3-(Dimethylboryl)pyridine: Synthesis, structure, and remarkable steric effects in scrambling reactions

Article abstract of DOI:10.1021/jo7018043

(Chemical Equation Presented) A facile method for the synthesis of 3-(dimethylboryl)pyridine (1a) is described. Compound 1a assembles into a rigid cyclic tetramer stabilized via intermolecular boron-nitrogen coordination bonds both in the crystalline state and in solution. The outstanding structural feature of 1a, as compared with previously reported 3-(diethylboryl)pyridine (2a) (which adopts a cone conformation), is that the tetramer of la adopts a 1,2-alternate conformation. To investigate the effect of substituents at the boron atom on the stabilities of the oligomers, scrambling experiments of the component molecules using 1, 2, and 3-(di-n-butylboryl)pyridines 3 were carried out. Although heating at 80-90°C for 20 h was required to attain the equilibrium of the scrambling reactions when the component molecules of the tetramers were 2 or 3, the scrambling in 1 proceeded under relatively mild conditions (60°C, 3 h). This difference in reaction conditions required for 1, as compared to conditions required for 2 or 3, could not be explained solely by the stabilities based on bond lengths or THC.^1g It appears that whereas only an S_N1-type pathway may be involved in the scrambling of 2 or 3, both S_N1- and S_N2-type mechanisms operate simultaneously during scrambling reactions of 1 or an intermediate mechanism between S_N1 and S_N2 operates, which was supported by kinetic studies and calculations using model compounds.

Full text of DOI:10.1021/jo7018043

3-(Dimethylboryl)pyridine: Synthesis, Structure, and Remarkable
Steric Effects in Scrambling Reactions
Shigeharu Wakabayashi,*,† Saori Imamura,† Yoshikazu Sugihara,‡ Makoto Shimizu,§
Toshikazu Kitagawa,§ Yasuhiro Ohki, and Kazuyuki Tatsumi
Department of Clinical Nutrition, Faculty of Health Science, Suzuka UniVersity of Medical Science,
Suzuka, Mie 510-0293, Japan, Department of Chemistry, Graduate School of Science and Engineering,
Yamaguchi UniVersity, Yamaguchi City, Yamaguchi 753-8512, Japan, Department of Chemistry for
Materials, Mie UniVersity, Tsu, Mie 514-8507, Japan, and Department of Chemistry, Graduate School of
Science and Research Center for Materials Science, Nagoya UniVersity, Furo-cho,
Chikusa-ku, Nagoya 464-8602, Japan
s-waka@suzuka-u.ac.jp
ReceiVed August 16, 2007
A facile method for the synthesis of 3-(dimethylboryl)pyridine (1a) is described. Compound 1a assembles
into a rigid cyclic tetramer stabilized via intermolecular boron-nitrogen coordination bonds both in the
crystalline state and in solution. The outstanding structural feature of 1a, as compared with previously
reported 3-(diethylboryl)pyridine (2a) (which adopts a cone conformation), is that the tetramer of 1a
adopts a 1,2-alternate conformation. To investigate the effect of substituents at the boron atom on the
stabilities of the oligomers, scrambling experiments of the component molecules using 1, 2, and 3-(di-
n-butylboryl)pyridines 3 were carried out. Although heating at 80-90 °C for 20 h was required to attain
the equilibrium of the scrambling reactions when the component molecules of the tetramers were 2 or 3,
the scrambling in 1 proceeded under relatively mild conditions (60 °C, 3 h). This difference in reaction
conditions required for 1, as compared to conditions required for 2 or 3, could not be explained solely
by the stabilities based on bond lengths or THC.1g It appears that whereas only an SN1-type pathway
may be involved in the scrambling of 2 or 3, both SN1- and SN2-type mechanisms operate simultaneously
during scrambling reactions of 1 or an intermediate mechanism between SN1 and SN2 operates, which
was supported by kinetic studies and calculations using model compounds.
Introduction
reduced, the mechanism for exchange with a ligand switches
from a dissociation mechanism to a bimolecular displace-
ment.1a-d,h,i Previously, Sugihara et al. reported that 3-(diethyl-
boryl)pyridine (2a) assembles into a rigid cyclic tetramer
stabilized via intermolecular boron-nitrogen coordination bonds
The effect of substituents at a tetrahedral boron atom on the
stability of amine-borane complexes and nucleophilic substitu-
tion at the boron atom have been extensively studied.1 The steric
bulk of the groups attached to the boron atom contributes to
the stability of the boron-nitrogen bond, and lowers the acidity
toward the amine ligand as the bulkiness of the substituents
increases.1e-g When steric crowding around the boron atom is
(1) (a) Cowley, A. H.; Mills, J. L. J. Am. Chem. Soc. 1969, 91, 2911.
(b) Budde, W. L.; Hawthorne, M. F. J. Am. Chem. Soc. 1971, 93, 3147. (c)
Walmsley, D. E.; Budde, W. L.; Hawthorne, M. F. J. Am. Chem. Soc. 1971,
93, 3150. (d) Lalor, F. J.; Paxson, T.; Hawthorne, M. F. J. Am. Chem. Soc.
