2-Bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, a new unexpected bifunctional building block for combinatorial chemistry

The first reported structure of a pyridin-2-ylboron derivative, viz. the title compound, C₁₁H₁₅BBrNO₂, (I), is compared with its regioisomer 2-bromo-5-(4,4,5,5-tetra­methyl-1,3,2-dioxa­borolan-2-yl)­pyridine, (II) [Sopková-de Oliveira Santos, Lancelot, Bouillon & Rault (2003). Acta Cryst. C59, o111-o113 ]. Structural differences are observed, firstly in the orientation of the dioxaborolane ring with respect to the pyridine ring and secondly in the bond angles of the BO₂ group. These differences do not explain the experimentally observed differences in chemical reactivity between (I) and (II) but do confirm the relatively lower stability of (I). However, ab initio calculations of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), based on the known crystal structures of the two compounds, show different distributions, which correspond to the differences observed during chemical reactions.

S1. Comment

In continuation of our work concerning the synthesis of new pyridinyl boronic acids and esters, we are now focusing on new and unexpected pyridin-2-yl boron derivatives. In comparison with the synthesis and isolation of pyridin-3-yl (Bouillon et al., 2002a) and pyridin-4-yl (Bouillon et al., 2002b) boronic acids and esters, the situation for pyridin-2-yl boronic acids and esters is quite different, since the instability of non-substituted pyridin-2-yl boronic acid has been demonstrated (Fischer & Havinga, 1974). Moreover, a brominated pyridine ring has been shown to be weakened by the introduction of an alkylborane moiety (Utimoto et al., 1976) so that it can be cleaved to give unsaturated nitriles. In this paper, the crystal structure of 2-bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, (I), is described and compared with its regioisomer 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, (II), which was solved earlier by us (Sopková-de Oliveira Santos et al., 2003), in order to try to find structural elements able to explain the differences in their stability and chemical reactivity. \sch

Fig. 1 shows a view of the asymmetric unit of (I). The dioxaborolane ring is in a half-chair conformation with an O1—C7—C8—O2 torsion angle of 28.0 (5)°; a similar numerical value was also found in (II) [O1—C7—C8—O2 − 20.9 (6)°]. The C6—BO₂ moiety is planar. The BO₂ group in (I) is rotated away from the plane of the pyridine ring by 13.0 (7)°. This deviation is higher than the value of 6.5 (6)° observed in the regioisomer, (II), and may be larger either because of crystal-packing effects or because of repulsion between adjacent N and O atoms [N1···O2 3.011 (6) Å]. No such repulsion is possible in (II). The existence of repulsion between adjacent N and O atoms in (I) is also the origin of the greater observed assymmetry between the C—B—O bond angles in the BO₂ group (Table 1) than is observed in the aryl tetramethyl-1,3,2-dioxaborolane deposited in the Cambridge Structural Database (CSD, Version 5.24; Allen, 2002). The average difference calculated for the 13 independent hits from the CSD is 3°, in comparison with 8° in (I).

The crystal packing of ester (I) is similar to that of ester (II), and so it is probably not the origin of the higher deviation of the BO₂ group plane from the pyridine ring plane.

The difference in the geometry of the BO₂ group cannot in itself explain the experimentally observed differences during chemical reactions. In an aromatic nucleophilic substitution with nucleophiles that are compatible with the boronic ester moiety (Matteson, 1999), ester (II) gave good to excellent results: only bromine was substituted, leaving the boronic ester unchanged. The case of ester (I) was quite different, since every attempt led essentially to decomposition products.

The different reactivity of the two esters can be explained by our modelling results of the distribution of the LUMO (lowest unoccupied molecular orbital) in the structures. The ab initio calculation carried out on the crystal structures using the program MOPAC (method Austin Model 1 or AM1; Stewart, 1990) showed that the LUMO is by far the most dense on atom C2 next to the Br atom in ester (II). In ester (I), on the other hand, the LUMO is equally dense on all three C atoms sensitive to nucleophilic attack, namely atoms C2 (next to Br), C4 and C6 (next to B). This explains why the reaction of (I) with a nucleophile does not provide a single product but several decomposition products, probably resulting from different simultaneous attacks.

S2. Experimental

The title compound was synthesized from 2,6-dibromopyridine using the method described by Bouillon et al. (2003). Suitable crystals of the title ester, (I), were obtained by slow evaporation from acetonitrile at room temperature.

S3. Refinement

H atoms were treated as riding, with C—H distances in the range 0.93–0.96 Å (Sheldrick,1997).

Computing details

Data collection: CAD-4-PC Software (Enraf-Nonius, 1996); cell refinement: CAD-4-PC Software; data reduction: JANA98 (Petříček & Dušek, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. A view of the molecule of (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small circles of arbitrary radii.

