The Emergence of Solution Phase Homochirality

via Crystal Engineering of Amino Acids

- Supporting Information Martin Klussmann, Toshiko Izumi, Andrew J. P. White, Alan Armstrong, Donna G. Blackmond
Department of Chemistry and Department of Chemical Engineering and Chemical Technology,
Imperial College, London SW7 2AZ, United Kingdom
d.blackmond@imperial.ac.uk

Materials
All chemicals were obtained from commercial sources (Fluka, Aldrich, Acros) and used as
received, water was distilled from a Bibby Sterilin D4000 water still.

Screening experiments
Heterogeneous mixtures of a scalemic amino acid (non-racemic, non-enantiopure, typically
around 50% ee) and additive (generally 1.0 molar equivalents, urea: 54w%) were stirred in
water (typically 2-4ml) at room temperature for at least 12 hours before a solution sample was
taken by syringe filration for determination of amino acid ee by RP-HPLC (see ref (1) for
details). In all experiments, excess solid was used to ensure solutions saturated both in the
enantiopure and racemic solid phase. Generally, only a single measurement was done for the
screening. In case of a significant deviation from the eutectic ee of the amino acid without
additive, a solid sample was taken to ensure its ee was scalemic. Deviations of the measured
solution % ee from the amino acid eutectic % ee up to 3% were generally regarded as
insignificant.

Detailed study: Valine and fumaric acid

The experiments were performed at 25C, values given are an average of at least two samples;
otherwise as described above for the screening experiments.
Table 2: Solution data for DL-valine and fumaric acida
b
c
d
d
# [Val]0b
[fum]0
fum eq
[Val]
[fum]
e
1
0.00
74.1
0.0
2 87.2
2.9
0.03
74.7
0.7
3 87.4
29.9
0.35
29.4
1.0
4 87.4
43.0
0.50
9.2
4.0
5 97.8
96.6
1.00
7.1
7.3
a) In water at 25C, equilibration time 18-79 hours, concentration values in mg/g water, fum: fumaric
acid; b) initial total composition; c) initial molar ratio; d) solution concentration; e) value taken from ref.
(1).

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Table 3: Solution data for L-valine and fumaric acida

b
c
d
d
# [Val]0b
[fum]0
fum eq
[Val]
[fum]
e
1
0.00
60.1
0.0
2 81.2
12.1
0.15
66.0
6.6
3 49.8
10.8
0.22
49.9
10.3
4 59.4
14.9
0.25
48.6
9.4
5 50.2
20.8
0.42
40.2
12.3
6 81.5
98.2
1.22
40.6
11.9
a) In water at 25C, equilibration time 13-79 hours, concentration values in mg/g water, fum: fumaric
acid; b) initial total composition; c) initial molar ratio; d) solution concentration; e) value taken from ref.
(1).

Table 4: Solution data for D/L-valine in the presence of an excess solid fumaric acida
b

# [Val]0
ee0
[fum]0
fum eq
ee
1 150.1
44.4
74.0
0.50
98.9
2 149.5
44.8
111.8
0.75
98.8
3 149.0
44.5
148.6
1.01
98.9
4 150.5
44.3
301.5
2.02
98.9
5 85.4
75.8
99.3
1.17
99.2
a) In water at 25C, equilibration time 5-116 hours, concentration values in mg/g water, fum: fumaric
acid; b) initial total composition; c) initial molar ratio; d) solution composition.

Detailed study: Phenylalanine and fumaric acid

The experiments were performed at 25C, values given are an average of at least two samples;
otherwise as described above for the screening experiments.
Table 5: Solution data for D/L-phenylalanine in the presence of an excess solid fumaric acida
b

bc

#
[Phe]0
ee0
[fum]0
fum eq
ee
1
171.6
50.1
85.7
0.71
98.5
2
172.8
49.9
172.8
1.42
98.6
3
169.6
50.0
254.1
2.13
98.7
4
172.4
50.0
344.2
2.84
98.2
a) In water at 25C, equilibration time 16-87 hours, concentration values in mg/g water, fum: fumaric
acid; b) initial total composition; c) initial molar ratio; d) solution composition.