1971, 93, 3156. (e) Toyota, S.; Ohki, M. Bull. Chem. Soc. Jpn. 1990, 63,
1168. (f) Toyota, S.; Ohki, M. Bull. Chem. Soc. Jpn. 1991, 64, 1554. (g)
Toyota, S.; Ohki, M. Bull. Chem. Soc. Jpn. 1992, 65, 1832. (h) Toyota, S.;
Futawaka, T.; Ikeda, H.; Ohki, M. J. Chem. Soc., Chem. Commun. 1995,
2499. (i) Vedrenne, P.; Guen, V. L.; Toupet, L.; Gall, T. L.; Mioskowski,
C. J. Am. Chem. Soc. 1999, 121, 1090.
† Suzuka University of Medical Science.
‡ Yamaguchi University.
§ Mie University.
Nagoya University.
10.1021/jo7018043 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/06/2007
J. Org. Chem. 2008, 73, 81-87
81

Wakabayashi et al.
and undergoes scrambling with 3-(diethylboryl)-5-(2-methoxy-
ethoxy)pyridine (2c).2 It is important to investigate how the
substituent at a boron atom influences the self-assembling feature
of 3-borylpyridine from the viewpoint of the molecular design
of more sophisticated systems. Furthermore, since little is known
about the kinetics of these self-assembling systems,3 the
mechanism of the scrambling reaction is worthy of investigation.
To address these issues, we prepared two compounds:
3-(dimethylboryl)pyridine (1a) and 3-(di-n-butylboryl)pyridine
(3a), where the B-ethyl groups of 2a are replaced by methyl or
n-butyl groups, respectively. The synthesis of 3a has been
reported by Terashima et al.4a Here we report the synthesis of
1a and its structural features. In addition, the effects of
substituents at the boron on the stabilities of the oligomers were
examined by scrambling reactions using 1, 2, and 3. Studies on
the concentration dependence of the reactants and DFT calcula-
tions using simplified models are also presented in an attempt
to provide simple rationalizations for the observed effects.
was synthesized from 3-bromo-5-methoxpyridine8 in 21%
overall yield as colorless crystals (mp 158-160 °C).7 Impor-
tantly, in the above approach methyllithium predominantly
attacked the boron atom of the boronate and not the carbon
atom of the methoxy group. Compounds 2b and 3b were
prepared in a conventional manner.4 The expected structures
of all these borylpyridines were fully supported by spectral
data and elemental analysis, and the compounds were stable
and showed no sign of degradation after storage for 1 year at
-30 °C.
Vapor Pressure Osmometry, Mass Spectrometry, and
NMR Spectroscopy. Vapor pressure osmometry (VPO) was
performed on a Knauer digital vapor pressure osmometer (using
benzil as a standard) to estimate the average aggregate size of
the compounds. Various concentrations of 1a in chloroform
(from 0.014 to 0.101 mol dm-3
) at 40 °C, and in tetrahydrofuran
(from 0.012 to 0.082 mol dm-3
) at 45 °C, provided values of
3.7 and 3.8, respectively, suggesting that 1a forms a tetramer
on average in these solvents. In each experiment, the VPO plots
between the concentration and the reading were linear (r )
0.9990 in chloroform, r ) 0.9995 in THF) within experimental
error. Since the measured values are independent of the solvent
(even in tetrahydrofuran, which has a high affinity for trivalent
boron atoms), it appears that the boron atom in 1a is protected
from coordination with an oxygen atom of the solvent by head-
to-tail intermolecular interactions. Furthermore, 3a in chloroform
at 40 °C gives a VPO value of 3.7, consistent with the formation
of a tetramer.
Results and Discussion
Synthesis. A common method for introducing a dialkylboryl
group onto a pyridine ring involves the lithiation of bromopy-
ridine followed by trapping with trialkylborane or dialkyl-
methoxyborane.4 However, this method is not suitable for the
synthesis of 1 since trimethylborane required for 1 is very
expensive and difficult to handle.5 We instead chose a nucleo-
philic substitution approach using alkyl pyridylboronate with
methyllithium. The reaction of 3-bromopyridine with n-butyl-
lithium, followed by triisopropylborate at -78 °C, provided
isopropyl 3-pyridylboronate, which was treated with hydro-
chloric acid at ambient temperature.4a,6 The resulting boronic
acid was subsequently heated at 80 °C in methanol to give
methyl 3-pyridylboronate (4)7 (45% yield) together with free
In the EIMS (20 eV) spectrum of 1a, in addition to the M+
- Me peak (m/z 104, relative intensity 100%) and the parent
peak as a monomer (M+, 119, 50%), extremely weak peaks of
2M+ - Me (223, 6%), 3M+ - Me (342, 4%), and 4M+ - Me
(461, 1%) were observed. This result indicates that the energy
required for ionization was so high that the aggregated molecule
dissociated. In contrast, the negative charge accelerating ESI-
MS measurement of 1a in THF in the presence of LiCl provided
charged peaks of moderate intensity at m/z 511.5 (intensity,
100%), 392.5 (28%), and 273.4 (6%), corresponding to the [4M
+ Cl]-, [3M + Cl]-, and [2M + Cl]- charge states, respectively
(Figure S5 in the Supporting Information). The observed and
theoretical isotopic distributions of each fragment were in close
agreement, consistent with the formation of tetramers. ESI-TOF-
MS spectrum of 1b in THF-CH3CN (ca. 1:1) in the presence
of LiCl showed charged peaks at m/z 631.4 (43%), 482.3
(100%), and 333.2 (66%), which are assignable to [4M + Cl]-,
[3M + Cl]-, and [2M + Cl]-, respectively. Similarly, ESI-
TOF-MS spectra of 3a and 3b in THF in the presence of LiCl
displayed charged peaks at m/z 847.8 (29%), 644.6 (28%), and
441.4 (32%) (3a), and 967.8 (100%), 734.6 (21%), and 501.4
(35%) (3b), which are assignable to [4M + Cl]-, [3M + Cl]-,
and [2M + Cl]-, respectively.
