N-(2,3,5,6-Tetrafluoropyridin-4-yl)formamide

Newell, B.D.; McMillen, C.D.; Lee, J.P.

doi:10.1107/S2414314622008045

organic compounds

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ISSN: 2414-3146

Volume 7| Part 8| August 2022| x220804

https://doi.org/10.1107/S2414314622008045

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N-(2,3,5,6-Tetrafluoropyridin-4-yl)formamide

Bailey D. Newell,^a Colin D. McMillen ^b and John P. Lee ^a ^*

^aThe University of Tennessee at Chattanooga, Department of Chemistry and Physics, #2252, 615 McCallie Avenue, Chattanooga, TN 37403, USA, and ^bClemson University, Department of Chemistry, Clemson, SC 29634, USA
^*Correspondence e-mail: John-Lee@utc.edu

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 23 June 2022; accepted 10 August 2022; online 16 August 2022)

The title compound, C₆H₂F₄N₂O, displays amide bond lengths of 1.218 (3) Å and 1.366 (3) Å for the C=O and C—N bonds, respectively. The C_p—N—C—O (p = pyridine) torsion angle of 179.0 (2)° indicates an anti-conformation for the grouping. Intermolecular hydrogen bonding is observed between the amine N—H group and the carbonyl O atom, which generates chains of molecules propagating along the b-axis direction.

Keywords: crystal structure; amide bond; perfluorinated pyridine; formamide; hydrogen bonding.

CCDC reference: 2196118

Structure description

The title compound, N-(2,3,5,6-tetrafluoropyridin-4-yl)formamide, (I), contains a perfluorinated pyridine heterocycle and a formamide group para to the pyridine N atom. These groups have shown utility in independent biochemical applications. For example, fluoroaromatic compounds are used in positron emission tomography (Hashizume et al., 1996 ) and pyridine rings can act as the bioisosteres of amides (Sun et al., 2019 ). The structure reported here combines these components and could be of interest for biochemical applications. A search of the CCDC shows no structures that contain a pyridine ring functionalized with a formamide group in the 4-position (Groom et al., 2016 ).

The crystal structure of (I) represents the first example of a perfluorinated pyridine ring with a formamide functional group (Fig. 1). The amide bond lengths for (I) are 1.218 (3) Å and 1.366 (3) Å for the C=O and C—N bonds, respectively, which are in good agreement with the corresponding bonds in the related compounds N-phenylformamide (Omondi et al., 2014 ), N-(2,6-difluorophenyl)formamide (Omondi et al., 2009b ), and N-(2,6-dibromophenyl)formamide (Omondi et al., 2009a ). As observed in other structures, the amide bond lengths for (I) are consistent with little to no N=C/C—O bond resonance contribution. The formamide group and pyridine ring in (I) are somewhat twisted with a dihedral angle of 13.21 (5)°. This is similar to N-phenylformamide (Omondi et al., 2014) (dihedral angle between the benzene ring and formamide groups = 10.5°) but in contrast to N-(2,6-difluorophenyl)formamide (Omondi et al., 2009b) and N-(2,6-dibromophenyl)formamide (Omondi et al., 2009a) where the equivalent dihedral angles are 58.4 and 83.2°, respectively. The latter structures indicate that the steric effects likely increase from H to F to Br; however, this large deviation from planarity is not observed in (I). Furthermore, the torsion angle of 179.0 (2)° for C3—N2—C6—O1 in (I) indicates a near anti-conformation, but in structures with a benzene ring, the carbonyl–benzene conformation is syn regardless of aromatic substituents (Omondi et al., 2009a,b, 2014). Taken together, these indicate that the pyridine ring is playing a role in the structure beyond the sterics of the aromatic ring substituents. The pyridyl related compounds N-(3,5-dichloro-2-pyridyl)formamide (Resinger et al., 2005 ) and formyl(2-pyridyl)amine (Bock et al., 1996 ) also show an anti-conformation for the carbonyl and pyridine ring as well as near coplanarity of the functional groups as observed for the title compound.

Figure 1
Displacement ellipsoid perspective view (50% probability) for the title structure showing the atom-numbering scheme.

In the extended structure of (I) the molecules are linked by N—H⋯O hydrogen bonds with a bond angle of 171 (3)° (Table 1), which suggests evidence of intermediate–strong hydrogen bonding (Arunan et al., 2011 ). The hydrogen bonding generates chains of molecules propagating along the b-axis direction in the extended structure (Fig. 2) with adjacent molecules in the chain related by 2₁ screw axis symmetry. Neighboring sets of chains form an L shape through a nearly orthogonal (84°) orientation of the pyridine rings in each chain (Fig. 3). This brings about short contacts between the pyridyl nitrogen atoms and the π systems of these orthogonal pyridine rings (N⋯centroid = 3.502 Å; shortest N⋯C = 3.032 Å).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2⋯O1ⁱ	0.87 (3)	1.96 (3)	2.814 (3)	171 (3)
Symmetry code: (i) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Figure 2
Intermolecular hydrogen bonding forming a chain propagating along the b-axis direction where hydrogen bonds are represented with dashed lines.

