Emergence of a single solid chiral state from a nearly racemic amino acid derivative

Article abstract of DOI:10.1021/ja7106349

The evolution of a single chiral solid state is reported for an amino acid derivative starting from a nearly racemic mixture of solid left- and right-handed crystals. Attrition-enhanced dissolution and recrystallization processes based on solubility considerations of the Gibbs-Thomson rule, coupled with solution-phase racemization, drive this near-equilibrium system inexorably to single chirality in the solid phase. Copyright

Full text of DOI:10.1021/ja7106349

Published on Web 01/04/2008
Emergence of a Single Solid Chiral State from a Nearly Racemic Amino Acid
Derivative
Wim L. Noorduin,† Toshiko Izumi,‡ Alessia Millemaggi,§ Michel Leeman,| Hugo Meekes,†
Willem J. P. Van Enckevort,† Richard M. Kellogg,*,| Bernard Kaptein,*,§ Elias Vlieg,*,† and
Donna G. Blackmond*,‡
IMM Solid State Chemistry, Radboud UniVersity Nijmegen, ToernooiVeld 1, 6525 ED Nijmegen, Netherlands,
Department of Chemistry and Department of Chemical Engineering, Imperial College, London SW7 2AZ U.K., DSM
Pharmaceutical ProductssAdVanced Synthesis, Catalysis & DeVelopment, P.O. Box 18,
6160 MD Geleen, Netherlands, and Syncom B.V., Kadijk 3, 9747 AT Groningen, Netherlands
Received November 27, 2007; E-mail: r.m.kellogg@syncom.nl; Bernard.Kaptein@dsm.com; e.vlieg@science.ru.nl;
d.blackmond@imperial.ac.uk
Scheme 1. Analogy between Solid-Solution Equilibrium for (a) an
Intrinsically Achiral Molecule; and (b) a Chiral Molecule
Undergoing Solution-Phase Racemization
Understanding how the single-handedness of biological molecules
came about has been of intense interest since Pasteur first separated
mirror-image crystals of a tartrate salt.1 Several models have been
proposed to address the question of how enantiomerically pure
solutions or crystalline phases could have emerged from a presum-
ably racemic prebiotic world.2-9 Viedma6 recently demonstrated
the inexorable and random emergence of solid-phase single chirality
for the intrinsically achiral inorganic compound NaClO3 initially
present as a racemic mixture of two enantiomorphic solid phases
in equilibrium with the achiral aqueous phase (Scheme 1a). Grinding
the slurry of crystals with glass beads promotes dynamic dissolution/
crystallization processes that result in the conversion of one solid
enantiomorph into the other. The conversion relies on the fact that
the solid-phase chiral identity of the intrinsically achiral NaClO3
is lost upon dissolution.
Scheme 2. Chemical and Physical Equilibria in the Racemization
and Crystallization/ Dissolution Processes for 1
An intriguing analogy to this simple demonstration of “chiral
amnesia”10 is presented by a molecular system of true enantiomers
that forms separate R and S solid-phase crystals (known as a
conglomerate11), and that can be induced to undergo racemization
in solution.10,12 (Scheme 1b). We report here the first experimental
proof-of-concept for the emergence of a single solid-phase chiral
state for an intrinsically chiral molecule starting from a nearly
racemic mixture of enantiomorphic crystals. This finding extends
Viedma’s model to biologically relevant enantiomeric molecules,
holding profound implications for our understanding of the origin
of single chirality in living systems.
The imine of 2-methyl-benzaldehyde and phenylglycinamide 1
(Scheme 2) forms a conglomerate in the solid phase and racemizes
rapidly in solution with added base (t1/2 < 2 min at 25 °C with the
organic base DBU in MeOH, pKa ) 12). Solution-solid mixtures
of 1 (4 g) at varying overall ee were magnetically stirred (1250
rpm) at ambient temperature in MeOH or MeCN (36 g) in the
absence and in the presence of 2.5 mm glass beads (10 g). After
establishing solution-solid equilibrium, solution-phase racemization
was initiated by adding DBU (5 mol %). Samples of the solid were
collected over time and the enantiomeric purity was measured using
two independent chiral HPLC methods. Experiments were carried
out in all participating laboratories.
single solid chiral state from an initial small imbalance in crystal
composition as low as 2-3% ee (see Figure 1 (left) and Supporting
Information). The solid of single chirality thus obtained is stable
over time in the presence of the racemizing solution. For a stirred
slurry in the absence of glass beads, the solid phase ee remained
unchanged from its initial value.
This result demonstrates that a slight enantioimbalance in 1
directs the trend to a single solid chiral state. We also observed
that seeding a racemic system of crystals of 1 with chiral additives
could also direct the establishment of a single chiral solid. For
example, concentrations as low as 0.1 mol % enantiopure phenyl-
glycine (Phg) as an additive provide a sufficient chiral bias for
achieving attrition-induced solid-phase single chirality (Figure 1,
right).13-16 (S)-Phg leads to an R chiral end state, (R)-Phg to S
chirality, and with a resolution time that decreases for higher Phg