boronic acid (19%). Crude 4 was treated with 4 equiv of
methyllithium at -78 °C to furnish 1a in 81% yield as colorless
crystals (mp 169-171 °C). Similarly, methoxy derivative 1b
(2) (a) Sugihara, Y.; Miyatake, R.; Takakura, K.; Yano, S. J. Chem. Soc.,
Chem. Commun. 1994, 1925. (b) Sugihara, Y.; Takakura, K.; Murafuji, T.;
Miyatake, R.; Nakasuji, K.; Kato, M.; Yano, S. J. Org. Chem. 1996, 61,
6829.
(3) (a) Gazzaz, H. A.; Robinson, B. H. Langmuir 2000, 16, 8685. (b)
Stahl, I.; Kiedrowski, G. J. Am. Chem. Soc. 2006, 128, 14014. (c) Menger,
F. M.; Shi, L. J. Am. Chem. Soc. 2006, 128, 9338.
(4) (a) Terashima, M.; Kakimi, H.; Ishikura, M.; Kamata, K. Chem.
Pharm. Bull. 1983, 31, 4573. (b) Ishikura, M.; Mano, T.; Oda, I.; Terashima,
M. Heterocycles 1984, 22, 2471.
(5) The price and boiling point of trimethylborane is U.S. $1080.00/10
g and -20 °C, respectively. In addition, this reagent is not commercially
available in Japan because it is a high-pressure gas.
The 11B NMR spectra of 1a, 1b, 3a, and 3b in CDCl3
displayed a strong signal at -2.05, -1.61, -1.38, and -1.11
ppm, respectively, showing that monomer-oligomer equilibrium
(7) Takeuchi, M.; Kijima, H.; Hamachi, I.; Shinkai, S. Bull. Chem. Soc.
Jpn. 1997, 70, 699. In this paper and in private communications, Takeuchi
et al. described the synthesis of 4, involving the hydrolysis of 2a (ref 4a)
followed by esterification in 19% yield. On the basis of the procedure
reported by Ogawa et al. (J. Am. Chem. Soc. 1996, 118, 5783) and Wong
et al. (J. Org. Chem. 2002, 67, 1041), which does not involve the production
of boronic acid, we attempted the synthesis by reacting the lithiate of
3-pyridyl with trimethylborate, followed by removal of solvent and treatment
with methanol. Unfortunately, polymeric materials were obtained.
(8) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69.
(6) (a) Fischer, F. C.; Havinga, E. Recueil 1965, 84, 439. (b) Li, W.;
Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider,
P. J. J. Org. Chem. 2002, 67, 5394.
82 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of 3-(Dimethylboryl)pyridine
TABLE 2. Scrambling Reactionsa
entry
reactants
conditionsb
1
2
3
4
5
6
1a and 1b
2a and 2b
3a and 3b
1a and 1b
1a and 2a
1a and 3a
60 °C, 3 h
80 °C, 20 h
90 °C, 19 h
60 °C, 3 hc
60 °C, 6 h
60 °C, 10 h
a Reactions were carried out in toluene-d8 in an NMR tube at the stated
temperature, unless otherwise noted. b The reactions were monitored until
1
no further changes in the H NMR spectra were observed. c Reaction was
carried out in 1,2-dichloroethane-d4.
85.7% (B1) and 89.5% (B2), which are slightly higher than those
(79.7%, 84.2%) of 2a. Hence, the coordination bonds of the
tetramer of 1a seem to be slightly stronger than those of 2a.
Scrambling and Mixing Behavior. Scrambling experiments
of the component molecules provided further information
concerning the stability of the tetramers. It has been reported
that the dimer composed of 2-(diethylboryl)pyridines (5a, 5b)
remained stable even at 130 °C for 24 h,9 although complete
scrambling of the component molecules of 3-(diethylboryl)-
pyridine (2a, 2c) tetramers occurred upon heating at 100 °C
for 24 h.2b Furthermore, 3-[4′-(diethylboryl)phenyl]pyridine (6a)
is scrambled with the corresponding methoxy derivative 6b at
ambient temperature.10 On the basis of these experiments and
calculations, it has been pointed out that the relative stabilities
of the tetramers are correlated with both the magnitude of the
THC at the boron atom (2a, average 82%; 5a, 97%; 6a, 68%)
and the length of the intermolecular boron-nitrogen coordina-
tion bond (2a, average 1.638 Å; 5a, 1.611 Å; 6a, average 1.673
Å).10
FIGURE 1. An ORTEP drawing of compound 1a: (a) top view and
(b) side view.
