2-Fluoro-l-histidine

Abstract

The title compound, C₆H₈FN₃O₂, an analog of histidine, shows a reduced side-chain pK_a (ca 1). The title structure exhibits a shortening of the bond between the proximal ring N atom and the F-substituted ring C atom, indicating an increase in π-bond character due to an inductive effect of fluorine.

Related literature

For the structure of l-histidine, see Madden, et al. (1972 ▶). For the use of 2-fluoro-l-histidine in biochemistry, see Eichler et al. (2005 ▶); Wimalasena et al. (2007 ▶). For a related synthetic procedure, see DeClerq et al. (1978 ▶).

Experimental

Crystal data

• C₆H₈FN₃O₂

• M _r = 173.15

• Orthorhombic,

• a = 5.1880 (3) Å

• b = 7.3480 (5) Å

• c = 18.7169 (12) Å

• V = 713.51 (8) ų

• Z = 4

• Mo Kα radiation

• μ = 0.14 mm⁻¹

• T = 150 K

• 0.16 × 0.14 × 0.13 mm

Data collection

• Bruker APEXII CCD area-detector diffractometer

• Absorption correction: numerical (SADABS; Sheldrick, 2000 ▶) T _min = 0.978, T _max = 0.983

• 3663 measured reflections

• 1352 independent reflections

• 1257 reflections with I > 2σ(I)

• R _int = 0.022

Refinement

• R[F ² > 2σ(F ²)] = 0.043

• wR(F ²) = 0.125

• S = 1.06

• 1352 reflections

• 109 parameters

• H-atom parameters constrained

• Δρ_max = 0.42 e Å⁻³

• Δρ_min = −0.47 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 1996 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: Mercury (Version 2.3; CCDC, 2009 ▶); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 ▶).

Supplementary Material

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Comment

We have investigated the structure of 2-fluoro-L-histidine (2-FHis) by single-crystal X-ray crystallography. The objective is to utilize this structure for future use in determining protein crystal structures which incorporate this unnatural amino acid. An isosteric analog of histidine, 2-FHis has a greatly reduced side-chain pK_a, on the order of 1, and can be used to probe the role of histidine in enzyme mechanisms or biomolecular interactions (Eichler et al., 2005; Wimalasena et al., 2007). The present crystal structure is similar to L-histidine (Madden et al., 1972), but with distinct differences that are certainly due to an inductive effect of the fluorine. The fluorine atom substituted at C-2 of the imidazole ring (corresponding to C(6) in the crystal structure) pulls the shared electrons towards the central carbon from both the ring nitrogen atoms, resulting in a number of changes in bond angles and bond lengths. The compound is situated on a general position in the orthorhombic space group P2₁2₁2₁. The angle around the C atom, N(2)—C(6)—N(3), is 115.7 (2)°, as compared to 112.2 (2)° in L-histidine, which is consistent with an increase in the sp² character at C(6). In addition, angles at N(2) and N(3) are reduced to 104.9 (2)° and 102.7° (as compared to 106.9 (2)°) and 104.9 (2)°), respectively. The bond lengths to N(3) are altered as well, with the bond to C(4) increased to 1.405 (3) Å from 1.382 (2) Å in L-histidine and the bond to C(6) decreased to 1.292 (3) Å from 1.327 (3) Å in L-histidine. The molecule contains an intramolecular hydrogen bond between N(3) of the imidazole side-chain and the amine N(1) with a N–N distance of 2.860 (3) Å. This hydrogen bond is also increased in length from 2.72 Å in L-histidine, again indicative of the electron-withdrawing effect of the fluorine substitution. The structure also contains a number of intermolecular hydrogen bonding interactions: between the carboxylic acid O(2) and the imidazole N(2) of a symmetry related (3/2 - x,1 - y,-1/2 + z) molecule with a O–N distance of 2.741 (3) Å; between the carboxylic acid O(1) and the amine N(1) of a symmetry related (2 - x,-1/2 + y,1/2 - z) molecule with a O–N distance of 2.801 (3) Å; between the carboxylic acid O(2) and the amine N(1) of a symmetry related (1 - x,-1/2 + y,1/2 - z) molecule with a O–N distance of 3.012 (3) Å; and between the carboxylic acid O(1) and the amine N(1) of a symmetry related (1 + x,y,z) molecule with a O–N distance of 2.883 (3) Å.

