2-Fluoro-l-histidine

Andra, K.K.; Bullinger, J.C.; Bann, J.G.; Eichhorn, D.M.

doi:10.1107/S1600536810038663

organic compounds

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ISSN: 2056-9890

Volume 66| Part 11| November 2010| Page o2713

https://doi.org/10.1107/S1600536810038663

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2-Fluoro-L-histidine

Kiran K. Andra,^a John C. Bullinger,^a James G. Bann ^a and David M. Eichhorn ^a ^*

^aDepartment of Chemistry, Wichita State University, 1845 Fairmount, Wichita, KS 67260-0051, USA
^*Correspondence e-mail: david.eichhorn@wichita.edu

(Received 14 September 2010; accepted 27 September 2010; online 2 October 2010)

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, P 2₁ 2₁ 2₁
a = 5.1880 (3) Å
b = 7.3480 (5) Å
c = 18.7169 (12) Å
V = 713.51 (8) Å³
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[F² > 2σ(F²)] = 0.043
wR(F²) = 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).

Supporting information

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S1600536810038663/im2231sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536810038663/im2231Isup2.hkl

checkCIF report

Comment top

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.

Related literature top

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 top

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.

Structure description top

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).

Computing details top

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

Figures top

	Fig. 1. Mercury plot showing thermal ellipsoids on the 50% probability level.
	Fig. 2. Mercury plot showing the hydrogen bonding network.

2-Fluoro-L-histidine top

Crystal data top

C₆H₈FN₃O₂	F(000) = 360
M_r = 173.15	D_x = 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 top

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

Refinement top

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(F_o²) + (0.0739P)² + 0.5836P] where P = (F_o² + 2F_c²)/3
1352 reflections	(Δ/σ)_max = 0.035
109 parameters	Δρ_max = 0.42 e Å⁻³
0 restraints	Δρ_min = −0.47 e Å⁻³

Crystal data top

C₆H₈FN₃O₂	V = 713.51 (8) Å³
M_r = 173.15	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 5.1880 (3) Å	µ = 0.14 mm⁻¹
b = 7.3480 (5) Å	T = 150 K
c = 18.7169 (12) Å	0.16 × 0.14 × 0.13 mm

Data collection top

Bruker APEXII CCD area-detector diffractometer	1352 independent reflections
Absorption correction: numerical (SADABS; Sheldrick, 2000)	1257 reflections with I > 2σ(I)
T_min = 0.978, T_max = 0.983	R_int = 0.022
3663 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.043	0 restraints
wR(F²) = 0.125	H-atom parameters constrained
S = 1.06	Δρ_max = 0.42 e Å⁻³
1352 reflections	Δρ_min = −0.47 e Å⁻³
109 parameters

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
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 (Å²) top

	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, º) top

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

Experimental details

Crystal data
Chemical formula	C₆H₈FN₃O₂
M_r	173.15
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	150
a, b, c (Å)	5.1880 (3), 7.3480 (5), 18.7169 (12)
V (Å³)	713.51 (8)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.14
Crystal size (mm)	0.16 × 0.14 × 0.13

Data collection
Diffractometer	Bruker APEXII CCD area-detector
Absorption correction	Numerical (SADABS; Sheldrick, 2000)
T_min, T_max	0.978, 0.983
No. of measured, independent and observed [I > 2σ(I)] reflections	3663, 1352, 1257
R_int	0.022
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.043, 0.125, 1.06
No. of reflections	1352
No. of parameters	109
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.42, −0.47

Computer programs: APEX2 (Bruker, 2005), SAINT (Bruker, 1996), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Acknowledgements

This work was supported in part through an NIH 5P20 RR17708 award to JGB.

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