TABLE 1. Selected Geometric Properties of the Tetramer of 1aa
Bond Lengths (Å)
B(1)-N(2)
B(1)-C(2)
B(1)-C(6)
B(1)-C(7)
1.640(3)
1.632(3)
1.611(4)
1.623(3)
B(2)-N(1)
B(2)-C(9)
B(2)-C(13)
B(2)-C(14)
1.633(3)
1.637(3)
1.608(3)
1.620(3)
Bond Angles (deg)
N(2)-B(1)-C(2)
N(2)-B(1)-C(6)
N(2)-B(1)-C(7)
C(2)-B(1)-C(6)
C(2)-B(1)-C(7)
C(6)-B(1)-C(7)
B(1)-N(2)-C(8)
B(1)-N(2)-C(12)
C(8)-N(2)-C(12)
106.8(2)
106.1(2)
110.8(2)
112.8(2)
107.6(2)
112.6(2)
121.8(2)
120.9(2)
116.9(2)
N(1)-B(2)-C(9)
N(1)-B(2)-C(13)
N(1)-B(2)-C(14)
C(9)-B(2)-C(13)
C(9)-B(2)-C(14)
C(13)-B(2)-C(14)
B(2)-N(1)-C(1)
B(2)-N(1)-C(5)
C(1)-N(1)-C(5)
106.2(2)
111.3(2)
107.3(2)
108.9(2)
110.5(2)
112.4(2)
123.5(2)
119.6(2)
116.9(2)
Dihedral Angles (deg)
C(9)-C(8)-N(2)-B(1)
C(11)-C(12)-N(2)-B(1)
C(2)-C(1)-N(1)-B(2)
C(4)-C(5)-N(1)-B(2)
-172.1(2)
172.4(2)
-178.2(2)
178.5(2)
a Numbers in parentheses are estimated standard deviations.
To gain insight into the steric effect of B-alkyl groups on the
stability of the tetramers, we performed scrambling reactions
using 1, 2, and 3. When an equimolar mixture of 1a and 1b in
toluene-d8 was heated at 60 °C, 1H NMR spectroscopy showed
that 1a and 1b were readily scrambled into tetramers (see Figure
S6 in the Supporting Information). Although the products were
not isolated, the scrambled products would give rise to new 1H
NMR signals. The ESI-TOF-MS spectrum of the scrambled
products in THF-CH3CN (ca.1:1) in the presence of LiCl
showed charged peaks at m/z 601.8, 571.8, and 541.7, corre-
sponding to [(1a)(1b)3 + Cl]-, [(1a)2(1b)2 + Cl]-, and [(1a)3-
(1b) + Cl]-, respectively, which support the formation of
scrambled products (see Figure S7 in the Supporting Informa-
tion). As summarized in Table 2, heating at 80-90 °C for 20
h was required to attain equilibrium of the component molecules
in the scrambled tetramers of 2a and 2b, or 3a and 3b.
Surprisingly, the rate of scrambling decreased in the order 1 >
2 g 3; this was unexpected since the stability of 1, judging
from the bond length or THC, is almost the same or slightly
is exclusively to the side of the oligomer. The VPO, ESI-MS,
and 11B NMR studies of 1 and 3 clearly indicate that these
borylpyridines mainly form cyclic tetramers in solution.
Structure in the Crystalline State. Compound 1a could be
recrystallized from chloroform or benzene. Single-crystal X-ray
crystallographic studies revealed the cyclic tetrameric structure
of 1a, as shown in Figure 1 and outlined in Tables 1 and S1 in
the Supporting Information. The outstanding structural feature
of 1a is a 1,2-alternate conformation, which is in contrast with
the cone conformation of the tetramer of 2a.2 Two of the four
pyridine rings (P1 and P3) face each other in the upward and
downward directions and are perpendicular to the plane of the
tetramer, whereas the other set of pyridine rings (P2 and P4)
lie on this plane.
The distance between the boron atom and the nitrogen atom
is 1.633 and 1.640 Å, which is almost the same as that (1.636,
1.639 Å) of the tetramer of 2a. The bond angles constituted by
the boron atom and the three substituents enable us to calculate
the tetrahedral character (THC) of the boron atom as proposed
by Toyota and Ohki,1g allowing correlation to the strength of
the coordination bonds rather than to the length of the
coordination bond. The THC values for 1a are estimated to be
(9) Murafuji, T.; Mouri, R.; Sugihara, Y.; Takakura, K.; Mikata, Y.;
Yano, S. Tetrahedron 1996, 52, 13933.
(10) Wakabayashi, S.; Sugihara, Y.; Takakura, K.; Murata, S.; Tomioka,
H.; Ohnishi, S.; Tatsumi, K. J. Org. Chem. 1999, 64, 6999.
J. Org. Chem, Vol. 73, No. 1, 2008 83

Wakabayashi et al.
FIGURE 2. 1H NMR spectra of a mixture of 1a and 7 in CDCl3 at ambient temperature. The spectrum at 0 min was measured at -20 °C, after
mixing 1a and 7 at -15 °C. Signals assigned to 8a were indicated by asterisks.
higher than that of 2 and 3.11 This led us to investigate the
kinetics of the scrambling (vide infra).
Further information was derived from the following two
experiments. First, even when 1,2-dichloroethane-d4 was used
instead of toluene-d8 as the solvent, the conditions required for
scrambling remained unchanged, indicating little assistance of
the solvent in the cleavage of the B-N coordination bonds
(entry 4 in Table 2). Second, 2a or 3a could surprisingly be
scrambled with 1a at 60 °C after 6-10 h (entries 5 and 6 in
of the tetramer in the 1H NMR spectrum as a function of time.
