How space-filling is a pyridine lone pair?

Article abstract of DOI:10.1002/ejoc.201101008

The torsional barriers of 2′-substituted 2-arylpyridines have been probed experimentally (by using dynamic NMR spectroscopy) and computationally (by using density functional theory). Due to the compressibility of the lone pair, the torsional barriers of the arylpyridines are up to 4.2 kcal/mol smaller than those of the carba-analogous biphenyls. Furthermore, the ground states of the 2-arylpyridines are less twisted than those of the biphenyls. Finally, due to an out-of-collinearity distortion, the intramolecular repulsion is attenuated in both rotational transition states, in the syn coplanar conformer (in which the pyridine nitrogen and the substituent R face each other) and in the anti coplanar conformer (in which they are on opposite sides of the molecule).

Full text of DOI:10.1002/ejoc.201101008

FULL PAPER
DOI: 10.1002/ejoc.201101008
How Space-Filling Is a Pyridine Lone Pair?
Andrea Mazzanti,*[a] Lodovico Lunazzi,[a] Susan Lepri,[b] Renzo Ruzziconi,*[b] and
Manfred Schlosser*[c]
Keywords: Steric hindrance / NMR spectroscopy / Biaryls / Density functional calculations / Torsional energy diagrams
The torsional barriers of 2Ј-substituted 2-arylpyridines have
been probed experimentally (by using dynamic NMR spec-
troscopy) and computationally (by using density functional
theory). Due to the compressibility of the lone pair, the tor-
sional barriers of the arylpyridines are up to 4.2 kcal/mol
smaller than those of the carba-analogous biphenyls.
Furthermore, the ground states of the 2-arylpyridines are less
twisted than those of the biphenyls. Finally, due to an out-of-
collinearity distortion, the intramolecular repulsion is attenu-
ated in both rotational transition states, in the syn coplanar
conformer (in which the pyridine nitrogen and the substitu-
ent R face each other) and in the anti coplanar conformer (in
which they are on opposite sides of the molecule).
The torsional barriers of methylamine and ethane (hav-
ing H–N–H and H–C–H bond angles of 107.1[6,7] and
107.7°[8]) amount to 1.96[9] and 2.88 kcal/mol,[10] respec-
tively. The piperidine invertomer, in which the lone pair oc-
cupies the equatorial as opposed to the axial position, is
energetically favored by just 0.36 kcal/mol[11] (by 0.40 kcal/
mol according to force-field calculations[12] or by a still
moderate 0.74 kcal/mol according to a reinvestigation[13]).
According to a recent DFT calculation,[14] 2-phenylpyr-
idine has a significantly smaller twist angle of 21° than bi-
phenyl (44°[15–17]) and the energy it requires to attain the
coplanar structure, the transition state of the aryl–hetaryl
rotation, is lower (Etors = 1 kcal/mol[14]) than that reported
for the carba-analogous biphenyl (Etors ≈ 2 kcal/mol[17,18]).
Assuming the additivity of two repulsive interactions, ex-
perimental findings[19] can be extrapolated to an estimate
of 1.2 kcal/mol for the 2-phenylpyridine torsional barrier.
With other topologies, it is not always easy to predict the
space requirements of pyridines relative to benzenes. This
can be deduced from the landmark work of Boekelheide,
Vögtle, and Nozaki and their co-workers[20–23,29,30]
(Table 1).
The flip barrier[20,21] of 2,6-ansa-pyridines is, in the case
of a heptamethylene chain, only moderately smaller than
that of the carba-analogous biphenyl (9.0 vs. 11.5 kcal/mol
for Z = N and CH, respectively; Table 1).[22,23] Also, in the
case of some metaparacyclophanes containing two
CH2SCH2 links between the two aryl rings, the differences
are quite small.[24,25]
However, the activation energies vary by more than
10 kcal/mol when a 2,6-pyridinediyl or a 1,3-phenylene ring
is incorporated into the oligomethylene chain (14.8 vs.
