The C-F bond as a tool in the conformational control of amides

Article abstract of DOI:10.1016/S0022-1139(02)00243-9

The conformation of 2-fluoro-N-(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-fluorine-amide gauche effect and an α-fluoroamide effect. The structure reveals the influence of two recently observed stereoelectronic effects associated with the C-F bond, which has resulted in the successful prediction of the solid state conformation of amide 4. A gauche relationship (-69.9°) was observed for atoms N(1)-C(4)-C(5)-F and a syn planar (2.0°) relationship was observed for N(1)-C(3)-C(2)-F. The paper demonstrates the predictive power of using the C-F bond as a tool in influencing the conformation of amides and peptides.

Full text of DOI:10.1016/S0022-1139(02)00243-9

Journal of Fluorine Chemistry 119 (2003) 9±13
The C±F bond as a tool in the conformational control of amides
b
a,b
Caroline R.S. Briggs , David O'Hagan , Judith A.K. Howard , Dmitrii S. Yu®t
a,*
b
a
School of Chemistry and Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, UK
b
Science Laboratories, Department of Chemistry, University of Durham, South Road, Durham DH13LE, UK
Received 24 May 2002; received in revised form 11 June 2002; accepted 3 August 2002
Dedicated to Professor Tatlow on the occasion of his 80th birthday.
Abstract
The conformation of 2-¯uoro-N-(2-¯uoroethyl)-propionamide 4 in the solid state indicates the in¯uence of both a b-¯uorine-amide gauche
effect and an a-¯uoroamide effect. The structure reveals the in¯uence of two recently observed stereoelectronic effects associated with the
C±F bond, which has resulted in the successful prediction of the solid state conformation of amide 4. A gauche relationship (À69.98) was
observed for atoms N(1)±C(4)±C(5)±F and a syn planar (2.08) relationship was observed for N(1)±C(3)±C(2)±F. The paper demonstrates the
predictive power of using the C±F bond as a tool in in¯uencing the conformation of amides and peptides.
#
2002 Elsevier Science B.V. All rights reserved.
Keywords: Bond; Amide; Conformation
1
. Introduction
carbonyl and syn to the N±H bond as depicted in 1. In that
study we reported the X-ray structures of a-¯uoroamides and
in each case the O=C±C±F atoms had a trans planar con-
formation. An ab initio calculation measuring the rotational
The ¯uorine atom is sterically the closest to hydrogen and
many studies, both theoretical and experimental, suggest
that the steric in¯uence of ¯uorine over hydrogen is very
small [1,2]. Also carbon-bound ¯uorine and carbon-bound
hydrogen are poor hydrogen bonding partners and thus the
introduction of ¯uorine for hydrogen in an organic molecule
does not signi®cantly increase the co-ordinating ability at
that centre [3,4]. However, electronically the difference
between the two is profound and the replacement of ¯uorine
for hydrogen in organic compounds can change signi®cantly
the properties of a given system, particularly when the
0
energy pro®le of a model a-¯uoroamide 1 (R, R ˆ Me)
À1
indicated a deep energy well of up to 8.0 kcal mol with an
À1
energy difference of ꢀ7.0 kcal mol between the cis and
trans conformers. A similar but weaker effect is also
observed in a-¯uoroaldehydes [10], a-¯uoroketones [11]
and a-¯uoroesters [12]; but the energy difference between
the cis and trans conformations in these cases is smaller (0.8±
À1
2.0 kcal mol ).
¯
uorine atom is located close to functional groups [5,6].
The dif®culty of course is predicting the impact of such a
uorine substitution and this dif®culty has led to some
¯
frustration in anticipating the behaviour and reactivity of
selectively ¯uorinated compounds leading to such terms as
`
¯ustrates' being coined [7], which testify to this dif®culty.