Figure 3
Extended structure as viewed looking down the b-axis showing the L-shape that is formed by the orthogonal pyridine rings of neighboring chains.

Synthesis and crystallization

A 50 ml round-bottom flask was charged with 2,3,5,6-tetrafluoropyridin-4-amine (0.1078 g, 0.6491mmol), p-toluenesulfonic acid (0.0046 g, 0.027 mmol), trimethyl orthoformate (0.28 ml, 2.6 mmol), and toluene (5 ml). A Dean–Stark apparatus was filled with toluene (10 ml), and the solution was refluxed for 16 h. A homogenous colorless solution was obtained. Crystals were obtained by dichloromethane layered with hexanes, yielding orange needles. ¹⁹F{¹H} NMR (CDCl₃, δ): 91.1 (2F, d, –CF), 154.9 (2F, d, –CF). ¹H NMR (CDCl₃, δ): 9.00 (1H, s, –O=CH), 7.70 (1H, s, –NH).

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₆H₂F₄N₂O
M_r	194.10
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	100
a, b, c (Å)	5.1183 (4), 6.2707 (6), 20.6294 (16)
V (Å³)	662.11 (10)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.21
Crystal size (mm)	0.28 × 0.06 × 0.05

Data collection
Diffractometer	Bruker D8 Venture Photon 2
Absorption correction	Multi-scan (SADABS; Bruker, 2018 )
T_min, T_max	0.897, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	3556, 1309, 1200
R_int	0.029
(sin θ/λ)_max (Å⁻¹)	0.618

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.028, 0.066, 1.09
No. of reflections	1309
No. of parameters	122
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.14, −0.19
Absolute structure	Flack x determined using 424 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−0.1 (6)
Computer programs: APEX3 and SAINT (Bruker, 2018), SHELXT2014/5 (Sheldrick, 2015a ), SHELXL2016/6 (Sheldrick, 2015b ), and SHELXTL (Sheldrick, 2008 ).

Structural data

CCDC reference: 2196118

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314622008045/hb4409sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314622008045/hb4409Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314622008045/hb4409Isup3.cml

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2018); cell refinement: SAINT (Bruker, 2018); data reduction: SAINT (Bruker, 2018); program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016/6 (Sheldrick, 2015b); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

N-(2,3,5,6-Tetrafluoropyridin-4-yl)formamide top

Crystal data top

C₆H₂F₄N₂O	D_x = 1.947 Mg m⁻³
M_r = 194.10	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 2461 reflections
a = 5.1183 (4) Å	θ = 3.4–26.0°
b = 6.2707 (6) Å	µ = 0.21 mm⁻¹
c = 20.6294 (16) Å	T = 100 K
V = 662.11 (10) Å³	Column, colourless
Z = 4	0.28 × 0.06 × 0.05 mm
F(000) = 384

Data collection top

Bruker D8 Venture Photon 2 diffractometer	1200 reflections with I > 2σ(I)
Radiation source: Incoatec IµS	R_int = 0.029
φ and ω scans	θ_max = 26.0°, θ_min = 3.4°
Absorption correction: multi-scan (SADABS; Bruker, 2018)	h = −6→6
T_min = 0.897, T_max = 1.000	k = −7→7
3556 measured reflections	l = −25→25
1309 independent reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.028	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.066	w = 1/[σ²(F_o²) + (0.0317P)² + 0.041P] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max < 0.001
1309 reflections	Δρ_max = 0.14 e Å⁻³
122 parameters	Δρ_min = −0.19 e Å⁻³
0 restraints	Absolute structure: Flack x determined using 424 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: dual	Absolute structure parameter: −0.1 (6)