2-bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Crystal data

C11H15BBrNO2	Dx = 1.488 Mg m^−3
Mr = 283.96	Melting point: 401 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71069 Å
a = 6.4917 (8) Å	Cell parameters from 25 reflections
b = 12.327 (1) Å	θ = 18–23°
c = 15.844 (1) Å	µ = 3.23 mm^−1
V = 1267.9 (2) Å^3	T = 293 K
Z = 4	Prism, colourless
F(000) = 576	0.65 × 0.35 × 0.08 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	1857 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.038
Graphite monochromator	θmax = 30.0°, θmin = 2.1°
θ/2θ scans	h = −9→9
Absorption correction: gaussian GAUSSIAN98 (Frisch et al., 1998)	k = 0→17
Tmin = 0.140, Tmax = 0.660	l = 0→22
4581 measured reflections	3 standard reflections every 60 min
3689 independent reflections	intensity decay: 3.8%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.062	H-atom parameters constrained
wR(F^2) = 0.166	w = 1/[σ^2(Fo^2) + (0.0878P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.97	(Δ/σ)max = 0.003
3689 reflections	Δρmax = 0.57 e Å^−3
161 parameters	Δρmin = −0.79 e Å^−3
0 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.02 (2)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Br1	0.06477 (12)	0.48664 (6)	0.41940 (4)	0.0776 (3)
C2	0.2434 (10)	0.4161 (4)	0.4982 (3)	0.0500 (13)
C3	0.4517 (11)	0.4148 (4)	0.4825 (4)	0.0600 (15)
H3	0.5054	0.4464	0.4339	0.072*
C4	0.5767 (11)	0.3662 (5)	0.5397 (4)	0.0606 (14)
H4	0.7183	0.3632	0.5312	0.073*
C5	0.4876 (8)	0.3209 (4)	0.6117 (3)	0.0489 (13)
H5	0.5699	0.2881	0.6524	0.059*
C6	0.2777 (9)	0.3249 (4)	0.6222 (3)	0.0450 (12)
N1	0.1530 (7)	0.3742 (3)	0.5656 (3)	0.0451 (10)
B	0.1730 (10)	0.2706 (5)	0.7015 (4)	0.0432 (14)
O1	0.2950 (5)	0.2368 (3)	0.7680 (3)	0.0574 (10)
O2	−0.0263 (5)	0.2496 (3)	0.7116 (2)	0.0532 (10)
C7	0.1640 (9)	0.1704 (5)	0.8213 (3)	0.0525 (14)
C71	0.2287 (12)	0.1855 (7)	0.9124 (4)	0.080 (2)
H71A	0.3698	0.1638	0.9189	0.09 (2)*
H71B	0.1428	0.1419	0.9482	0.11 (3)*
H71C	0.2144	0.2604	0.9277	0.09 (3)*
C72	0.2005 (12)	0.0533 (5)	0.7955 (5)	0.076 (2)
H72A	0.1649	0.0442	0.7371	0.14 (4)*
H72B	0.1166	0.0064	0.8295	0.11 (3)*
H72C	0.3431	0.0354	0.8035	0.08 (2)*
C8	−0.0525 (10)	0.2112 (5)	0.7996 (3)	0.0524 (13)
C81	−0.2187 (10)	0.1240 (8)	0.7989 (5)	0.081 (2)
H81A	−0.3487	0.1561	0.7844	0.09 (2)*
H81B	−0.2281	0.0915	0.8539	0.067 (19)*
H81C	−0.1841	0.0694	0.7581	0.16 (5)*
C82	−0.1194 (16)	0.3095 (7)	0.8494 (5)	0.101 (3)
H82A	−0.0124	0.3632	0.8481	0.15 (4)*
H82B	−0.1457	0.2887	0.9068	0.075 (19)*
H82C	−0.2427	0.3389	0.8250	0.13 (4)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.1015 (5)	0.0815 (5)	0.0498 (3)	0.0145 (4)	0.0040 (4)	0.0246 (3)
C2	0.067 (4)	0.047 (3)	0.036 (3)	0.008 (2)	0.004 (3)	0.006 (2)
C3	0.079 (4)	0.051 (3)	0.050 (3)	−0.003 (3)	0.016 (3)	0.008 (2)
C4	0.058 (3)	0.061 (3)	0.062 (4)	−0.004 (3)	0.013 (3)	−0.001 (3)
C5	0.055 (3)	0.050 (3)	0.042 (3)	−0.003 (2)	0.002 (2)	0.007 (2)
C6	0.060 (3)	0.034 (3)	0.042 (3)	−0.005 (2)	0.005 (3)	−0.002 (2)
N1	0.063 (3)	0.036 (2)	0.036 (2)	0.0008 (18)	0.0012 (19)	0.0059 (18)
B	0.057 (4)	0.037 (3)	0.035 (3)	0.004 (3)	0.001 (3)	0.003 (2)
O1	0.055 (2)	0.066 (2)	0.051 (2)	−0.008 (2)	−0.0047 (19)	0.020 (2)
O2	0.051 (2)	0.071 (2)	0.0377 (19)	0.0027 (19)	−0.0007 (16)	0.0186 (18)
C7	0.063 (3)	0.056 (3)	0.039 (3)	−0.010 (3)	0.000 (3)	0.015 (3)
C71	0.086 (5)	0.112 (6)	0.043 (3)	−0.021 (4)	−0.012 (4)	0.027 (4)
C72	0.074 (4)	0.062 (4)	0.093 (6)	0.006 (3)	0.007 (4)	0.015 (4)
C8	0.057 (3)	0.060 (3)	0.040 (3)	0.012 (3)	0.008 (3)	0.010 (2)
C81	0.055 (4)	0.114 (6)	0.075 (5)	−0.016 (4)	−0.005 (3)	0.045 (5)
C82	0.146 (8)	0.100 (6)	0.056 (4)	0.047 (7)	0.031 (5)	0.022 (4)

