tert-Butyl 3-(3-methyl-1-oxidopyridin-1-ium-2-yl)benzoate

In the title compound, C₁₇H₁₉NO₃, which was obtained by oxidation of the corresponding pyridine derivative, the dihedral angle between the benzene and the pyridine rings is 68.2 (1)°. In the crystal, C—H...O hydrogen bonds to carboxyl and N-oxide O-atom acceptors gives a cyclic dimer substructure with an R²₂(18) motif which is extended into a undulating sheet structure lying parallel to (100) through weak C—H...O_oxide hydrogen bonds. Also present are π–π ring inter­actions [ring centroid separation = 3.561 (2) Å].

Key indicators

• Single-crystal X-ray study
• T = 173 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.053
• wR factor = 0.158
• Data-to-parameter ratio = 14.1

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT213_ALERT_2_C Atom C18             has ADP max/min Ratio .....        3.5 prolat
PLAT220_ALERT_2_C Large Non-Solvent  C     Ueq(max)/Ueq(min) Range        4.6 Ratio
PLAT222_ALERT_3_C Large Non-Solvent  H     Uiso(max)/Uiso(min) ...        5.8 Ratio
PLAT242_ALERT_2_C Low    'MainMol' Ueq as Compared to Neighbors of        C15 Check
PLAT906_ALERT_3_C Large K value in the Analysis of Variance ......      2.644 Check
PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L=  0.600         24 Report

Alert level G
PLAT005_ALERT_5_G No Embedded Refinement Details found in the CIF      Please Do !
PLAT909_ALERT_3_G Percentage of Observed Data at Theta(Max) Still          54 %

   0 ALERT level A = Most likely a serious problem - resolve or explain
   0 ALERT level B = A potentially serious problem, consider carefully
   6 ALERT level C = Check. Ensure it is not caused by an omission or oversight
   2 ALERT level G = General information/check it is not something unexpected

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   3 ALERT type 2 Indicator that the structure model may be wrong or deficient
   4 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   1 ALERT type 5 Informative message, check

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S1. Comment

The title compound, C₁₇H₁₉NO₃, is a key intermediate in the synthesis of the experimental drug lumacaftor for the therapy of cystic fibrosis (Norman, 2014; McColley, 2014).

In the crystal structure of this compound (Fig. 1), the benzene and pyridine rings give a twisted conformation to the molecule, with an interplanar dihedral angle of 68.2 (1)°. The carboxyl group is essentially coplanar with the benzene ring [torsion angle C12—C11—C14—O2 = −174.7 (2)°]. The methyl C atoms of the tert-butyl group display somewhat elongated ellipsoids which is not unusual for this group. In the crystal there is an absence of classic hydrogen-bonding, but dual C—H···O hydrogen bonding interactions to carboxyl and oxide O-atom acceptors [C12—H···O2ⁱ and C4—H···O1ⁱ, respectively] (Table 1) give a cyclic dimer substructure (Fig. 2), with an R²₂(18) motif (Bernstein et al., 1995). The cyclic aggregates are arranged in rows along c (Fig. 3) which are linked through weak C8—H···O1ⁱⁱ hydrogen bonds, forming zigzag layered structures which lie parallel to (100) (Fig. 4). Similar hydrogen-bonding contacts have been observed in other pyridine oxides (McKay et al., 2006; Babu et al., 2007; Bowers et al., 2005). Present also in the crystal are π–π ring interactions between inversion-related pyridine rings [ring centroid separation = 3.561 (2) Å].

Related literature

For the synthesis of the title compound, see: Siesel (2009), Bremner et al. (1997). For related structures, see: McKay et al. (2006); Babu et al. (2007); Bowers et al. (2005). For background on the drug lumacaftor, see: Norman (2014); McColley (2014). For graph set analysis, see: Bernstein et al. (1995).

S2. Experimental

The title compound was synthesized by stirring 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine (Siesel, 2009) and m-chloroperoxybenzoic acid in dichloromethane. The mixture was treated with solid sodium sulfite, potassium carbonate and magnesium sulfate and the solvent was removed (Bremner et al., 1997). The resulting viscous oil crystallized after two weeks at room temperature giving the title compound (m.p. 352–354 K).