We have recently described two conformational effects
associated with the C±F bond in selectively ¯uorinated
amides [8,9]. The ®rst highlighted the preferred conforma-
tion of the F±C±C(O)±N(H) moiety in a-¯uoroamides where
the C±F bond prefers to adopt a conformation anti to the
The second stereoelectronic involving C±F bonds in
amides reported [9] that N-b-¯uoroethylamides preferred a
conformation which had the C±F and C±N(CO) bonds gauche
rather than anti to each other as shown in structure 2.
Theoretical calculations on an N-acetyl-b-¯uoroethylamine
model system 2 (R ˆ Me) predicted the gauche conformation
*
Corresponding author. Tel.: ‡44-1334-467176;
fax: ‡44-1334-463808.
E-mail address: do1@st-andrews.ac.uk (D. O'Hagan).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 2 4 3 - 9

10
C.R.S. Briggs et al. / Journal of Fluorine Chemistry 119 (2003) 9±13
Table 1
Ê
Bond lengths (A) for amide 4
O(1)±C(3)
N(1)±C(3)
N(1)±C(4)
F(1)±C(2)
1.229(5)
1.320(5)
1.458(6)
1.395(5)
F(2)±C(5)
C(1)±C(2)
C(2)±C(3)
C(4)±C(5)
1.350(10)
1.507(8)
1.544(6)
1.476(9)
Fig. 1. The gauche preference for 1,2-difluoroethane.
Table 2
Bond angles (8) for amide 4
C(3)±N(1)±C(4)
F(1)±C(2)±C(1)
F(1)±C(2)±C(3)
C(1)±C(2)±C(3)
O(1)±C(3)±N(1)
122.3(4)
O(1)±C(3)±C(2)
N(1)±C(3)±C(2)
N(1)±C(4)±C(5)
F(2)±C(5)±C(4)
117.9(3)
116.8(3)
112.3(4)
112.1(6)
108.9(4)
109.6(3)
111.5(4)
125.2(4)
Fig. 2. Conformational mobility in amides. Rotations around C±C(O) and
0
N±C dictate R and R orientations.
Table 3
À1
Torsion angles (8) for amide 4
to be 1.8 kcal mol lower in energy than the anti conforma-
tion and this conformation persisted in X-ray crystal struc-
C(4)±N(1)±C(3)±O(1)
À0.5(6)
F(1)±C(2)±C(3)±N(1)
2.0(5)
tures of small molecule models. The classical gauche effect in
¯
C(4)±N(1)±C(3)±C(2) À179.2(4)
F(1)±C(2)±C(3)±O(1) À176.9(4)
C(1)±C(2)±C(3)±N(1) À118.6(4)
C(3)±N(1)±C(4)±C(5) 114.1(5)
N(1)±C(4)±C(5)±F(2) À62.9(6)
uorine chemistry recognises that 1,2-di¯uoroethane 3
Fig. 1) prefers a gauche rather than an anti conformation
C(1)±C(2)±C(3)±O(1)
62.6(5)
(
with a stabilisation energy measured between 0.5 and
À1
0
.9 kcal mol [13±16]. Clearly this ¯uorine-amide gauche
effect as depicted for 2 has approximately a two- to three-fold
increase in stabilisation energy of the gauche versus the anti
conformer relative to 1,2-di¯uoroethane 3.
amine is substituted by ¯uorine with predominant retention
of con®guration [17,18]. Treatment of 6 with phthaloyl
chloride followed by distillation generated 2-¯uoropropio-
nyl chloride 7. The acid chloride 7 was then coupled to 2-
¯uoroethylamine to generate amide 4 (Scheme 1). Enantio-
meric analysis of the resulting (S)-2-¯uoro-N-(2-¯uor-
oethyl)-propionamide 4 was determined to be 80% ee,
consistent with previous analysis of this diazotisation reac-
tion [8].
Amide 4 is a liquid at room temperature, however an X-
ray structure was solved by generating a crystal in a glass
capillary at low temperature (see Sections 3 and 3.4;
Tables 1±3).
