional 20 min, and then a solution of the
appropriate aldehyde (10 mmol in 10 mL of dry THF) was added
in 10 min. The yellow solution faded during addition, and after
stirring for 15 min the reaction was quenched with 20 mL of H2O.
The extracted organic layer (Et2O) was dried (Na2SO4) and
evaporated. The crude, a mixture of alkene and alcohol, was purified
by a silica gel chromatography column (petroleum ether/EtAc 95:5
(18) Diemer, V.; Chaumeil, H.; Defoin, A.; Fort, A.; Boeglin, A.; Carre´,
C. Eur. J. Org. Chem. 2006, 2727-2738. Liu, R; Gomes, P. T.; Costa, S.
I.; Duarte, M. T.; Braquinho, R.; Fernandes, A. C.; Chien, J. C. W.; Singh,
R. P.; Marques, M. M. J. Organomet. Chem. 2005, 690, 1314-1323.
(19) Casarini, D.; Lunazzi, L.; Verbeeck, R. Tetrahedron 1996, 52,
2471-2480. Rieche, A.; Gross, H.; Ho¨ft, E. Org. Synth. 1967, 47, 51.
(20) Sieglitz, A.; Jassoy, H. Ber. D. Chem. 1921, 54B, 2133-2138.
J. Org. Chem, Vol. 73, No. 7, 2008 2817

NMR Spectroscopy. The spectra were recorded at 600 MHz
for 1H and 150.8 MHz for 13C. The assignments of the 1H and 13
programs6 (see the Supporting Information): the standard Berny
algorithm in redundant internal coordinates and default criteria of
convergence were employed. The reported energy values are not
ZPE corrected. Harmonic vibrational frequencies were calculated
for all the stationary points. For each optimized ground state the
frequency analysis showed the absence of imaginary frequencies,
whereas each transition state showed a single imaginary frequency.
Visual inspection of the corresponding normal mode was used to
confirm that the correct transition state had been found. NMR
chemical shift calculations were obtained with the GIAO method
at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level. TMS, cal-
culated at the same level of theory, was used as a reference to scale
the absolute shielding value.
C
signals were obtained by bidimensional experiments (edited-
gHSQC21 and gHMBC22 sequences). The samples for obtaining
spectra at temperatures lower than -100 °C were prepared by
connecting to a vacuum line the NMR tubes containing the
compound and a small amount of C6D6 (for locking purpose) and
condensing therein the gaseous CHF2Cl and CHFCl2 (4:1 v/v) under
cooling with liquid nitrogen. The tubes were subsequently sealed
in Vacuo and introduced into the precooled probe of the spectrom-
eter. Low temperature 13C spectra were acquired with a 5 mm dual
probe, without spinning, with a sweep width of 38 000 Hz, a pulse
width of 4.9 µs (70° tip angle), and a delay time of 2.0 s. Proton
decoupling was achieved with the standard Waltz-16 sequence. A
line broadening function of 1-5 Hz was applied to the FIDs before
Fourier transformation. Usually 512 to 1024 scans were acquired.
Temperature calibrations were performed before the experiments,
using a Cu/Ni thermocouple immersed in a dummy sample tube
filled with isopentane and under conditions as nearly identical as
possible. The uncertainty in the temperatures was estimated from
the calibration curve to be (2 °C. The line shape simulations were
performed by means of a PC version of the QCPE program DNMR
6 n° 633, Indiana University, Bloomington, IN.
Acknowledgment. L.L. and A.M. received financial support
from the University of Bologna (RFO) and from MUR-COFIN
2005, Rome (national project “Stereoselection in Organic
Synthesis”).
Supporting Information Available: DFT computed structures
of the two most stable conformers (A and B) of compound 1; DFT
computed transition states of 3; Computed energy diagram for
compound 4; variable temperature NMR spectra of compounds 2,
4, and 5; experimental details and spectroscopic data for the reaction
Calculations. Geometry optimization were carried out at the
B3LYP/6-31G(d) level by means of the Gaussian 03 series of
1
intermediates; X-ray data of compounds 2 and 4; H, 13C NMR
spectra and HPLC traces of 1-5; chemical shift calculations of 2,
4, and 5; computational data of 1-6. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Bradley, S. A.; Krishnamurthy, K. Magn. Res. Chem. 2005, 43,
117-123. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Res. Chem. 1993, 31, 287-292.
(22) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 648-653.
JO7026917
2818 J. Org. Chem., Vol. 73, No. 7, 2008