¹H NMR (DMSO-d₆, 300 MHz): δ 1.54 (s, 9H), 2.03 (s, 3H), 7.34–7.38 (m, 2H), 7.57–7.65 (m, 2H), 7.85 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 8.23 (d, J = 5.3 Hz, 1H) p.p.m. ¹³C NMR (DMSO-d₆, 75 MHz): δ 19.3 (CH₃), 27.7 (3 CH₃), 80.9 (C), 124.9 (CH), 127.1 (CH), 128.8 (CH), 129.1 (CH), 130.1 (CH), 131.6 (C), 132.8 (C), 134.0 (CH), 135.5 (C), 137.1 (CH), 147.5 (C), 164.6 (C═O) p.p.m. IR (neat): ν 3066, 2975, 2931, 1411, 1366, 1312, 1254, 1230, 1161, 1118, 1082, 1050, 959, 850, 787, 757, 738, 698, 569 cm⁻¹.

S3. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Computing details

Data collection: CrysAlis PRO (Agilent, 2014); cell refinement: CrysAlis PRO (Agilent, 2014); data reduction: CrysAlis PRO (Agilent, 2014); program(s) used to solve structure: SIR2002 (Burla et al., 2003); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); software used to prepare material for publication: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2006).

Figures

	Fig. 1. The molecular structure of the title compound, with atom labels and 50% probability displacement ellipsoids for non-H atoms.
	Fig. 2. Short C—H···O and π–π contacts in the crystal structure of the title compound. H atoms engaged in hydrogen bonding are drawn as spheres and all other H atoms are omitted. Symmetry code: (iii) −x + 1, −y, −z + 1. For other codes, see Table 1.
	Fig. 3. Rows of cyclic hydrogen-bond aggregates along along c.
	Fig. 4. The undulating sheet structure extending along the general b-axis direction.

tert-Butyl 3-(3-methyl-1-oxidopyridin-1-ium-2-yl)benzoate

Crystal data

C17H19NO3	F(000) = 608
Mr = 285.33	Dx = 1.243 Mg m^−3
Monoclinic, P21/c	Melting point = 352–354 K
Hall symbol: -P 2ybc	Cu Kα radiation, λ = 1.54184 Å
a = 13.6690 (7) Å	Cell parameters from 3088 reflections
b = 10.8170 (6) Å	θ = 3.4–66.0°
c = 10.9271 (7) Å	µ = 0.69 mm^−1
β = 109.365 (7)°	T = 173 K
V = 1524.25 (16) Å^3	Prismatic fragment, colourless
Z = 4	0.16 × 0.11 × 0.1 mm

Data collection

Agilent Xcalibur, Ruby, Gemini ultra diffractometer	2730 independent reflections
Radiation source: sealed X-ray tube	1984 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.066
Detector resolution: 10.3575 pixels mm^-1	θmax = 67.7°, θmin = 3.4°
ω scans	h = −16→13
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2014)	k = −12→12
Tmin = 0.884, Tmax = 1	l = −13→12
15403 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.053	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.158	H-atom parameters constrained
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0816P)^2 + 0.290P] where P = (Fo^2 + 2Fc^2)/3
2730 reflections	(Δ/σ)max < 0.001
194 parameters	Δρmax = 0.19 e Å^−3
0 restraints	Δρmin = −0.20 e Å^−3