Analysis of the X-ray structure of 4 (Fig. 3a) shows the
C±F bond a- to the amide carbonyl orientated cis to the N±
H and trans to the C=O bond, with the N(1)±C(3)±C(2)±F
torsion angle of 2.0(5)8 close to the optimal planar situation
and consistent with previous observations [8]. Also for the
b-¯uoroethylamide moiety, the C±F and C±N bonds adopt
a near optimal gauche arrangement relative to each other
with a N(1)±C(4)±C(5)±F dihedral angle of À62.9(6)8.
Again this conformation is consistent with previous obser-
vations [9].
Following from these observations it was anticipated that
the preferred conformation around an amide bond could be
controlled by the strategic placement of ¯uorine atoms. The
amide bond is planar over six atoms (C±CO±NH±C), with
rotational possibilities around the CO±C and N±C and NC±
C bonds (Fig. 2) in¯uencing the conformation beyond these
six atoms. In this paper we report the synthesis and solid
state structure of amide 4, a molecule which incorporates
two ¯uorine atoms, one on each side of the amide bond. The
molecule was designed such that the stereoelectronic in¯u-
ence of the two C±F bonds and the planarity of the amide
group would allow the minimum energy conformation of the
entire molecule to be predetermined based on previous
observations [8,9].
2
. Results and discussion
Amide 4 was prepared from (S)-alanine 5 by a diazotisa-
tion reaction in the presence of HF-pyridine whereby the
Scheme 1. Reagents and conditions: (i) HF/pyridine (70/30), NaNO
RT, 4 h.
2
; (ii) phthaloyl dichloride, reflux, 4 h; (iii) FCH
2
CH
2
NH
3
Cl, pyridine, DCM, À78 8C to

C.R.S. Briggs et al. / Journal of Fluorine Chemistry 119 (2003) 9±13
11
Fig. 3. (a) The X-ray structure of 4 showing the gauche relationship between C±F and C±N(CO) and the planar conformation around F±C. The
absolute configuration of the molecule could not be determined by X-ray crystallography and the molecule shown corresponds to the expected
diastereoisomer based on an origin of (S)-alanine as a starting material. (b) The intermolecular interactions in the crystal packing of 4 is dominated by
hydrogen bonding.

12
C.R.S. Briggs et al. / Journal of Fluorine Chemistry 119 (2003) 9±13
3
From the unit cell image of the X-ray structure it can be
seen that molecules in the crystal are linked together in
1.62 (3H, dd, 2J
5.01 (1H, dq, 2J
ˆ 6:9 Hz and J
ˆ 23:6 Hz, CH );
HÀH
HÀH
HÀF
HÀF
3
2
ˆ 6:9 Hz and J
ˆ 48:6 Hz, CHF);
1
3
chains along the c-direction by NÀH Á Á Á Oꢁx; y; z ‡ 1†
10.29 (1H, s (br), OH); C NMR (75 MHz, CDCl ); d
3
C
Ê
Ê
2
hydrogen bonds (N Á Á Á O 2:870ꢁ4† A, H Á Á Á O 2:06ꢁ6† A,
(ppm) 18.1 (d,
1
JCÀF ˆ 22:1 Hz, CH3); 85.0 (d,
ꢂ
2
angle NÀH Á Á Á 153ꢁ4† ). There are no signi®cantly short
JCÀF ˆ 181:9, CHF); 176.3 (d, JCÀF ˆ 24:3 Hz, COOH);
1
2
9
intermolecular contacts between ¯uorine and hydrogen and
clearly the weak F Á Á Á H bonding interactions are overridden
by the much stronger hydrogen bonding between amide
groups.