Table 2). It is apparent that these observations cannot be
Within 3-10% disappearance of the tetramer, the tetramer
decreased almost linearly. The results are summarized in Table
3. The discrepancies in rates obtained from the methyl proton
probe and the methoxy proton probe in 1b seem to be within
experimental error.
explained solely by stability as judged from bond length or THC,
or by the unimolecular dissociative process of B-N bonds.12
Hawthorne et al. reported that nucleophilic substitutions with
tri-n-butylphosphine in the trimethylamine-borane complex
involve a second-order displacement process (SN2-B) as well
as a dissociative process (SN1-B).1b-d To determine whether an
SN2-B mechanism is involved in the above scrambling reactions,
we studied the reaction kinetics using model compounds.13 In
a preliminary experiment, when a mixture of 1a (tetramer) and
4 equiv of 4-(dimethylamino)pyridine (7) in CDCl3 was allowed
to stand at ambient temperature, a set of new 1H NMR signals
started to grow within 5 min (Figure 2). After 90 min the signals
of the tetramer of 1a disappeared almost completely, and the
obtained spectrum suggested the formation of a new 1:1 complex
of 1a and 7. The NOE, observed between the protons of the
methyl groups at δ 0.16 and the H-2′, -6′, suggests that this is
a dimethyborane-pyridine type complex 8a. A byproduct (ca.
15%), observed at 90 min and showing NMe2 and BMe2 signals
(δ 3.09 and 0.12, respectively) in a 1:1 ratio, may be due to
isomeric 1:1 complex 8b.
It was found that the data indicate that the rate of the reaction
of 1a or 1b with 7 is faster than that of 2b and is dependent on
the concentration of 7, although the second-order rate equation
is not completely obeyed. In contrast, the rate of the reaction
of 2b with 7 was not affected by the concentration of 7. The
results of these concentration-dependence studies indicate that
the former reaction proceeds by an SN2-type mechanism as well
as an SN1-type one, or by an intermediate mechanism between
SN1 and SN2 pathways, as demonstrated by Jencks and
Richard.14 In contrast, the reaction of 2b with 7 seems to proceed
predominantly by an SN1-type mechanism. We believe this is
due to steric effects as 7 approaches the tetrahedral boron atom
of the tetramer.
Calculations. DFT calculations at the B3LYP/6-31G* level
of theory for simplified models support the above conclusions.15
We estimated the activation energies for the exchange of
pyridine (9) with the pyridine-dialkylborylbenzene complex
The kinetics of the reaction of the 1a, 1b, and 2b tetramers
with 7 were studied at 0 °C in CDCl3. In each run, the initial
reaction rate was measured by monitoring the disappearance
(13) As model compounds for monomer, we also used pyridine,
4-methylpyridine, or 4-methoxypyridine. However, standing at ambient
temperature for several days remained unchanged.
(14) (a) Jencks, W. P. Chem. Soc. ReV. 1982, 10, 345. (b) Amyes, T. L.;
Toteva, M. M.; Richard, J. P. In ReactiVe Intermediate Chemistry; Moss,
R. A., Platz, M. S., Jones, M., Jr., Eds.; John Wiley & Sons, Inc.: Hoboken,
NJ, 2004; p 41.
(15) For the calculations of the complex of borane with aldehyde, THF,
and ammonia, etc., see: DiMare, M. J. Org. Chem. 1996, 61, 8378. Also
see ref 1h.
(11) Since single crystals of 3 could not be obtained, the molecular
structure was calculated by AM1. The THC value of the boron atom and
the length of the B-N bond in 3a are estimated to average 80.8% and
1.634 Å, respectively.
(12) Using AM1 calculations, we also estimated the enthalpic contribution
to the free energy change associated with self-assembly: 1a, 11.2 kcal/
mol; 2a, 10.9 kcal/mol; 3a, 9.2 kcal/mol. This order is not consistent with
the scrambling conditions, nor does it support sole unimolecular dissociation
of the B-N bond during scrambling.
84 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of 3-(Dimethylboryl)pyridine
TABLE 3. Kinetics of the Reaction of Borylpyridines 1a, 1b, and 2b with 7a
[substrate],
mol dm-3
[7],
-∆{[substrate]/([substrate] +
[substrate‚7])}/∆t, min-1
rate × 105,b
substrate
mol dm-3
mol dm-3 min-1
c
1a
0.113
0.116
0.114
0.120
0.230
0.464
6.98 × 10-4
7.9 c
12.2
17.3
1.05 × 10-3
1.52 × 10-3
d
1b
2b
0.060
0.113
0.114
0.113
0.229
0.120
0.109
0.216
0.429
0.205
8.58 × 10-4 c (6.23 × 10-4
)
5.1c (3.7) d
12.0 (9.5)
14.1 (13.1)
16.2 (16.8)
23.1 (22.3)
1.06 × 10-3 (8.41 × 10-4
1.24 × 10-3 (1.15 × 10-3
1.43 × 10-3 (1.49 × 10-3
)
)
)
1.01 × 10-3 (9.73 × 10-4
)
d
0.105
0.109
0.112
0.105
0.211
0.451
1.72 × 10-4
1.8d
1.9
2.0
1.71 × 10-4
1.79 × 10-4
a Reactions were carried out in an NMR tube at 0 °C. b Rates were calculated by multiplying the decreasing rate with the initial concentration of the
substrate. c Obtained from the methyl proton probe. d Obtained from the methoxy proton probe.
TABLE 4. Calculated Energies (au) of 9-11 and the Dissociation
Energies of 10a
∆E,
kcal/mol
FIGURE 3. Initial two pathways for the scrambling reaction of 1a.