Ͼ27 kcal/mol; Table 1)[26,27] and by at least 7 kcal/mol for
the dithia analogues (Ͻ13.6 vs. 20.5 kcal/mol; Table 1).[27]
Finally, the ring inversion of parametacyclophane and its
Introduction
The space requirements of a naked proton being negligi-
ble, a priori no major difference should exist between the
size of the lone pair at a carbanionic center and the C–H
bond resulting from its protonation. In both cases, it is a
doublet of electrons that fills the spatial volume. The same
reflections apply to the isoelectronic comparison between
the lone pair residing on the nitrogen atom of an amine
and the corresponding +N–H bond. However, the electron
density contours differ. Lone pairs will surround their only
poles of attraction, be it nitrogen or negatively charged car-
bon, as spherically as possible.[1,2] In contrast, a C–H or
+N–H bond is more slender and elongated as the binding
electron pairs are tightly held between two nuclei.[1,2] There-
fore, whatever experimental test is applied, the lone pair
proves to be “smaller” than the bond resulting from its pro-
tonation. The difference is considerable if one refers to
Charton’s set of υ (upsilon)[3] parameters. Although being
derived from van der Waals radii,[4] they almost coincide
with Taft’s kinetically based Es values.[5] Charton’s scale
ranks the amino entity (υNH = 0.35) substantially below
2
NH3
the ammonium group (υ+
= 0.49), the υ parameter of
which is almost identical with that of a methyl group (υCH
3
= 0.52).
[a] Department of Organic Chemistry “A.Mangini”,
University of Bologna,
Viale Risorgimento 4, 40136 Bologna, Italy
Fax: +39-051-2093654
E-mail: andrea.mazzanti@unibo.it
[b] Chemistry Department, University of Perugia,
Via Elce di Sotto 10, 06100 Perugia, Italy
E-mail: ruzzchor@unipg.it
[c] Institute of Chemical Science and Engineering,
Ecole Polytechnique Fédérale (EPFL-BCh),
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101008.
Eur. J. Org. Chem. 2011, 6725–6731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Mazzanti, L. Lunazzi, S. Lepri, R. Ruzziconi, M. Schlosser
FULL PAPER
Table 1. Comparison of the ring-flip activation energies of 1,3-ansa-benzenes (Z = CH) with those of 2,6-ansa-pyridines (Z = N).
[a] The ground state has a different symmetry, so there is no flip barrier. See ref.[30]
diene (20.6 and 8.3 kcal/mol, respectively; Table 1) is im-
In view of the minute torsional barrier,[14] there was no
peded by barriers that surpass those encountered for the chance of freezing out the rotation about the central axis of
corresponding pyridine compounds, again by nearly a diastereotopically 4-labeled 2-phenylpyridine,[38] not even
10 kcal/mol (Table 1).[28–30]
at –173 °C (100 K). At temperatures as low as this, the 2-
The torsional barriers of ortho-substituted biphenyls rep- (o-tolyl)pyridine derivative 2 did not show decoalescence
resent reliable criteria for scaling steric bulk.[31] Up to now, either. The torsional barriers of compounds 1 and 2, shown
such “B values” have been determined for more than two in parentheses in Table 2, were obtained by computation.
dozen substituents.[31–33] The measurements were ac- In contrast, the signals of the diastereotopic nuclei of model
complished by variable-temperature (“dynamic”) NMR compounds 3–5 broadened upon cooling and eventually
spectroscopy, monitoring the flip of the axially chiral bi- split into two separate peaks.
phenyl conformer into its mirror image by means of dia-
stereotopicity probes such as an isopropyl,[34] isopropyldi-
Table 2. Experimental and computational torsional energies[a]
methylsilyl,[31] or hexafluoro-α-hydroxyisopropyl[32] group
located at the 3Ј-position.[35]
(ΔG϶) for the 2-arylpyridines 1–5 and, for comparison, the carba-
analogous biaryls.
Compound
R
ΔG϶ [kcal/mol]
Z = N
Z = CH[b]
Results and Discussion
1
2
3
4
5
H
CH3
CH2CH3
CH(CH3)2
C(CH3)3
(1.0)[c]
(3.1)[e]
5.9[f]
(2.0)[d]
7.4[e]
It was deemed instructive to apply this technique to a
series of 2-arylpyridines to compare the effective size of the
pyridine lone pair with a transparent model system. The
selected congeners of 2-phenylpyridine (1) carried a methyl
(2), ethyl (3), isopropyl (4), and tert-butyl (5) group at the
8.6
6.9[f]
11.1[e]
11.6[f]
15.5[e]
[a] Calculated energies are given in parentheses. [b] Ref.[34a]
[c] Ref.[14] [d] Ref.[17] [e] Present work: determined by B3LYP/6-
2Ј-position. Harboring magnetically nonequivalent nuclei, 311++G(2d,p) calculations of the compound without the substitu-
ent at the 4-position. [f] Present work: experimental (NMR) data.
ethyl- and isopropyl-substituted compounds are self-moni-
toring. An isopropyldimethylsilyl diastereotopicity probe
was nevertheless attached to the 4-position of all the 2-aryl-
pyridines except in the case of the isopropyl-substituted
compound[35] (Scheme 1).