Experimental

The compound was synthesized according to a modification of the published procedure (DeClerq, et al., 1978). Trifluoroacetic anhydride was used instead of acetic anhydride to protect the amino group in the first step, which obviates the use of acylase I. In addition, hydrolysis of the N-trifluoro acetyl group was carried out with 1 N NaOH in the last step of the synthesis (overall yield, starting from L-histidine methyl ester, is 2.5%). Crystals were grown by slow evaporation of an aqueous solution at room temperature.

Refinement

Refinement utilized merged data due to the absence of significant anomalous scattering. Hydrogen atoms were included in calculated positions and were not refined.

Figures

Fig. 1.

Mercury plot showing thermal ellipsoids on the 50% probability level.

Fig. 2.

Mercury plot showing the hydrogen bonding network.

Crystal data

C6H8FN3O2	F(000) = 360
Mr = 173.15	Dx = 1.612 Mg m−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4008 reflections
a = 5.1880 (3) Å	θ = 3.7–20.4°
b = 7.3480 (5) Å	µ = 0.14 mm−1
c = 18.7169 (12) Å	T = 150 K
V = 713.51 (8) Å3	Plate, colorless
Z = 4	0.16 × 0.14 × 0.13 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	1352 independent reflections
Radiation source: fine-focus sealed tube	1257 reflections with I > 2σ(I)
graphite	Rint = 0.022
phi and ω scans	θmax = 26.0°, θmin = 3.0°
Absorption correction: numerical (SADABS; Sheldrick, 2000)	h = −6→6
Tmin = 0.978, Tmax = 0.983	k = −9→9
3663 measured reflections	l = −22→17

Refinement

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.125	H-atom parameters constrained
S = 1.06	w = 1/[σ2(Fo2) + (0.0739P)2 + 0.5836P] where P = (Fo2 + 2Fc2)/3
1352 reflections	(Δ/σ)max = 0.035
109 parameters	Δρmax = 0.42 e Å−3
0 restraints	Δρmin = −0.47 e Å−3

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
C1	0.9310 (5)	0.5230 (3)	0.24487 (13)	0.0145 (5)
C2	0.8280 (5)	0.5747 (3)	0.31908 (13)	0.0136 (5)
H2A	0.9601	0.6496	0.3445	0.016*
C3	0.7728 (6)	0.4010 (4)	0.36301 (13)	0.0173 (6)
H3A	0.6410	0.3273	0.3380	0.021*
H3B	0.9322	0.3275	0.3663	0.021*
C4	0.6798 (5)	0.4441 (3)	0.43659 (14)	0.0162 (5)
C5	0.7962 (5)	0.4134 (4)	0.50022 (13)	0.0168 (6)
H5	0.9572	0.3548	0.5077	0.020*
C6	0.4353 (5)	0.5534 (4)	0.51566 (14)	0.0175 (6)
F1	0.2479 (3)	0.6321 (2)	0.55168 (9)	0.0310 (5)
N1	0.5862 (4)	0.6829 (3)	0.31144 (11)	0.0141 (5)
H1A	0.5249	0.7074	0.2687	0.017*
H1B	0.5049	0.7222	0.3497	0.017*
N2	0.6359 (4)	0.4835 (3)	0.55190 (12)	0.0176 (5)
H2B	0.6594	0.4828	0.5985	0.021*
N3	0.4443 (4)	0.5346 (3)	0.44706 (12)	0.0175 (5)
O1	1.1696 (3)	0.4958 (3)	0.24076 (10)	0.0183 (4)
H1	1.2086	0.4683	0.1986	0.027*
O2	0.7692 (4)	0.5062 (3)	0.19595 (9)	0.0210 (4)