Special details

Experimental. Absorption correction: CrysAlis PRO (Agilent, 2014). Agilent Technologies, Version 1.171.37.31 (release 14–01-2014 CrysAlis171. NET) (compiled Jan 14 2014,18:38:05) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'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 > 2σ(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
O3	0.10663 (13)	0.27239 (17)	0.77336 (16)	0.0605 (5)
O2	0.13706 (12)	0.21671 (17)	0.97944 (16)	0.0562 (5)
O1	0.43812 (13)	0.23977 (15)	0.67190 (18)	0.0573 (5)
N2	0.40653 (13)	0.15378 (17)	0.58465 (19)	0.0442 (5)
C11	0.23596 (14)	0.12519 (18)	0.86088 (19)	0.0367 (5)
C12	0.26102 (14)	0.12596 (18)	0.7478 (2)	0.0362 (5)
H12	0.2256	0.1801	0.6788	0.043*
C9	0.36423 (15)	−0.0318 (2)	0.9494 (2)	0.0464 (5)
H9	0.3995	−0.0859	1.0184	0.056*
C7	0.33842 (14)	0.04709 (19)	0.7351 (2)	0.0383 (5)
C10	0.28839 (15)	0.0467 (2)	0.9625 (2)	0.0423 (5)
H10	0.2721	0.0471	1.0405	0.051*
C1	0.36110 (14)	0.04809 (19)	0.6119 (2)	0.0407 (5)
C8	0.38909 (15)	−0.0320 (2)	0.8361 (2)	0.0444 (5)
H8	0.441	−0.0865	0.8277	0.053*
C14	0.15541 (15)	0.20928 (19)	0.8791 (2)	0.0387 (5)
C6	0.33577 (16)	−0.0479 (2)	0.5220 (2)	0.0474 (5)
C5	0.35176 (17)	−0.0325 (3)	0.4037 (2)	0.0563 (6)
H5	0.3352	−0.0976	0.3419	0.068*
C3	0.41890 (16)	0.1679 (2)	0.4671 (2)	0.0507 (6)
H3	0.4472	0.2428	0.448	0.061*
C15	0.02417 (19)	0.3638 (2)	0.7682 (2)	0.0550 (6)
C4	0.39149 (17)	0.0768 (3)	0.3761 (2)	0.0556 (6)
H4	0.3997	0.0887	0.2939	0.067*
C13	0.2918 (2)	−0.1661 (2)	0.5543 (3)	0.0640 (7)
H13A	0.2693	−0.2192	0.4773	0.096*
H13B	0.2323	−0.1472	0.5822	0.096*
H13C	0.3451	−0.2089	0.6243	0.096*
C16	−0.0668 (2)	0.2999 (3)	0.7882 (4)	0.0834 (10)
H16A	−0.1239	0.3589	0.7744	0.125*
H16B	−0.0467	0.2675	0.8768	0.125*
H16C	−0.0894	0.2316	0.7263	0.125*
C17	0.0654 (2)	0.4624 (3)	0.8682 (4)	0.0920 (12)