Crystal studies
L-valine-fumaric

acid

The crystals were grown from an aqueous solution (3:1 L-valine : fumaric acid) by indiffusion of ethanol. (CCDC 627007).
DL-valine-fumaric

acid

Cocrystals with a 2:1 ratio were grown from an aqueous solution (2:1 DL-valine : fumaric
acid) by slow evaporation and were found to be identical to a structure reported previously in
the literature.2

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L-phenylalanine-fumaric

acid

Cocrystals with a 1:1 ratio were grown from an aqueous solution (2:1 L-phenylalanine:
fumaric acid) by evaporation and were found to be identical to a structure reported previously
in the literature.3
DL-phenylalanine-fumaric

acid

The crystals were grown from an aqueous solution (1:1

evaporation.

DL-phenylalanine

: fumaric acid) by

The asymmetric unit of the structure of DL-phenylalanine-fumaric acid contains one

molecule of phenylalanine and one molecule of fumaric acid (see Figure 1b in the manuscript
and Figure 4 here). The three NH protons of the phenylalanine molecule [on N(3)] and the
two OH protons of the fumaric acid [on O(25) and O(27)] are all involved in hydrogen
bonding to the two non-protonated oxygen atoms in the phenylalanine molecule [O(5) and
O(6)], and O(24) in the fumaric acid. Strangely, the O(26) oxygen atom of the fumaric acid
moiety is not involved in these hydrogen bonding interactions; the reasons for this are not
immediately apparent. These hydrogen bonds serve to form two-molecule-thick sheets,
bounded on their upper and lower faces by the pendent phenyl rings, giving the sheets a
corrugated profile (part of one of these sheets is shown in Figure 5). Adjacent sheets are offset
such that the protruding phenyl rings of one layer fit into the gap between phenyl rings in the
next, as shown in Figure 6. Adjacent fumaric acid molecules are interlinked by CHO
hydrogen bonds, as shown in Figure 7.
Crystal data for DL-phenylalanine-fumaric acid: (C9H11NO2)(C4H4O4), M = 281.26,
triclinic, P1 (no. 2), a = 5.499(3), b = 11.661(5), c = 11.909(5) , = 64.67(4), = 78.00(4),
= 84.17(4), V = 675.1(5) 3, Z = 2, Dc = 1.384 g cm3, (Cu-K) = 0.941 mm1, T = 173 K,
colourless needles, Oxford Diffraction Xcalibur PX Ultra diffractometer; 2092 independent
2
!measured reflections, F refinement, R1 = 0.050, wR2 = 0.126, 1355 independent observed
absorption-corrected reflections [|Fo| > 4(|Fo|), 2max = 126], 201 parameters. The NH and
OH protons were located from F maps and refined subject to an XH distance constraint of
0.90 . CCDC 634490.

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Figure 4 The asymmetric unit of DL-phenylalanine-fumaric acid showing the hydrogen

bonding interactions between the phenylalanine and fumaric acid molecules (50%
probability ellipsoids). The hydrogen bonding geometries [XO, HO (), X
HO ()] are a) 2.920(3), 2.03,170; b) 2.791(3), 1.89, 177; c) 2.871(3), 2.04, 152;
d) 2.564(3), 1.70, 161; e) 2.636(3), 1.77, 161.

Figure 5 View down the crystallographic a axis direction of part of one of the 2D sheets of
DL-phenylalanine and fumaric acid molecules present in the crystals of DLphenylalanine-fumaric acid, formed by the intermolecular NHO and OHO
hydrogen bonding.

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Figure 6 The packing of adjacent sheets in the structure of DL-phenylalanine-fumaric

acid showing how the protruding phenyl rings of one sheet fit into the gap
between phenyl rings of the next.

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Figure 7 The packing of adjacent fumaric acid molecules along the a axis direction present
in the crystals of DL-phenylalanine-fumaric acid showing the CHO contacts.
The CHO geometries [CO, HO (), CHO ()] are f) 3.547(3), 2.60, 171;
g) 3.770(3), 2.83, 167.

Supplementary references
(1) Klussmann M, White AJP, Armstrong A, Blackmond DG (2006) Angew. Chem. Int. Ed.
45:7985-7989.
(2) Alagar M, Krishnakumar RV, Subha Nandhini M, Natarajan S (2003) Acta Cryst.
E59:o857-o859.
(3) Alagar M, Krishnakumar RV, Rajagopal K, Nandhini MS, Natarajan S (2003) Acta
Cryst. E59:o952-o954

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