In particular, the diastereotopicity of compound 3 was
detected by the observation, at a very low temperature
(–160 °C), of two 1H lines for the silicon-bonded methyl
1
groups of the iPrMe2S substituent as well as of two H sig-
nals for the two geminal hydrogen atoms of the ethyl group.
The shift separation of the latter signals (99 Hz at
600 MHz) was much larger than that of the Me2Si lines
(19 Hz) and this larger value allowed us to obtain a very
accurate line-shape simulation (see Figure 1), which gave a
ΔG϶ value (5.9 kcal/mol, Table 2) with an uncertainty as
small as Ϯ0.1 kcal/mol.
The torsional barriers determined by line-shape analysis
of the 2Ј-ethyl-, 2Ј-isopropyl-, and 2Ј-tert-butyl-substituted
2-phenylpyridines (3–5) are lower than the values of the
Scheme 1. Model compounds 1–5 employed to probe the barriers
to rotation of 2-arylpyridines.
The synthesis of the samples 2–5 was straightforward. It carba-analogous biphenyls by 2.7–4.2 kcal/mol (Table 2).
relied on the well-established addition of organolithium to Thus the incorporation of an imine nitrogen into the 2-posi-
the corresponding pyridine followed by the re-aromatizing tion of a 2Ј-substituted biphenyl diminishes the torsional
elimination of lithium hydride (for details see the Exptl. barrier of the latter significantly. In this sense, the lone pair
Sect.).[36,37]
of a pyridine nitrogen atom is without doubt “smaller” or,
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How Space-Filling Is a Pyridine Lone Pair?
The infinite manifold of 2-aryl conformations encom-
passes two extreme geometries. Both of these represent
transition states in the free-energy diagrams (Scheme 2).
The structure locking the aryl and pyridyl rings in a perpen-
dicular position marks the transition state for the “wagging
motion” that equilibrates the twisted ground state of 2-
phenylpyridine with its mirror image. Because the corre-
sponding barrier is very low (about 1 kcal/mol), only time-
averaged spectra were recorded, even at –160 °C. The copla-
narity of the two rings is the other extreme spatial arrange-
ment to be encountered. This is the transition state through
which the “spinning motion” passes. Again, the barrier is
low (1–2 kcal/mol) as long as the 2-phenylpyridine remains
unsubstituted. However, a substituent R introduced into an
ortho position of the phenyl ring not only destroys the sym-
metry of the latter but also significantly increases the bar-
rier due to intramolecular ortho/orthoЈ repulsion in the co-
planar transition state. Free rotation being impeded, we
now have two enantiomeric conformers, one keeping the R
group in the upper and the other in the lower hemisphere
(Scheme 2). Thermal energy is required to overcome the
barrier and to enable the “spinning motion” again.
Figure 1. Temperature dependence of the 1H NMR signal
(600 MHz in CHF2Cl/CHFCl2) of the CH2 group of compound 3
(left). On the right, spectra simulated with the rate constants k.
more accurately termed, more deformable than an aromatic
C–H bond.
The numbers extracted from the variable-temperature
NMR spectra represent free energy differences between the
conformational ground and transition states. They do not
tell us anything about the pertinent structures. Extensive
quantum chemical calculations at the B3LYP/6-
311++G(2d,p) level of theory provided this information (all
calculations of compounds 2, 3, and 5 ignore the dia-
stereotopicity probe at the 4-position).[35]
As expected, the 2-arylpyridines 2–5 are found to be
twisted (skewed). However, their dihedral angles are con-
siderably smaller than those of their carba-analogues (see
Table 3). The big difference in the twist angles of the parent
compounds 2-phenylpyridine (21°[14]
)
and biphenyl Scheme 2. Torsional energy diagram of 2-arylpyridines (syn- and
anti-skew conformers being diastereoisomers, –45°/+45° syn-skew
and –135°/+135° anti-skew conformers being enantiomers).
(45°[15,16]) has previously been recognized.