R
10b
11b,c
9
CH3
C2H5
n-C4H9
-584.649436
-663.272125
-820.527985
-336.348099
-414.968063
-572.224191
-248.284981
-248.284981
-248.284981
10.3
12.0
11.8
highlights the importance of the SN2-type mechanism in
substitution reactions at the tetrahedral boron atom, as mentioned
by Hawthorne et al.1b-d and Ohki et al.1h
a Calculated at the B3LYP/6-31G* level. b For 10 and 11, compounds
bearing a methyl, ethyl, or n-butyl group as R are represented as a, b, or c,
respectively. c 11 denotes the trigonal structure at the boron atom.
The above experimental and theoretical data suggest that both
SN1- and SN2-type reaction pathways may be involved in
scrambling reactions of 1, as shown in Figure 3. An intermediate
mechanism between SN1 and SN2 might operate.14 The nucleo-
phile in the SN2-type displacement would be a small quantity
of monomer or open-chained oligomer present in equilibrium
with tetramer. Furthermore, once such species were regenerated
from cleavage of a cyclic tetramer by nucleophilic attack, they
might act as new catalytic nucleophiles and accelerate the
scrambling reaction. In contrast, the scrambling of 2 or 3 seems
to occur predominantly via an SN1-type mechanism. The
complex mixture of oligomers would, finally, converge on the
thermally equilibrated cyclic tetramers.
(10), where the alkyl group is either methyl, ethyl, or n-butyl.
The results for SN1- and SN2-type processes are summarized in
Tables 4 and 5, respectively.
In the SN1-type process, steric crowding around the boron
atom had a little influence on the dissociation energy (∆E) of
the B-N coordination bond (Table 4). Steric effects on the
activation energies were remarkably pronounced in reactions
dominated by an SN2-type mechanism, with bimolecular
substitution occurring extremely easily in methyl complex 10a.
In the process, the pentacoordinate structure 12a would be in
the transition state, with an energy 5.60 kcal/mol higher than
that of the initial state, 10a and 9 (Table 5). This energy gap is
smaller than the dissociation energy (10.3 kcal/mol) of 10a and
In summary, a simple route for the synthesis of 3-(dimeth-
ylboryl)pyridines 1 has been developed. Compound 1a forms a
rigid cyclic tetramer both in the crystalline state and in solution,
TABLE 5. Calculated Energies (au) of 9, 10, 12 and the Activation Energies for the Exchange Reactiona
R
10b
9
12b,c
∆Eq, kcal/mol
CH3
C2H5
n-C4H9
-584.649436
-663.272125
-820.527985
-248.284981
-248.284981
-248.284981
-832.925534
-911.451555
-1068.70265
5.60
66.2
69.2
a Calculated at the B3LYP/6-31G* level. b For 10 and 12, compounds bearing a methyl, ethyl, or n-butyl group as R are represented as a, b, or c,
respectively. c 12 denotes an SN2-like transition state, where the boron atom is in a hypervalent state.
J. Org. Chem, Vol. 73, No. 1, 2008 85

Wakabayashi et al.
1.9 mL, 5.94 mmol) at -78 °C for 4 min. After 1 h of stirring,
diethylmethoxyborane (0.78 mL, 3.0 mmol) was added and the
solution was stirred at -78 °C for 1 h and 0 °C for 0.5 h. The
mixture was poured into a mixture of ether (30 mL) and water (10
mL) and extracted. The aqueous layer was extracted with ether (2
× 15 mL). The combined extracts were washed with brine (2 ×
10 mL) and dried over MgSO4. The dried solution was concentrated
and subjected to silica gel (10 g) column chromatography with
benzene-hexane (1:1) as an eluent to afford 2b (0.322 g, 1.8 mmol,
stabilized via intermolecular boron-nitrogen coordination bonds.
The occurrence of both SN1- and SN2-type reaction mechanisms
or an intermediate one between SN1 and SN214 may account
for the scrambling behavior of 1. Therefore, the present study
provides insights useful for understanding substituent effects
on the kinetic stability of self-assembling molecular systems.
Experimental Section
1
yield 67%) as colorless crystals. Mp 169-170 °C. H NMR (400
MHz, CDCl3) δ 0.48 (t, 6H, J ) 7.5 Hz), 0.65 (q, 4H, J ) 7.5
Hz), 3.79 (s, 3H), 7.24 (s, 1H), 7.36 (s, 1H), 7.65 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ 9.2, 14.6, 55.5, 127.6, 128.3, 128.9, 142.2,
155.8. 11B NMR (128 MHz, CDCl3) δ 0.68. EIMS (70 eV) m/z
177 (M+, 45%), 148 (M+ - Et, 100%). ESI-TOF-MS (LiCl, THF-
CH3CN) m/z 743.5 (4M + Cl-, 26%), 566.4 (3M + Cl-, 44%),
389.2 (2M + Cl-, 100%). IR (KBr) 2905 (s), 1597, 1572 (s), 1456,
1406 (s), 1287 (s), 1252, 1177, 1049, 1036 (s), 858 cm-1. Anal.
Calcd for (C10H16BNO)4C6H6 ) C46H70B4N4O4: C, 70.26; H, 8.97;
N, 7.13. Found: C, 70.46; H, 8.89; N, 7.24.