F NMR (282 MHz, CDCl ); d (ppm) ˆ 185.5 (1F, dq,
3
F
3
JHÀF ˆ 48:5 and JHÀF ˆ 22:7 Hz), CIMS m/z (%): 93
(M ‡ 1, 100.0%). 2-Fluoropropionic acid 6 (1.77 g,
0.02 mol) and phthaloyl dichloride (5.87 g, 0.03 mol) were
heated under re¯ux for 4 h. The resulting acid chloride 7 was
distilled from the reaction mixture as a clear oil (0.86 g,
In conclusion it has been shown that the C±F bond adopts
a preferred gauche conformation to the C±N±(CO) bonds in
the N-b-¯uoroamide moiety and also adopts a preferred syn
conformation to the C±N(CO) bond in the a-¯uoroamide
moiety in the solid state. This outcome is essentially that
predicted on the basis of the previous evaluated in¯uence of
the C±F bond in other amide systems [8,9].
In view of the limited steric impact of ¯uorine over
hydrogen and with an awareness of the stereoelectronic
in¯uence of the C±F bond when placed adjacent to amide
bonds, the current observation suggests that the strategic
incorporation of the C±F bond into peptides could play a role
in the design and control of the conformation of a medicin-
ally important compounds.
1
38%); bp 54±56 8C ([19] 56 8C); H NMR (300 MHz,
2
CDCl ); d (ppm) ˆ 1.68 (3H, dd, JHÀH ˆ 6:9 and
3
H
3
2
JHÀF ˆ 23:0 Hz, CH ); 5.14 (1H, dq, JHÀH ˆ 6:9 Hz
3
2
19
and JHÀF ˆ 48:6 Hz, CHF); F NMR (282 MHz, CDCl );
3
d
J
(ppm)
ˆ
171.5 (1F, dq, 2J
ˆ 48:5 and
F
HÀF
3
ˆ 22:7 Hz). 2-Fluoropropionyl chloride 7 (0.86 g,
HÀF
7.83 mmol) in dry DCM (15 ml) at À78 8C and added
drop-wise to a stirred solution of 2-¯uoroethylamine hydro-
chloride (0.78 g, 7.83 mmol) and dry pyridine (0.76 ml,
9.37 mmol) in dry DCM (10 ml) also at À78 8C (dry ice/
IPA). The resulting bright orange solution was stirred and
allowed to warm slowly to ambient temperature over a
period of 4 h. The reaction mixture was quenched by addi-
tion of water (50 ml) and the product extracted into DCM
3
. Experimental
(3 Â 25 ml), dried (MgSO ), and concentrated under
4
reduced pressure to yield 4 as a viscous pale yellow oil
1
3
.1. General experimental procedures
(0.96 g, 90%); IR (neat, NaCl disc) 3427, 1671; H NMR
1.54 (3H, dd,
(
300 MHz, CDCl3); dH (ppm)
ˆ
2
3
HF/pyridine (70/30) was purchased from Acros Organics
Ltd. Sodium nitrite (Aldrich) was heated under vacuum at
40 8C for 4 h and solvents were dried and distilled prior to
J
ˆ 6:6 Hz and J
ˆ 24:6 Hz, CH ); 3.58 (2H, dq,
HÀF
HÀH
HÀH
HÀH
HÀF
HÀF
3
2J
2J
2J
ˆ 5:9 and J
3
ˆ 27:4 Hz, NHCH ); 4.48 (2H, dt,
2
3
1
ˆ 4:6 Hz and J
ˆ 47:4 Hz, CH F); 4.98 (1H, dq,
HÀF
2
2
use. Reactions requiring anhydrous conditions were carried
out under nitrogen. FT-IR spectra were recorded using a
Perkin-Elmer 2000 FT-IR as undiluted oils. NMR spectra
ˆ 6:7 Hz and J
ˆ 49:2 Hz, CH F); 6.80 (1H, s
HÀF
2
1
3
(br), NH); C NMR (75 MHz, CDCl ); d (ppm) 18.7
3
C
(d,2J
ˆ 21:6 Hz, CH3); 39.8 (d,
2
J
ˆ 19:4 Hz,
CÀF
CÀF
2
1
CH NH); 82.7 (d, 1J
were recorded on a Bruker Advance 300 MHz ( H at
3
ˆ 167:5 Hz, CH F); 89.1 (d,
2
CÀF
00.06 MHz, 13C at 74.45 MHz, 19F 282.3) spectrometer
in CDCl . Mass spectroscopy data were recorded on a VG
1
2
J
9
CÀF
ˆ 183:0, CHF); 171.5 (d,
J
CÀF
ˆ 19:4 Hz, CO);
1
3
F NMR (282 MHz, CDCl ); d (ppm) ˆ 183.2 (1F, ddq,
3
F
2J
lapses to
extraction); ±224.9 (1F, tt,
2J
ˆ 49:5 Hz,
3
J
ˆ 24:7 Hz,
4
J
ˆ 4:1 Hz col-
Autospec instrument. Preparative gas liquid chromatogra-
phy (GLC) was performed on a Varian Aerograph Model
9
FÀH
FÀH
FÀH
2
3
J
ˆ 48:6 Hz and
J
ˆ 24:7 after D O
FÀH
HÀF
2
2
20 (catharometer detector) gas chromatograph.
