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

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2-Fluoro-L-histidine

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 pKa (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[Madden, J. J., McGandy, E. L. & Seeman, N. C. (1972). Acta Cryst. B28, 2377-2382.]). For the use of 2-fluoro-L-histidine in biochemistry, see Eichler et al. (2005[Eichler, J. F., Cramer, J. C., Kirk, K. L. & Bann, J. G. (2005). ChemBioChem, 6, 2170-2173.]); Wimalasena et al. (2007[Wimalasena, D. S., Cramer, J. C., Janowiak, B. E., Juris, S. J., Melnyk, R. A., Anderson, D. E., Kirk, K. L., Collier, R. J. & Bann, J. G. (2007). Biochemistry, 46, 14928-14936.]). For a related synthetic procedure, see DeClerq et al. (1978[DeClerq, E., Billiau, A., Eddy, V. G., Kirk, K. L. & Cohen, L. A. (1978). Biochem. Biophys. Res. Commun. 82, 840-84.]).

[Scheme 1]

Experimental

Crystal data
  • C6H8FN3O2

  • Mr = 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[Sheldrick, G. M. (2000). SADABS. University of Göttingen, Germany.]) Tmin = 0.978, Tmax = 0.983

  • 3663 measured reflections

  • 1352 independent reflections

  • 1257 reflections with I > 2σ(I)

  • Rint = 0.022

Refinement
  • R[F2 > 2σ(F2)] = 0.043

  • wR(F2) = 0.125

  • S = 1.06

  • 1352 reflections

  • 109 parameters

  • H-atom parameters constrained

  • Δρmax = 0.42 e Å−3

  • Δρmin = −0.47 e Å−3

Data collection: APEX2 (Bruker, 2005[Bruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 1996[Bruker (1996). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: Mercury (Version 2.3; CCDC, 2009[CCDC (2009). Mercury. Version 2.3. Cambridge Crystallographic Data Centre, Cambridge, England.]); software used to prepare material for publication: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]).

Supporting information


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 pKa, 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.

Refinement top

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

Structure description 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 pKa, 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.

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
[Figure 1] Fig. 1. Mercury plot showing thermal ellipsoids on the 50% probability level.
[Figure 2] Fig. 2. Mercury plot showing the hydrogen bonding network.
2-Fluoro-L-histidine top
Crystal data top
C6H8FN3O2F(000) = 360
Mr = 173.15Dx = 1.612 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 4008 reflections
a = 5.1880 (3) Åθ = 3.7–20.4°
b = 7.3480 (5) ŵ = 0.14 mm1
c = 18.7169 (12) ÅT = 150 K
V = 713.51 (8) Å3Plate, colorless
Z = 40.16 × 0.14 × 0.13 mm
Data collection top
Bruker APEXII CCD area-detector
diffractometer
1352 independent reflections
Radiation source: fine-focus sealed tube1257 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.022
phi and ω scansθmax = 26.0°, θmin = 3.0°
Absorption correction: numerical
(SADABS; Sheldrick, 2000)
h = 66
Tmin = 0.978, Tmax = 0.983k = 99
3663 measured reflectionsl = 2217
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.043Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.125H-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 parametersΔρmax = 0.42 e Å3
0 restraintsΔρmin = 0.47 e Å3
Crystal data top
C6H8FN3O2V = 713.51 (8) Å3
Mr = 173.15Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 5.1880 (3) ŵ = 0.14 mm1
b = 7.3480 (5) ÅT = 150 K
c = 18.7169 (12) Å0.16 × 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)
Tmin = 0.978, Tmax = 0.983Rint = 0.022
3663 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0430 restraints
wR(F2) = 0.125H-atom parameters constrained
S = 1.06Δρmax = 0.42 e Å3
1352 reflectionsΔρmin = 0.47 e Å3
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
xyzUiso*/Ueq
C10.9310 (5)0.5230 (3)0.24487 (13)0.0145 (5)
C20.8280 (5)0.5747 (3)0.31908 (13)0.0136 (5)
H2A0.96010.64960.34450.016*
C30.7728 (6)0.4010 (4)0.36301 (13)0.0173 (6)
H3A0.64100.32730.33800.021*
H3B0.93220.32750.36630.021*
C40.6798 (5)0.4441 (3)0.43659 (14)0.0162 (5)
C50.7962 (5)0.4134 (4)0.50022 (13)0.0168 (6)
H50.95720.35480.50770.020*
C60.4353 (5)0.5534 (4)0.51566 (14)0.0175 (6)
F10.2479 (3)0.6321 (2)0.55168 (9)0.0310 (5)
N10.5862 (4)0.6829 (3)0.31144 (11)0.0141 (5)
H1A0.52490.70740.26870.017*
H1B0.50490.72220.34970.017*
N20.6359 (4)0.4835 (3)0.55190 (12)0.0176 (5)
H2B0.65940.48280.59850.021*
N30.4443 (4)0.5346 (3)0.44706 (12)0.0175 (5)
O11.1696 (3)0.4958 (3)0.24076 (10)0.0183 (4)
H11.20860.46830.19860.027*
O20.7692 (4)0.5062 (3)0.19595 (9)0.0210 (4)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0173 (12)0.0116 (11)0.0145 (12)0.0012 (11)0.0038 (11)0.0003 (9)
C20.0127 (11)0.0145 (12)0.0137 (12)0.0002 (10)0.0000 (10)0.0010 (10)
C30.0233 (13)0.0161 (11)0.0125 (12)0.0045 (12)0.0032 (11)0.0016 (9)
C40.0180 (12)0.0154 (11)0.0153 (13)0.0001 (10)0.0029 (10)0.0027 (10)
C50.0173 (13)0.0156 (12)0.0176 (13)0.0024 (11)0.0023 (11)0.0032 (10)
C60.0188 (13)0.0190 (13)0.0148 (13)0.0012 (11)0.0060 (11)0.0003 (10)
F10.0305 (9)0.0356 (10)0.0269 (9)0.0061 (8)0.0057 (8)0.0049 (7)
N10.0164 (10)0.0175 (10)0.0084 (10)0.0038 (9)0.0000 (9)0.0002 (8)
N20.0218 (11)0.0206 (11)0.0105 (10)0.0026 (9)0.0013 (8)0.0004 (9)
N30.0186 (10)0.0185 (10)0.0156 (11)0.0032 (10)0.0011 (9)0.0009 (9)
O10.0167 (9)0.0227 (9)0.0155 (9)0.0002 (8)0.0033 (7)0.0057 (8)
O20.0175 (9)0.0352 (10)0.0101 (9)0.0026 (9)0.0006 (7)0.0028 (8)
Geometric parameters (Å, º) top
C1—O21.248 (3)C4—N31.405 (3)
C1—O11.256 (3)C5—N21.376 (3)
C1—C21.536 (4)C5—H50.9500
C2—N11.492 (3)C6—N31.292 (3)
C2—C31.545 (4)C6—F11.317 (3)
C2—H2A1.0000C6—N21.344 (4)
C3—C41.493 (4)N1—H1A0.8800
C3—H3A0.9900N1—H1B0.8800
C3—H3B0.9900N2—H2B0.8800
C4—C51.354 (4)O1—H10.8400
O2—C1—O1127.0 (2)C5—C4—C3129.2 (2)
O2—C1—C2117.0 (2)N3—C4—C3120.7 (2)
O1—C1—C2116.0 (2)C4—C5—N2106.6 (2)
N1—C2—C1109.7 (2)C4—C5—H5126.7
N1—C2—C3109.6 (2)N2—C5—H5126.7
C1—C2—C3110.0 (2)N3—C6—F1125.6 (2)
N1—C2—H2A109.2N3—C6—N2115.7 (2)
C1—C2—H2A109.2F1—C6—N2118.7 (2)
C3—C2—H2A109.2C2—N1—H1A120.0
C4—C3—C2112.1 (2)C2—N1—H1B120.0
C4—C3—H3A109.2H1A—N1—H1B120.0
C2—C3—H3A109.2C6—N2—C5104.9 (2)
C4—C3—H3B109.2C6—N2—H2B127.6
C2—C3—H3B109.2C5—N2—H2B127.6
H3A—C3—H3B107.9C6—N3—C4102.7 (2)
C5—C4—N3110.1 (2)C1—O1—H1109.5