Methyl 3-Pyridylboronate (4). To a solution of 3-bromopyridine
(1.6 mL, 15.6 mmol) in ether (70 mL) was added a hexane solution
of n-butyllithium (1.5 M, 10.9 mL, 16.4 mmol) at -78 °C for 5
min. After 1 h of stirring, triisopropyl borate (4.3 mL, 18.6 mmol)
was added. The resulting yellow solution was stirred for 12 h. After
evaporation of the solvent in vacuo, to the pale yellow solid was
added water (15 mL) and concentrated hydrochloric acid (1.7 mL)
until pH 5-6 at 0 °C to produce the white precipitates. After
filtration, the solid (1.585 g) was suspended in anhyd methanol
(70 mL) and heated at 80 °C for 30 min to yield a mixture of the
boronate 4 and the free boronic acid as a colorless solid (1.417 g,
mp >200 °C). Since the contents of 4 is ca. 70% judging from the
1H NMR spectrum, the yield of 4 is estimated to be 45%. 1H NMR
(400 MHz, CDCl3) δ 3.52 (s), 6.86 (t, J ) 5.6 Hz), 7.00 (t, J ) 5.6
Hz), 7.26-7.39 (m), 7.77 (d, J ) 7.1 Hz), 8.05 (d, J ) 7.3 Hz),
8.14 (d, J ) 4.6 Hz), 8.40-8.85 (m), 9.32 (s), 9.41 (s), 9.62 (s),
10.14 (s), 10.45 (s), 10.51 (s), 10.56 (s). IR (KBr) 3700-2800 (br),
1609, 1589, 1417 (strong), 1363 (s), 1311 (s), 1204, 1155, 1074,
3-(Di-n-butylboryl)-5-methoxypyridine (3b). To a solution of
3-bromo-5-methoxypyridine (805 mg, 4.28 mmol) in ether (12 mL)
was added dropwise a hexane solution of n-butyllithium (1.6 M,
2.8 mL, 4.48 mmol) at -78 °C for 2 min. After 1 h of stirring, a
THF solution of triethylborane (1.0 M, 4.5 mL, 4.5 mmol) was
added and stirring was continued for 12 h. A solution of iodine
(1.2 g, 4.7 mmol) in THF (3 mL) was added slowly at ambient
temperature. After 1 h of stirring, the mixture was diluted with
ethyl acetate, and washed with 10% Na2S2O3 aq solution and brine.
The dried solution was concentrated and subjected to silica gel (15
g) column chromatography with benzene as an eluent to afford 3b
(542 mg, 2.33 mmol, yield 54%) as a colorless solid. Mp 175-
177 °C. 1H NMR (600 MHz, CDCl3) δ 0.65-1.30 (18H), 3.82 (s,
3H), 7.22 (s, 1H), 7.26 (s, 1H), 7.67 (s, 1H). 13C NMR (151 MHz,
CDCl3) δ 14.2, 23.8, 26.7, 28.2, 55.5, 127.2, 128.3, 128.6, 142.3,
155.7. 11B NMR (192 MHz, CDCl3) δ -1.11. IR (KBr) 2909 (s),
1570 (s), 1456, 1406, 1254 cm-1. EIMS (70 eV) 233 (M+, 18%),
174 (62%), 134 (100%). HRMS (EI) m/z calcd for C14H24BNO
233.1951, found 233.1969. ESI-TOF-MS (THF, LiCl) m/z 967.8
(4M + Cl-, 100%), 734.6 (3M + Cl-, 21%), 501.4 (2M + Cl-,
35%). Anal. Calcd for C14H24BNO: C, 72.12; H, 10.38; N, 6.01.
Found: C, 72.27; H, 10.15; N, 5.65.
713 cm-1
.
3-(Dimethylboryl)pyridine (1a). To 4 (497 mg, 70% contents,
2.30 mmol) in THF (12 mL) was added dropwise an etheral solution
of methyllithium (0.55 M, 18 mL, 9.9 mmol) at -78 °C for 12
min. The mixture was gradually warmed to ambient temperature
over 12 h. To this was added water (10 mL) and the solution was
extracted twice with ether (10 mL). The combined organic extracts
were washed with brine (2 × 5 mL), dried over MgSO4, and
concentrated. The crude product was subjected to silica gel (7 g)
column chromatography with a mixture of benzene and hexane (1:
1) as an eluent to afford 1a (222 mg, 1.87 mmol, yield 81%) as
1
colorless crystals. Mp 169-171 °C. H NMR (400 MHz, CDCl3)
δ 0.11 (s, 6H), 7.30 (dd, 1H, J ) 5.9, 7.6 Hz), 7.56 (s, 1H), 7.81
(dt, 1H, J ) 1.7, 7.3 Hz), 8.18 (d, 1H, J ) 5.6 Hz). 13C NMR (100
MHz, CDCl3) δ 11.0, 123.8, 128.3, 140.6, 143.6, 147.2. 11B NMR
(192 MHz, CDCl3) δ -2.05. EIMS (20 eV) m/z 461 (4M+ - Me,
1%), 342 (3M+ - Me, 4%), 223 (2M+ - Me, 6%), 119 (M+, 50%),
104 (M+ - Me, 100%). ESI-MS (LiCl in THF, negative mode)m/z
511.5 (4M + Cl-, 100%), 392.5 (3M + Cl-, 28%), 273.4 (2M +
Cl-, 6%). IR (KBr) 2924 (s), 2831, 1601, 1480, 1445, 1408 (s),
1333, 1298, 1291 (s), 1250, 1200, 1042 (s), 1028, 1017, 967 (s),
797, 702 (s) cm-1. Anal. Calcd for C7H10BN: C, 70.67; H, 8.47;
N, 11.77. Found: C, 70.29; H, 8.58; N, 11.65.