J
ˆ 47:4 Hz and
FÀH
‡
ˆ 27:8 Hz). CIMS m/z (%): 138 (M , 100.0%) HRMS
FÀH
3.2. Synthesis of 2-fluoro-N-(2-fluoroethyl)-
propionamide 4
(CI) calcd. for C H F NO (M ‡ 1) 138.0730 found 138.0737
5
9 2
(D ˆ À4:9 ppm).
(S)-Alanine (7.13 g, 0.08 mmol) 5 and HF/pyridine (70/
0) (100 ml) were stirred in a Te¯on bottle and cooled to
3.3. Chiral analysis
3
À78 8C (dry ice/IPA). NaNO (8.40 g, 0.12 mmol) was
Chiral GC±MS analysis of 4 was conducted using a
Supelco 24304 BetaDex 120 fused silica capillary column
(30:0 m  250 mm) on an Agilent HP 5890 instrument with a
5973N mass selective detector and 7683 series injector. The
2
added portion-wise with stirring. The reaction mixture
was left to reach ambient temperature over 4 h and stirred
for a further 12 h. The reaction was quenched by pouring
À1
into ice water (100 ml) and the product extracted into Et O
2
carrier gas was helium, with a ¯ow rate of 1.1 ml min and
a split ratio of 30:1. The injection volume was 1 ml and the
injection port temperature was 250 8C. The temperature
(
reduced pressure. Distillation afforded (S)-2-¯uoropropionic
3 Â 100 ml), dried (MgSO ) and concentrated under
4
À1
acid 6 as a clear oil (1.96 g, 27%); IR (neat, NaCl disc) 3327,
1
pro®les were 90 8C (50 min) then 25 8C min to 130 8C
(hold 30 min). The (S) enantiomer eluted (16.7 min) before
1
617, 1449, 1125; H NMR (300 MHz, CDCl ); d (ppm) ˆ
3
H

C.R.S. Briggs et al. / Journal of Fluorine Chemistry 119 (2003) 9±13
13
the (R) enantiomer (18.02 min) and indicated a ratio of 9:1 in
favour of (S).
Acknowledgements
We thank the EPSRC for funds to support a Studentship
(CRSB).
3
3
.4. X-ray crystal structure analysis
.4.1. Crystal data for 4
C H F NO, M ˆ 137:13, monoclinic, space group P2 ,
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2
1
Ê
a ˆ 4:5366(9), b ˆ 16:608(3), c ˆ 5:103(1) A, b ˆ
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Ê
1
1
13:94(3)8, U ˆ 351:4(1) A , Fꢁ000† ˆ 144, Z ˆ 2, Dc ˆ
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[
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.2186 for all data (399 re®ned parameters), conventional
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4
789.
[
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Ê
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0
[
[
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2
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[
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