Geometric parameters (Å, º)

Br1—C2	1.913 (6)	C7—C72	1.518 (9)
C2—N1	1.324 (7)	C7—C8	1.532 (9)
C2—C3	1.375 (9)	C71—H71A	0.9600
C3—C4	1.356 (9)	C71—H71B	0.9600
C3—H3	0.9300	C71—H71C	0.9600
C4—C5	1.396 (8)	C72—H72A	0.9600
C4—H4	0.9300	C72—H72B	0.9600
C5—C6	1.373 (8)	C72—H72C	0.9600
C5—H5	0.9300	C8—C82	1.510 (9)
C6—N1	1.351 (7)	C8—C81	1.523 (10)
C6—B	1.578 (8)	C81—H81A	0.9600
B—O2	1.328 (7)	C81—H81B	0.9600
B—O1	1.383 (7)	C81—H81C	0.9600
O1—C7	1.451 (6)	C82—H82A	0.9600
O2—C8	1.483 (6)	C82—H82B	0.9600
C7—C71	1.514 (8)	C82—H82C	0.9600
N1—C2—C3	125.3 (5)	H71A—C71—H71B	109.5
N1—C2—Br1	115.8 (4)	C7—C71—H71C	109.5
C3—C2—Br1	118.9 (4)	H71A—C71—H71C	109.5
C4—C3—C2	118.2 (5)	H71B—C71—H71C	109.5
C4—C3—H3	120.9	C7—C72—H72A	109.5
C2—C3—H3	120.9	C7—C72—H72B	109.5
C3—C4—C5	118.4 (6)	H72A—C72—H72B	109.5
C3—C4—H4	120.8	C7—C72—H72C	109.5
C5—C4—H4	120.8	H72A—C72—H72C	109.5
C6—C5—C4	119.7 (6)	H72B—C72—H72C	109.5
C6—C5—H5	120.2	O2—C8—C82	105.6 (5)
C4—C5—H5	120.2	O2—C8—C81	107.5 (5)
N1—C6—C5	122.0 (5)	C82—C8—C81	111.5 (7)
N1—C6—B	117.4 (5)	O2—C8—C7	102.2 (4)
C5—C6—B	120.5 (5)	C82—C8—C7	114.2 (6)
C2—N1—C6	116.4 (5)	C81—C8—C7	114.8 (5)
O2—B—O1	114.1 (5)	C8—C81—H81A	109.5
O2—B—C6	126.7 (5)	C8—C81—H81B	109.5
O1—B—C6	119.2 (5)	H81A—C81—H81B	109.5
B—O1—C7	106.1 (4)	C8—C81—H81C	109.5
B—O2—C8	106.7 (4)	H81A—C81—H81C	109.5
O1—C7—C71	108.8 (5)	H81B—C81—H81C	109.5
O1—C7—C72	106.7 (5)	C8—C82—H82A	109.5
C71—C7—C72	109.3 (6)	C8—C82—H82B	109.5
O1—C7—C8	102.8 (4)	H82A—C82—H82B	109.5
C71—C7—C8	115.3 (5)	C8—C82—H82C	109.5
C72—C7—C8	113.3 (5)	H82A—C82—H82C	109.5
C7—C71—H71A	109.5	H82B—C82—H82C	109.5
C7—C71—H71B	109.5