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C1	0.0173 (12)	0.0116 (11)	0.0145 (12)	−0.0012 (11)	0.0038 (11)	−0.0003 (9)
C2	0.0127 (11)	0.0145 (12)	0.0137 (12)	0.0002 (10)	0.0000 (10)	−0.0010 (10)
C3	0.0233 (13)	0.0161 (11)	0.0125 (12)	0.0045 (12)	0.0032 (11)	0.0016 (9)
C4	0.0180 (12)	0.0154 (11)	0.0153 (13)	−0.0001 (10)	0.0029 (10)	0.0027 (10)
C5	0.0173 (13)	0.0156 (12)	0.0176 (13)	−0.0024 (11)	0.0023 (11)	0.0032 (10)
C6	0.0188 (13)	0.0190 (13)	0.0148 (13)	−0.0012 (11)	0.0060 (11)	−0.0003 (10)
F1	0.0305 (9)	0.0356 (10)	0.0269 (9)	0.0061 (8)	0.0057 (8)	−0.0049 (7)
N1	0.0164 (10)	0.0175 (10)	0.0084 (10)	0.0038 (9)	0.0000 (9)	0.0002 (8)
N2	0.0218 (11)	0.0206 (11)	0.0105 (10)	−0.0026 (9)	−0.0013 (8)	0.0004 (9)
N3	0.0186 (10)	0.0185 (10)	0.0156 (11)	0.0032 (10)	0.0011 (9)	0.0009 (9)
O1	0.0167 (9)	0.0227 (9)	0.0155 (9)	−0.0002 (8)	0.0033 (7)	−0.0057 (8)
O2	0.0175 (9)	0.0352 (10)	0.0101 (9)	−0.0026 (9)	−0.0006 (7)	−0.0028 (8)

Geometric parameters (Å, °)

C1—O2	1.248 (3)	C4—N3	1.405 (3)
C1—O1	1.256 (3)	C5—N2	1.376 (3)
C1—C2	1.536 (4)	C5—H5	0.9500
C2—N1	1.492 (3)	C6—N3	1.292 (3)
C2—C3	1.545 (4)	C6—F1	1.317 (3)
C2—H2A	1.0000	C6—N2	1.344 (4)
C3—C4	1.493 (4)	N1—H1A	0.8800
C3—H3A	0.9900	N1—H1B	0.8800
C3—H3B	0.9900	N2—H2B	0.8800
C4—C5	1.354 (4)	O1—H1	0.8400
O2—C1—O1	127.0 (2)	C5—C4—C3	129.2 (2)
O2—C1—C2	117.0 (2)	N3—C4—C3	120.7 (2)
O1—C1—C2	116.0 (2)	C4—C5—N2	106.6 (2)
N1—C2—C1	109.7 (2)	C4—C5—H5	126.7
N1—C2—C3	109.6 (2)	N2—C5—H5	126.7
C1—C2—C3	110.0 (2)	N3—C6—F1	125.6 (2)
N1—C2—H2A	109.2	N3—C6—N2	115.7 (2)
C1—C2—H2A	109.2	F1—C6—N2	118.7 (2)
C3—C2—H2A	109.2	C2—N1—H1A	120.0
C4—C3—C2	112.1 (2)	C2—N1—H1B	120.0
C4—C3—H3A	109.2	H1A—N1—H1B	120.0
C2—C3—H3A	109.2	C6—N2—C5	104.9 (2)
C4—C3—H3B	109.2	C6—N2—H2B	127.6
C2—C3—H3B	109.2	C5—N2—H2B	127.6
H3A—C3—H3B	107.9	C6—N3—C4	102.7 (2)
C5—C4—N3	110.1 (2)	C1—O1—H1	109.5