At first sight one might expect the syn-coplanar transi-
tion state alone to benefit significantly from the relief of
crowding caused by the replacement of a stiff ortho-C–H
bond by the deformable nitrogen lone pair. However, the
free energy of the anti-coplanar transition state would be
only marginally lower, that is, by half of the difference
(1.0 kcal/mol) between the torsional barriers of biphenyl
and 2-phenylpyridine. Such a simplistic assumption would
neglect the nonrigidity of the 2-arylpyridine skeleton. Even
if confined to coplanarity, it is distorted. The lengthening
of the C(ipso)–C(ipsoЈ) bond can be ignored in this context
as it should be very similar in the biphenyl series. But the
simultaneous introduction of a 2-aza ring member and a
2Ј-ortho substituent R causes the para–ipso and the ipsoЈ–
paraЈ axes to bend out of collinearity (Scheme 3).
Table 3. Twist angles of the syn- and anti-skew 2-arylpyridine
ground states and those of the carba-analogous biaryls.
Compound
R
Twist angle [°]
Z = N[a]
Z = CH[b]
1
H
CH3
CH2CH3
CH(CH3)2
C(CH3)3
21
45
61
68
61
90
2[c]
3[c]
4
48;136
52;124
53;128
69[d]
5[c]
[a] Twist angles of syn- and anti-skew conformations of the 2-arylp-
yridines (first and second number, respectively). [b] Twist angle of
2-R-biphenyl. [c] Calculations of the corresponding compounds
without the diastereotopicity probe at the 4-position [B3LYP/6-
311++G(2d,p) level]. [d] The anti-skew conformation of 5 does not
correspond to an energy minimum.
Eur. J. Org. Chem. 2011, 6725–6731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Mazzanti, L. Lunazzi, S. Lepri, R. Ruzziconi, M. Schlosser
FULL PAPER
Conclusions
Due to the compressibility of the lone pair, the torsional
barriers of the arylpyridines are up to 4.2 kcal/mol smaller
than those of the carba-analogous biphenyls. Furthermore,
the ground states of the 2-arylpyridines are less twisted than
those of the biphenyls. Finally, due to an out-of-collinearity
distortion, the intramolecular repulsion is attenuated in
both rotational transition states, in the syn coplanar con-
former (in which the pyridine nitrogen and the substituent
R face each other) and in the anti coplanar conformer (in
which they are on opposite sides of the molecule).
Experimental Section
Scheme 3. Bending of the two (het)aromatic rings to minimize in-
tramolecular steric repulsions in the coplanar torsional transition
states.
1
General Methods: H and 13C NMR spectra of samples dissolved
in deuteriochloroform were recorded at 400 and 100.6 MHz,
respectively (Bruker Avance). Chemical shifts (δ) are given in ppm
relative to the internal standard tetramethylsilane. IR spectra were
recorded in chloroform solutions in the 4000–625 cm–1 frequency
range, and mass spectra were obtained by electron impact fragmen-
tation at an ionization potential of 70 eV with a source temperature
of 200 °C (Thermo-Finnigan MAT 95XP).
The resulting curvature in the array of the two (het)aro-
matic rings minimizes the local intramolecular steric repul-
sions. Therefore the DFT energies of the anti-coplanar tran-
sition states are only slightly higher (0.5–1.7 kcal/mol) than
those of the syn-coplanar transition states and are without
exception considerably smaller than those of the carba-
analogous conformers (e.g., 6.9 vs. 11.1 kcal/mol when R =
isopropyl). ortho-Substituted biphenyls are equally subject
to this out-of-collinearity distortion, but to a much lesser
extent.
The purity of all final products was testified by elemental analyses
and gas chromatography using two capillary columns of different
polarity [30 mϫ0.35 mmϫ0.25 μm DB 5MS (5% phenylmeth-
ylpolysiloxane) and 30 mϫ0.35 mmϫ0.25 μm DB23 (50% cya-
nopropylmethylpolysiloxane)]. Tetrahydrofuran and diethyl ether
were stored over potassium hydroxide pellets in the presence of
The calculated bend angles of the coplanar transition cuprous chloride, from which they were distilled, before being redis-
tilled from sodium wire after the characteristic blue color of in situ
generated sodium biphenyl ketyl (benzophenone-sodium “radical
anion”) had been found to persist. Pyridine was made anhydrous
by azeotropic distillation with toluene. “Petroleum ether” refers to
an alkane fraction with a boiling range of 40–60 °C. Air- and
moisture-sensitive compounds were stored in Schlenk tubes or bu-
rettes. They were protected by and handled under an atmosphere
of 99.995% pure nitrogen using appropriate glassware. Ethereal ex-
tracts were dried by using sodium sulfate if the product was isolated
by distillation or crystallization. Silica gel of particle size 0.040–
0.063 mm (230–400 mesh) was used for column chromatography.
states are listed together with the DFT energies of the
twisted ground and coplanar transition states (Table 4). The
total out-of-collinearity distortion can be expressed as the
sum of two bend angles, each of them being the sector en-
compassed by the ipso–para connecting line and the projec-
tion of the ipso–ipsoЈ axis (see the thin lines in Scheme 3).