H17A	0.129	0.4971	0.8596	0.138*
H17B	0.0806	0.4267	0.955	0.138*
H17C	0.0135	0.528	0.8556	0.138*
C18	−0.0024 (4)	0.4125 (6)	0.6342 (4)	0.165 (3)
H18A	0.0609	0.4401	0.6191	0.248*
H18B	−0.0502	0.4825	0.6229	0.248*
H18C	−0.0356	0.3473	0.5721	0.248*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0708 (11)	0.0713 (11)	0.0529 (10)	0.0386 (9)	0.0385 (8)	0.0204 (8)
O2	0.0531 (9)	0.0745 (12)	0.0468 (9)	0.0113 (8)	0.0244 (7)	0.0025 (8)
O1	0.0585 (10)	0.0479 (9)	0.0741 (11)	−0.0125 (7)	0.0335 (8)	−0.0086 (9)
N2	0.0360 (9)	0.0454 (10)	0.0567 (11)	0.0049 (7)	0.0228 (8)	0.0012 (9)
C11	0.0303 (9)	0.0366 (10)	0.0434 (11)	−0.0046 (8)	0.0127 (8)	0.0008 (9)
C12	0.0314 (9)	0.0351 (10)	0.0436 (11)	−0.0008 (8)	0.0145 (8)	0.0011 (9)
C9	0.0358 (10)	0.0452 (12)	0.0534 (13)	0.0003 (9)	0.0084 (9)	0.0118 (10)
C7	0.0314 (9)	0.0368 (10)	0.0482 (12)	−0.0021 (8)	0.0151 (8)	−0.0014 (9)
C10	0.0342 (10)	0.0456 (12)	0.0462 (12)	−0.0058 (9)	0.0122 (9)	0.0053 (10)
C1	0.0290 (9)	0.0414 (11)	0.0535 (13)	0.0075 (8)	0.0163 (9)	0.0025 (10)
C8	0.0325 (10)	0.0405 (12)	0.0584 (14)	0.0031 (8)	0.0126 (9)	0.0040 (10)
C14	0.0349 (10)	0.0416 (11)	0.0414 (12)	−0.0049 (8)	0.0150 (9)	−0.0008 (9)
C6	0.0381 (10)	0.0475 (12)	0.0578 (14)	0.0077 (9)	0.0177 (10)	−0.0038 (11)
C5	0.0464 (12)	0.0679 (16)	0.0557 (14)	0.0099 (11)	0.0185 (11)	−0.0111 (13)
C3	0.0404 (11)	0.0578 (14)	0.0605 (15)	0.0124 (10)	0.0255 (11)	0.0132 (12)
C15	0.0586 (14)	0.0583 (14)	0.0602 (14)	0.0281 (11)	0.0360 (12)	0.0115 (12)
C4	0.0412 (11)	0.0764 (18)	0.0542 (14)	0.0150 (11)	0.0224 (10)	0.0082 (13)
C13	0.0694 (16)	0.0486 (14)	0.0786 (18)	−0.0065 (12)	0.0306 (14)	−0.0162 (13)
C16	0.0440 (13)	0.0639 (18)	0.132 (3)	0.0037 (12)	0.0153 (16)	−0.0009 (18)
C17	0.0592 (16)	0.0502 (16)	0.160 (3)	0.0044 (13)	0.0279 (19)	−0.0169 (19)
C18	0.219 (5)	0.216 (6)	0.103 (3)	0.184 (5)	0.111 (3)	0.098 (3)