Experimental details

Crystal data
Chemical formulaC6H8FN3O2
Mr173.15
Crystal system, space groupOrthorhombic, P212121
Temperature (K)150
a, b, c (Å)5.1880 (3), 7.3480 (5), 18.7169 (12)
V3)713.51 (8)
Z4
Radiation typeMo Kα
µ (mm1)0.14
Crystal size (mm)0.16 × 0.14 × 0.13
Data collection
DiffractometerBruker APEXII CCD area-detector
Absorption correctionNumerical
(SADABS; Sheldrick, 2000)
Tmin, Tmax0.978, 0.983
No. of measured, independent and
observed [I > 2σ(I)] reflections
3663, 1352, 1257
Rint0.022
(sin θ/λ)max1)0.617
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.043, 0.125, 1.06
No. of reflections1352
No. of parameters109
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)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.

References

First citationBruker (1996). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationBruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationCCDC (2009). Mercury. Version 2.3. Cambridge Crystallographic Data Centre, Cambridge, England.  Google Scholar
First citationDeClerq, E., Billiau, A., Eddy, V. G., Kirk, K. L. & Cohen, L. A. (1978). Biochem. Biophys. Res. Commun. 82, 840–84.  PubMed Web of Science Google Scholar
First citationEichler, J. F., Cramer, J. C., Kirk, K. L. & Bann, J. G. (2005). ChemBioChem, 6, 2170–2173.  Web of Science CrossRef PubMed CAS Google Scholar
First citationMadden, J. J., McGandy, E. L. & Seeman, N. C. (1972). Acta Cryst. B28, 2377–2382.  CSD CrossRef CAS IUCr Journals Web of Science Google Scholar
First citationSheldrick, G. M. (2000). SADABS. University of Göttingen, Germany.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationWimalasena, D. S., Cramer, J. C., Janowiak, B. E., Juris, S. J., Melnyk, R. A., Anderson, D. E., Kirk, K. L., Collier, R. J. & Bann, J. G. (2007). Biochemistry, 46, 14928–14936.  Web of Science CrossRef PubMed CAS Google Scholar

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