The ortho-substituted ring pivots in such a way to increase
the distance between its R group and the ortho-hydrogen
atom facing the R group on the neighboring ring. The other
(het)aromatic ring always moves in the same direction.
Table 4. Relative DFT energies of the syn- and anti-skew ground states and the syn- and anti-coplanar transition states of 2-arylpyridines,
and, in parentheses, the bend angles in the coplanar transition states.
Compound
R
DFT energy [kcal/mol] (Bend angle [°])
Z = N[a]
Z = CH[a]
anti-skew[b]
syn-coplanar[b]
anti-coplanar[b]
coplanar rel. to skew
1
H
0.0
+0.6
+0.8
+0.6
0.4
(–3.8)
3.1
(+1.6)
3.4
(+2.2)
5.2
(+3.4)
9.0
(+6.1)
0.4
2.0
(–3.8)[c]
3.6
(2.0)[c]
7.1
2[d]
3[d]
4
CH3
(–9.1)x
4.6
(5.7)d
8.5
CH2CH3
CH(CH3)2
C(CH3)3
(–9.1)x
6.9
(6.4)d
11.1
(–11.2)x
10.6
(7.9)d
15.1
5[d]
–
[e]
(–13.5)x
(9.6)d
[a] Bend angles as defined in the text are given in parentheses. [b] DFT energies [B3LYP/6-311++G(2d,p) level] of the syn- and anti-skew
and syn- and anti-coplanar conformers all of them relative to the syn-skew ground state. [c] The syn- and anti-skew conformers are
identical. [d] Calculations on the corresponding compounds without the substituent at the 4-position. [e] The anti-skew conformer is not
an energy minimum.
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How Space-Filling Is a Pyridine Lone Pair?
In general, the product-to-support ratio was approximately 1:20.
The silica was suspended in petroleum ether and, as soon as all the
air bubbles had escaped, was washed into the column. When the
level of the liquid was still 3–5 cm above the layer of the solid, the
dry powder, obtained by absorption of the dissolved crude product
mixture onto a small volume (some 5–10 mL) of silica and subse-
quent evaporation to dryness, was poured onto the top of the col-
umn.
7 H), 0.29 (s, 6 H) ppm. 13C NMR: δ = 154.7, 148.6, 147.9, 141.9,
137.3, 129.7, 129.0, 128.9, 128.3, 126.6, 125.7, 26.0, 17.3 (2 C), 15.5,
13.3, –5.9 (2 C) ppm. MS: m/z (%) = 283 (93) [M]+, 268 (4), 241
(47), 182 (100), 167 (10), 77 (10), 59 (20), 43 (6). C18H25NSi
(283.48): calcd. C 76.26, H 8.89; found C 75.98, H 9.20. HRMS
(ESI): calcd. for C18H26NSi [M + H]+ 284.1845; found 284.1829.
2-(2-Isopropylphenyl)pyridine (4): At –75 °C, tert-butyllithium
(2.7 mmol) in pentanes (1.6 mL) and pyridine (0.39 g, 4.9 mmol)
were added consecutively to 2-bromoisopropylbenzene (0.50 g,
2.5 mmol) in diethyl ether (15 mL). The cooling bath was removed
and the mixture was kept at 25 °C for 12 h. After the addition of
water (25 mL), the organic phase was collected and dried, and the
solvent was evaporated at reduced pressure. Chromatography of
the residue on silica gel (eluent: 2:8 diethyl ether/petroleum ether
mixture) gave a colorless oily product. Yield: 0.257 g, 52%; b.p.
102–105 °C/0.2 Torr (Hickmann distillation). 1H NMR: δ = 8.68
(dt, J = 4.0, 0.8 Hz, 1 H), 7.73 (td, J = 7.7, 1.8 Hz, 1 H), 7.4 (m,
3 H), 7.3 (m, 3 H), 3.17 (sept., J = 6.9 Hz, 1 H), 1.19 (d, J = 6.9 Hz,
6 H) ppm. C14H15N (197.28): calcd. C 85.24, H 7.66, N 7.10; found
C 85.10, H 8.11, N 7.39.