Special details top

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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
F1	0.9516 (3)	−0.1033 (2)	0.60146 (7)	0.0280 (4)
F2	0.5417 (3)	−0.0546 (2)	0.68314 (6)	0.0218 (4)
F3	0.3999 (3)	0.6218 (2)	0.58674 (7)	0.0246 (4)
F4	0.8168 (3)	0.5429 (2)	0.51143 (7)	0.0246 (4)
O1	−0.0674 (4)	0.4673 (3)	0.73924 (8)	0.0239 (4)
N1	0.8836 (4)	0.2207 (3)	0.55635 (10)	0.0194 (5)
N2	0.2513 (4)	0.3050 (3)	0.68341 (10)	0.0176 (5)
H2	0.208 (6)	0.193 (5)	0.7052 (15)	0.030 (8)*
C1	0.8095 (5)	0.0761 (4)	0.59878 (12)	0.0186 (6)
C2	0.6040 (5)	0.0998 (4)	0.64033 (11)	0.0172 (5)
C3	0.4581 (5)	0.2879 (4)	0.64007 (11)	0.0153 (5)
C4	0.5327 (5)	0.4385 (4)	0.59394 (11)	0.0168 (5)
C5	0.7440 (5)	0.3963 (4)	0.55472 (11)	0.0188 (6)
C6	0.1120 (5)	0.4818 (4)	0.70070 (12)	0.0195 (6)
H6	0.155131	0.616615	0.682599	0.023*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0275 (9)	0.0267 (8)	0.0299 (8)	0.0124 (7)	0.0063 (8)	0.0033 (6)
F2	0.0255 (8)	0.0183 (7)	0.0215 (7)	0.0018 (7)	0.0038 (7)	0.0059 (6)
F3	0.0292 (9)	0.0193 (7)	0.0253 (8)	0.0059 (7)	0.0041 (8)	0.0053 (6)
F4	0.0272 (8)	0.0280 (8)	0.0187 (7)	−0.0051 (7)	0.0039 (7)	0.0064 (6)
O1	0.0232 (10)	0.0228 (9)	0.0255 (9)	0.0014 (9)	0.0100 (9)	−0.0038 (7)
N1	0.0152 (11)	0.0287 (11)	0.0143 (10)	−0.0001 (9)	−0.0007 (10)	−0.0007 (8)
N2	0.0183 (11)	0.0174 (10)	0.0170 (10)	−0.0002 (9)	0.0036 (11)	0.0011 (8)
C1	0.0167 (13)	0.0196 (12)	0.0195 (12)	0.0029 (10)	−0.0009 (12)	−0.0008 (10)
C2	0.0183 (13)	0.0185 (12)	0.0149 (12)	−0.0013 (10)	−0.0003 (12)	0.0013 (9)
C3	0.0146 (11)	0.0197 (11)	0.0117 (11)	−0.0002 (10)	−0.0011 (11)	−0.0029 (8)
C4	0.0182 (13)	0.0176 (11)	0.0146 (11)	0.0010 (11)	−0.0021 (11)	0.0005 (9)
C5	0.0211 (13)	0.0220 (12)	0.0132 (12)	−0.0055 (11)	−0.0026 (12)	0.0026 (10)
C6	0.0198 (14)	0.0183 (12)	0.0205 (12)	0.0005 (11)	0.0016 (13)	−0.0021 (9)

Geometric parameters (Å, º) top

F1—C1	1.341 (3)	N2—C3	1.390 (3)
F2—C2	1.348 (3)	N2—H2	0.87 (3)
F3—C4	1.343 (3)	C1—C2	1.365 (3)
F4—C5	1.335 (3)	C2—C3	1.396 (3)
O1—C6	1.218 (3)	C3—C4	1.394 (3)
N1—C5	1.313 (3)	C4—C5	1.376 (4)
N1—C1	1.316 (3)	C6—H6	0.9500
N2—C6	1.366 (3)

C5—N1—C1	116.0 (2)	N2—C3—C2	118.0 (2)
C6—N2—C3	128.9 (2)	C4—C3—C2	115.4 (2)
C6—N2—H2	113 (2)	F3—C4—C5	119.8 (2)
C3—N2—H2	118 (2)	F3—C4—C3	121.1 (2)
N1—C1—F1	116.7 (2)	C5—C4—C3	119.1 (2)
N1—C1—C2	124.4 (2)	N1—C5—F4	116.3 (2)
F1—C1—C2	118.9 (2)	N1—C5—C4	125.0 (2)
F2—C2—C1	121.0 (2)	F4—C5—C4	118.7 (2)
F2—C2—C3	118.9 (2)	O1—C6—N2	120.2 (2)
C1—C2—C3	120.1 (2)	O1—C6—H6	119.9
N2—C3—C4	126.5 (2)	N2—C6—H6	119.9

C5—N1—C1—F1	−179.4 (2)	N2—C3—C4—F3	−1.1 (4)
C5—N1—C1—C2	−0.8 (4)	C2—C3—C4—F3	176.8 (2)
N1—C1—C2—F2	−179.1 (2)	N2—C3—C4—C5	179.8 (2)
F1—C1—C2—F2	−0.6 (3)	C2—C3—C4—C5	−2.3 (3)
N1—C1—C2—C3	−0.7 (4)	C1—N1—C5—F4	−179.5 (2)
F1—C1—C2—C3	177.9 (2)	C1—N1—C5—C4	0.7 (4)
C6—N2—C3—C4	−15.2 (4)	F3—C4—C5—N1	−178.2 (2)
C6—N2—C3—C2	167.0 (2)	C3—C4—C5—N1	0.9 (4)
F2—C2—C3—N2	−1.3 (3)	F3—C4—C5—F4	2.0 (3)
C1—C2—C3—N2	−179.8 (2)	C3—C4—C5—F4	−178.9 (2)
F2—C2—C3—C4	−179.3 (2)	C3—N2—C6—O1	179.0 (2)
C1—C2—C3—C4	2.2 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O1ⁱ	0.87 (3)	1.96 (3)	2.814 (3)	171 (3)

Symmetry code: (i) −x, y−1/2, −z+3/2.

Funding information

Acknowledgements are made to the University of Tennessee at Chattanooga, and the Grote Chemistry Fund at UTC.

References

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organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

N-(2,3,5,6-Tetra­fluoropyridin-4-yl)formamide

Structure description

Synthesis and crystallization

Refinement

Structural data

Funding information

References

organic compounds

N-(2,3,5,6-Tetrafluoropyridin-4-yl)formamide