Geometric parameters (Å, º)

O3—C14	1.317 (3)	C5—C4	1.376 (4)
O3—C15	1.487 (3)	C5—H5	0.95
O2—C14	1.206 (3)	C3—C4	1.361 (4)
O1—N2	1.299 (2)	C3—H3	0.95
N2—C3	1.359 (3)	C15—C18	1.483 (4)
N2—C1	1.380 (3)	C15—C17	1.497 (4)
C11—C12	1.387 (3)	C15—C16	1.501 (4)
C11—C10	1.393 (3)	C4—H4	0.95
C11—C14	1.491 (3)	C13—H13A	0.98
C12—C7	1.401 (3)	C13—H13B	0.98
C12—H12	0.95	C13—H13C	0.98
C9—C10	1.383 (3)	C16—H16A	0.98
C9—C8	1.388 (3)	C16—H16B	0.98
C9—H9	0.95	C16—H16C	0.98
C7—C8	1.386 (3)	C17—H17A	0.98
C7—C1	1.479 (3)	C17—H17B	0.98
C10—H10	0.95	C17—H17C	0.98
C1—C6	1.392 (3)	C18—H18A	0.98
C8—H8	0.95	C18—H18B	0.98
C6—C5	1.390 (3)	C18—H18C	0.98
C6—C13	1.504 (4)
C14—O3—C15	122.35 (17)	N2—C3—H3	119.4
O1—N2—C3	119.87 (19)	C4—C3—H3	119.4
O1—N2—C1	119.92 (18)	C18—C15—O3	102.03 (19)
C3—N2—C1	120.2 (2)	C18—C15—C17	112.2 (3)
C12—C11—C10	120.00 (18)	O3—C15—C17	110.4 (2)
C12—C11—C14	121.76 (18)	C18—C15—C16	111.3 (4)
C10—C11—C14	118.22 (19)	O3—C15—C16	110.0 (2)
C11—C12—C7	120.12 (19)	C17—C15—C16	110.6 (2)
C11—C12—H12	119.9	C3—C4—C5	119.7 (2)
C7—C12—H12	119.9	C3—C4—H4	120.2
C10—C9—C8	120.4 (2)	C5—C4—H4	120.2
C10—C9—H9	119.8	C6—C13—H13A	109.5
C8—C9—H9	119.8	C6—C13—H13B	109.5
C8—C7—C12	119.43 (19)	H13A—C13—H13B	109.5
C8—C7—C1	121.94 (18)	C6—C13—H13C	109.5
C12—C7—C1	118.60 (18)	H13A—C13—H13C	109.5
C9—C10—C11	119.8 (2)	H13B—C13—H13C	109.5
C9—C10—H10	120.1	C15—C16—H16A	109.5
C11—C10—H10	120.1	C15—C16—H16B	109.5
N2—C1—C6	119.4 (2)	H16A—C16—H16B	109.5
N2—C1—C7	116.60 (18)	C15—C16—H16C	109.5
C6—C1—C7	124.0 (2)	H16A—C16—H16C	109.5
C7—C8—C9	120.21 (19)	H16B—C16—H16C	109.5
C7—C8—H8	119.9	C15—C17—H17A	109.5
C9—C8—H8	119.9	C15—C17—H17B	109.5
O2—C14—O3	124.45 (19)	H17A—C17—H17B	109.5
O2—C14—C11	123.18 (19)	C15—C17—H17C	109.5
O3—C14—C11	112.37 (18)	H17A—C17—H17C	109.5
C5—C6—C1	119.2 (2)	H17B—C17—H17C	109.5
C5—C6—C13	121.2 (2)	C15—C18—H18A	109.5
C1—C6—C13	119.6 (2)	C15—C18—H18B	109.5
C4—C5—C6	120.1 (2)	H18A—C18—H18B	109.5
C4—C5—H5	119.9	C15—C18—H18C	109.5
C6—C5—H5	119.9	H18A—C18—H18C	109.5
N2—C3—C4	121.3 (2)	H18B—C18—H18C	109.5
C10—C11—C12—C7	0.6 (3)	C15—O3—C14—C11	−179.0 (2)
C14—C11—C12—C7	178.89 (18)	C12—C11—C14—O2	−174.72 (19)
C11—C12—C7—C8	0.4 (3)	C10—C11—C14—O2	3.6 (3)
C11—C12—C7—C1	178.40 (17)	C12—C11—C14—O3	6.0 (3)
C8—C9—C10—C11	0.6 (3)	C10—C11—C14—O3	−175.61 (18)
C12—C11—C10—C9	−1.1 (3)	N2—C1—C6—C5	−3.4 (3)
C14—C11—C10—C9	−179.44 (19)	C7—C1—C6—C5	173.95 (18)
O1—N2—C1—C6	−174.47 (18)	N2—C1—C6—C13	176.57 (19)
C3—N2—C1—C6	5.1 (3)	C7—C1—C6—C13	−6.1 (3)
O1—N2—C1—C7	8.0 (3)	C1—C6—C5—C4	−0.5 (3)
C3—N2—C1—C7	−172.40 (17)	C13—C6—C5—C4	179.6 (2)
C8—C7—C1—N2	−113.6 (2)	O1—N2—C3—C4	176.59 (19)
C12—C7—C1—N2	68.4 (2)	C1—N2—C3—C4	−3.0 (3)
C8—C7—C1—C6	68.9 (3)	C14—O3—C15—C18	177.7 (4)
C12—C7—C1—C6	−109.0 (2)	C14—O3—C15—C17	58.2 (3)
C12—C7—C8—C9	−0.9 (3)	C14—O3—C15—C16	−64.1 (3)
C1—C7—C8—C9	−178.79 (19)	N2—C3—C4—C5	−0.9 (3)
C10—C9—C8—C7	0.4 (3)	C6—C5—C4—C3	2.6 (3)
C15—O3—C14—O2	1.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C4—H4···O1^i	0.95	2.44	3.204 (3)	137
C12—H12···O2^i	0.95	2.39	3.327 (2)	169
C8—H8···O1^ii	0.95	2.50	3.438 (3)	169

Symmetry codes: (i) x, −y+1/2, z−1/2; (ii) −x+1, y−1/2, −z+3/2.