Preparation of 2-Arylpyridines 1–5
4-(Isopropyldimethylsilyl)pyridine:
At
–75 °C,
butyllithium
(13 mmol) in hexanes (7.8 mL) and chloro(isopropyl)dimethylsilane
(1.8 g, 13 mmol) in diethyl ether (20 mL) were added consecutively
to 4-bromopyridine (2.0 g, 13 mmol; set free from its commercial
hydrochloride with saturated aqueous potassium carbonate, ex-
tracted with diethyl ether, and dried). After 45 min at 25 °C, the
solvent was stripped off and the residue distilled; b.p. 55–57 °C/
1
1 Torr; colorless oil; yield: 1.70 g (73%). H NMR: δ = 8.54 (d, J
= 5.6 Hz, 2 H), 7.35 (d, J = 5.6 Hz, 2 H), 0.95 (s, 7 H), 0.25 (s, 6
H) ppm. 13C NMR: δ = 148.6 (2 C), 148.5, 128.7 (2 C), 17.3 (2 C),
13.2, –5.9 (2 C) ppm. MS: m/z (%) = 179 (22) [M]+, 164 (3), 136
(100), 122 (10), 106 (18), 83 (41), 43 (23). C10H17NSi (179.33):
calcd. C 66.97, H 9.55, N 7.81; found C 67.05, H 9.91, N 7.92.
The same product was obtained when a mixture of 2-bromopyr-
idine (0.20 g, 1.3 mmol), 2-isopropylphenylboronic acid (0.27 g,
1.6 mmol), aq. 2.0 m potassium carbonate (1.3 mmol), and tetrakis-
(triphenylphosphane)palladium (0.047 g, 0.041 mmol) in benzene
(10 mL) and ethanol (8.0 mL) was heated at 70 °C for 6 h. Upon
chromatography (elution with a 3:7 mixture of diethyl ether and
petroleum ether) a colorless oil exhibiting all properties of com-
pound 4 was isolated (yield: 0.230 g, 92%).
2-Chloro-4-(isopropyldimethylsilyl)pyridine: The compound was
prepared analogously from 4-bromo-2-chloropyridine (2.5 g,
13 mmol); colorless liquid; b.p. 61–63 °C/1 Torr; yield: 1.92 g
1
(69%). H NMR: δ = 8.33 (dd, J = 7.8, 1.8 Hz, 1 H), 7.38 (t, J =
1.8 Hz, 1 H), 7.27 (dd, J = 9.5, 1.8 Hz, 1 H), 1.0 (m, 7 H), 0.27 (s,
6 H) ppm. 13C NMR: δ = 153.1, 151.2, 148.5, 129.0, 127.0, 17.2 (2
C), 13.1, –5.9 (2 C) ppm. MS: m/z (%) = 213 (20) [M]+, 172 (82),
170 (100), 156 (10), 93 (13), 83 (15), 43 (26). C10H16ClNSi (213.78):
calcd. C 56.18, H 7.54, N 6.55; found C 56.00, H 8.03, N 7.11.
4-(Isopropyldimethylsilyl)-2-(2-tert-butylphenyl)pyridine (5): Com-
pound 5 was obtained from 4-(isopropyldimethylsilyl)pyridine
(1.7 g, 5.6 mmol) and 1-bromo-2-tert-butylbenzene (1.0 g,
4.7 mmol). Chromatography of the crude brown oil (elution with a
1:4 diethyl ether and petroleum ether mixture) allowed to collect a
first fraction consisting of a mixture of 2-tert-butyl-4-(isopropyldi-
methylsilyl)- and 2-[(2-tert-butyl)phenyl]-4-(isopropyldimethylsilyl)-
pyridine in an approximately 1:1 molar ratio. Two subsequent chro-
matographic fractions contained unreacted 4-(isopropyldimethyl-
silyl)pyridine (0.35 g) and 4,4Ј-bis(isopropyldimethylsilyl)-2,2Ј-bi-
pyridine (0.14 g), respectively. The expected product was separated
as a pale-yellow oil (0.042 g, 2.9%) by semi-preparative HPLC of
the first fraction after elution with a 90:10 (v/v) mixture of acetoni-
2-Phenylpyridine (1): At –75 °C, phenyllithium (7.6 mmol) in dibut-
yl ether (4.2 mL) was added to pyridine (1.2 g, 15 mmol) in diethyl
ether (15 mL). The cooling bath was removed and the mixture kept
at 25 °C for 12 h. The solvent and excess of pyridine were evapo-
rated at reduced pressure and the residue was eluted from silica gel
(60 mL) with a 3:7 (v/v) mixture of diethyl ether and petroleum
ether to give a colorless oil. Yield: 0.75 g (64%); b.p. 142–143 °C/
15 Torr (Hickmann distillation, ref.[39–42] 140 °C/12 Torr); m.p. of
the picrate 156–158 °C (ref.[39,40,42] m.p. 157 °C). 1H NMR
(200 MHz): δ = 8.73 (dd, J = 5.1, 0.6 Hz, 1 H), 8.0 (m, 2 H), 7.8
(m, 2 H), 7.5 (m, 3 H), 7.3 (m, 1 H) ppm.