Vapor Pressure Osmometry Results. 1a: 3.7 in chloroform at
40 °C [benzil (10.9, 35.7, 71.7, 124.7 for 0.006, 0.021, 0.044, 0.080
mol dm-3, respectively), 1a (6.5, 17.4, 27.7, 44.3 for 0.014, 0.036,
0.060, 0.101 mol dm-3, respectively)]; 3.8 in THF at 45 °C [benzil
(20.3, 41.4, 77.5, 122.0 for 0.0072, 0.0207, 0.042, 0.070 mol dm-3
,
respectively), 1a (8.9, 14.7, 23.7, 39.9 for 0.012, 0.030, 0.049, 0.082
mol dm-3, respectively)]. 2b: 3.9 in chloroform at 40 °C [benzil
(12.3, 34.9, 71.4, 123.6 for 0.0061, 0.0199, 0.0427, 0.0820 mol
dm-3, respectively), 2b (5.3, 13.0, 20.9, 33.7 for 0.0118, 0.0295,
0.0492, 0.0820 mol dm-3, respectively)], 4.1 in THF at 45 °C
[benzil (11.4, 38.8, 69.3, 129.7 for 0.0053, 0.0212, 0.0394, 0.0788
mol dm-3, respectively), 2b (3.8, 12.7, 19.7, 31.7 for 0.0118, 0.0295,
0.0491, 0.0724 mol dm-3, respectively)]; 3.8 in N,N-dimethylfor-
mamide at 90 °C [benzil (4.4, 17.7, 33.5, 64.2 for 0.0055, 0.0213,
0.0405, 0.0765 mol dm-3, respectively), 2b (4.4, 17.7, 33.5, 64.2
for 0.0055, 0.0213, 0.0405, 0.0765 mol dm-3, respectively)]. 3a:
3.7 in chloroform at 40 °C [benzil (13.0, 36.1, 74.1, 135.9 for
0.0061, 0.0205, 0.0442, 0.085 mol dm-3, respectively), 3a (8.7,
3-(Dimethylboryl)-5-methoxypyridine (1b). The preparation
was carried out from 3-bromo-5-methoxypyridine8 in a manner
similar to that described for 1a. Colorless crystals. Mp 158-
1
160 °C. Yield, 21% from 3-bromo-5-methoxypyridine. H NMR
(400 MHz, CDCl3) δ 0.10 (s, 6H), 3.83 (s, 3H), 7.24 (s, 1H), 7.31
(d, 1H, J ) 2.7 Hz), 7.80 (d, 1H, J ) 2.7 Hz). 13C NMR (100
MHz, CDCl3) δ 11.2, 55.6, 127.3, 128.3, 128.9, 140.5, 156.0. 11B
NMR (128 MHz, CDCl3) δ -1.61. IR (KBr) 2919, 1595, 1572 (s),
1455, 1406 (s), 1294 (s), 1283 (s), 1250, 1177, 1038 (s), 970 (s),
878 (s), 704 cm-1. EIMS (70 eV) m/z 432 (3M+ - Me, 2%), 283
(2M+ - Me, 5%), 149 (M+, 57%), 134 (M+ - Me, 100%). HRMS
(EI) m/z calcd for C8H12BNO 149.1012, found 149.1052. ESI-TOF-
MS (THF-CH3CN, LiCl) m/z 631.4 (43%, 4M + Cl-), 482.3
(100%, 3M + Cl-), 333.2 (66%, 2M + Cl-).
18.7, 28.3, 46.5 for 0.015, 0.038, 0.063, 0.105 mol dm-3
respectively)].
,
Kinetic Method. To CDCl3 solution of 1a, 1b, or 2b in an NMR
tube was added a pre-cooled CDCl3 solution of 7 at ca. -15 °C
1
and the mixture was quickly transferred to NMR apparatus. H
3-(Diethylboryl)-5-methoxypyridine (2b). To a solution of
3-bromo-5-methoxypyridine (500 mg, 2.7 mmol) in ether (10 mL)
was added dropwise a hexane solution of n-butyllithium (1.5 M,
NMR spectra were measured at intervals of 5 min at 0 °C for
1-1.5 h.
86 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of 3-(Dimethylboryl)pyridine
Supporting Information Available: General methods, 1H NMR
spectra of 1a, 1b, 2b, and 3b, and ESI-MS spectrum of 1a, H
NMR and ESI-TOF-MS spectra of the scrambled product of 1a
and 1b, X-ray crystallographic details for 1a, and computational
details for 9, 10a-c, 11a-c, and 12a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Professor S. Murata
of the University of Tokyo, Professor N. Koga of Nagoya
University, and Professor K.-T. Wong of National Taiwain
University for valuable discussions. We also acknowledge Mr.
Y. Maeda and Dr. K. Oyama (Chemical Instrument Room,
RCMS) of Nagoya University, Professor K. Hirai of Mie
University, and Professor K. Tomizawa of Suzuka National
College of Technology for NMR and MS spectroscopy.
1
JO7018043
J. Org. Chem, Vol. 73, No. 1, 2008 87