1
trile/water mixture using a C18 column. H NMR: δ = 8.57 (d, J
= 4.8 Hz, 1 H), 7.55 (dd, J = 8.0, 0.9 Hz, 1 H), 7.40 (d, J = 0.9 Hz,
1 H), 7.3 (m, 2 H), 7.22 (td, J = 7.5, 1.0 Hz, 1 H), 7.10 (dd, J =
7.5, 1.5 Hz, 1 H), 1.17 (s, 9 H), 0.95 (br. s, 7 H), 0.26 (s, 6 H) ppm.
13C NMR: δ = 162.0, 148.0, 147.7, 146.8, 141.1, 131.4, 129.9, 127.8,
126.8, 126.6, 125.1, 36.4, 32.3 (3 C), 17.3 (2 C), 13.3, –5.9 (2
C) ppm. MS: m/z (%) = 311 (38) [M]+, 296 (65), 268 (7), 238 (21),
210 (100), 73 (27), 57 (31). C20H29NSi (311,54): calcd. C 77.11, H
9.38, N 4.50; found C 77.00, H 9.56, N 4.57. When 2-chloro-4-
(dimethylisopropylsilyl)pyridine was treated with 2-tert-butylphen-
ylboronic acid in the presence of tetrakis(triphenylphosphane)pal-
ladium under Suzuki–Miyaura conditions[43] a complex mixture of
products was obtained. Only traces of the expected product were
detected by GC–MS analysis.
4-(Isopropyldimethylsilyl)-2-(2-tolyl)pyridine (2): At –75 °C, tert-
butyllithium (2.9 mmol) in pentanes (1.7 mL) and 4-(isopropyldi-
methylsilyl)pyridine (0.53 g, 3.0 mmol) were added consecutively to
2-bromotoluene (0.50 g, 2.9 mmol) in diethyl ether (10 mL). After
5 h at 25 °C the mixture was concentrated, absorbed onto a small
quantity of silica gel, and dried before being poured into a
chromatography column. Elution with a 1:4 (v/v) mixture of diethyl
ether and petroleum ether mixture gave a colorless oil. Yield:
1
0.530 g, 67%. H NMR: δ = 8.65 (d, J = 5.1 Hz, 1 H), 7.48 (s, 1
H), 7.4 (m, 1 H), 7.3 (m, 4 H), 2.36 (s, 3 H), 0.98 (br. s, 7 H), 0.28
(s, 6 H) ppm. C17H23NSi (269.46): calcd. C 75.78, H 8.60, N 5.20;
found C 75.68, H 8.66, N 5.38.
4-(Isopropyldimethylsilyl)-2-(2-ethylphenyl)pyridine (3): Compound
3 was prepared analogously from 1-bromo-2-ethylbenzene (0.50 g,
Variable-Temperature NMR Spectroscopy: NMR spectra were re-
corded by using a spectrometer operating at a field of 14.4 T
1
2.5 mmol)
and
4-(isopropyldimethylsilyl)pyridine
(0.20 g,
(600 MHz for H) (Varian INOVA). The variable-temperature ex-
2.5 mmol) and obtained as a pale-yellow oil. Yield: 0.28 g (56%);
b.p. 145–147 °C/1.4 Torr (Hickmann distillation). 1H NMR: δ =
8.65 (dd, J = 4.8, 1.0 Hz, 1 H), 7.48 (t, J = 1.1 Hz, 1 H), 7.3 (m, 5
H), 2.71 (q, J = 7.5 Hz, 2 H), 1.12 (t, J = 7.5 Hz, 3 H), 0.98 (br. s,
periments of compound 5 were performed in CDFCl2 whereas the
spectra of compounds 2–4 were recorded in a CHF2Cl/CHFCl2/
C6D6 mixture (9:3:1, v/v). The NMR tubes containing the com-
pounds were prepared by using a vacuum line. First a small amount
Eur. J. Org. Chem. 2011, 6725–6731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6729

A. Mazzanti, L. Lunazzi, S. Lepri, R. Ruzziconi, M. Schlosser
FULL PAPER
(50 μL) of hexadeuteriobenzene was introduced by means of a
microsyringe for locking purposes (this step was not necessary for
the sample of 5). The NMR tube was then immersed in liquid ni-
trogen and evacuated to condense about 0.45 mL of chlorodifluor-
omethane (Freon 22) and about 0.15 mL of dichlorofluoromethane
(Freon 21) transferred as gases from lecture bottles (in the case of
compound 5, 0.65 mL of CDFCl2 was transferred). The tubes were
subsequently sealed under reduced pressure (0.01 mbar) by using a
methane/oxygen torch. Avoiding any rapid temperature change, the
samples were cautiously warmed to 25 °C, at which the Freons de-
velop a pressure of about 8 atm. After a few hours at ambient tem-
perature, the samples could be safely introduced into the probe
head of the spectrometer, already cooled to –30 °C. Low-tempera-
ture 600 MHz 1H NMR spectra (compounds 2–5) were acquired
without spinning using a 5 mm dual direct probe with a 9000 Hz
sweep width, 2.0 μs (20° tip angle) pulse width, 3 s acquisition time,
and 1 s delay time. A shifted sine bell weighting function[44] equal
to the acquisition time (i.e., 3 s) was applied before the Fourier
transformation. Usually 32–64 scans were collected. Low-tempera-
ture 150.8 MHz 13C NMR spectra (compounds 2, 4, and 5) were
acquired without spinning and under proton decoupling conditions
with a 38000 Hz sweep width, 4.2 μs (60° tip angle) pulse width,
1 s acquisition time, and 1 s delay time. A line-broadening function
of 1–2 Hz was applied before the Fourier transformation. Usually
128–512 scans were collected.
sition states. The energy values listed in Tables 2 and 4 represent
total electronic energies. In general, it was shown that these give
the best fit with experimental dynamic NMR spectroscopic data.[53]
Therefore the computed values were not corrected for zero-point
energy contributions or other thermodynamic parameters. This
avoids artifacts that might result from the ambiguous choice of
reference temperature, empirical scaling factors,[54] and idealization
of low-frequency vibrators as harmonic oscillators, which cause dif-
ficulties in the correct evaluation of the entropic contribution.[55,56]
Supporting Information (see footnote on the first page of this arti-
cle): Variable-temperature NMR spectra of 4, computational data
for 2–5 and their carba-analogues, and NMR spectra of 2–5 and
their precursors.
Acknowledgments
The authors are grateful to the University of Bologna (RFO funds
2009), the Ministero dellЈUniversità e Ricerca, Roma (MUR PRIN
2008 prot. 2008LYSEBR-004), and the Schweizerische National-
fonds zur Förderung der wissenschaftlichen Forschung, Bern (grant
20-100Ј336-02) for financial support. They are particularly in-
debted to Dr. E. Solari of the EPFL-ISIC Analytical Services, Lau-
sanne, and REDOX, Monza, Italy, for the elemental analyses of 2–
4.
When operating the NMR apparatus at low temperature, a flow of
dry nitrogen was first passed through a precooling unit adjusted to
–50 °C. Then the gas entered an inox steel heat-exchanger im-
mersed in liquid nitrogen and connected to the NMR probe head
by a vacuum-insulated transfer line. Gas flows of 10–30 L min–1
were required to descend to the desired temperature. Temperature
calibrations were performed before the experiments by using a digi-
tal thermometer and a Cu/Ni thermocouple placed in an NMR
tube filled with isopentane. The conditions were kept as identical
as possible in all subsequent work. In particular, the sample was
not spun and the gas flow was the same as that used during the
acquisition of the spectra. The uncertainty in temperature measure-
ments can be estimated as Ϯ2 °C.
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Received: July 12, 2011
Published Online: September 27, 2011
Eur. J. Org. Chem. 2011, 6725–6731
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6731