concentrations.
These findings may be rationalized taking into account Viedma’s6
model involving a dynamic process of crystal dissolution and
growth enhanced by attrition, along with considerations of total
surface area as a driving force for crystal growth. According to the
Gibbs-Thomson rule, smaller crystals produced by attrition dis-
solve more readily than larger ones. In a saturated solution, this
leads to Ostwald ripening17 in which large crystals grow at the cost
of smaller ones regardless of their handedness. A small imbalance
in the handedness of large compared to small crystals may occur
because of a small initial enantiomeric excess or may be induced
by minute amounts of chiral species present in the solution. In the
In the presence of glass beads, which impart mechanical energy
to the system inducing continuous attrition of the crystals, we found
that the ee of the solid rises inexorably over time, evolving to a
† Radboud University Nijmegen.
‡ Imperial College.
§ DSM Pharmaceutical ProductssAdvanced Synthesis, Catalysis & Develop-
ment.
| Syncom B.V.
9
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J. AM. CHEM. SOC. 2008, 130, 1158-1159
10.1021/ja7106349 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
absence of accelerating influences. Our results demonstrate for the
first time that the concept of attrition-enhanced solid-phase enan-
tioenrichment may be extended from simple achiral salts to include
biologically relevant enantiomeric molecules such as those respon-
sible for recognition, replication, and ultimately for the chemical
basis of life.26
Acknowledgment. Authors from Syncom, DSM, and Radboud
University are grateful for partial support from SNN (Cooperation
Northern Netherlands) and the European Fund for Regional
Development (EFRO). D.G.B. acknowledges funding from the
EPSRC and AstraZeneca. D.G.B. is grateful for stimulating
discussions with C. Viedma, J.S. Bradley, A. Armstrong, J. Blacker,
and M. Klussmann. D.G.B. holds a Royal Society Wolfson Research
Merit Award.
Figure 1. Attrition-enhanced evolution of solid-phase ee for 1 in MeCN:
(left) starting from initial ee values of 1 as shown; (right) starting from
racemic 1 with added Phg as shown. Lines are a guide to the eye.
latter case, Lahav’s “rule of reversal”18,19 applies. The continued
fragmentation of crystals by attrition also provides a relative increase
in the surface area of the hand that has established an excess.
Although crystal growth and dissolution have approximately equal
rates under near equilibrium conditions, the attrition-enhanced
asymmetry described here coupled with solution-phase racemization
produces a net flow of mass allowing depopulation of one chiral
solid state toward the other via the solution phase. Paradoxically,
the “chiral amnesia” induced by solution racemization provides the
driving force for the evolution of solid-phase single chirality.6,10
Crystallization-induced transformations of conglomerates as a
route to chiral purification is practiced extensively for diastereomers
that epimerize in solution,20 taking advantage of a difference in
solubility. Our results stand in striking contrast to Dimroth’s
principle, which although applied today primarily to the separation
of diastereomers, was originally formulated for the general case of
coupled physical and chemical equilibria. According to this
principle, a general system as shown in Scheme 1b of two solid
enantiomorphs in equilibrium with a solution in which racemization
occurs represents a balance such that solid-phase enrichment should
not occur.20-22 In our example, the continuous grinding of the solid
enantiomorphs creates the essential solubility gradient for the
dissolution and recrystallization processes that drive the system until
all the solid material of one enantiomer is converted to the solid of
the opposite hand. Once a state of single chirality is achieved, the
system is “locked”, because primary nucleation to form and sustain
new crystals from the opposite enantiomer in the racemizing
solution is kinetically prohibited under the conditions of the
experiment. This provides a stable, irreversible route to extremely
enantiopure compounds in high yield and with productivity limited
only by the amount of solid material present at the outset. These
concepts may readily be extended to other chiral systems.
Thus the emergence of a state of solid-phase single chirality for
true enantiomers may be achieved in a near equilibrium process
through an interplay between attrition-catalyzed dissolution and
Ostwald ripening of crystals. This route to single chirality may be
compared with physical models invoking, on the one hand,
thermodynamic control for solution-phase enantioenrichment,7,23
and on the other hand, “far-from-equilibrium” crystallization
processes.2a,5,24,25
The state of solid-phase single chirality for an enantiomeric
compound that forms a conglomerate is not more stable than the
racemic state for the same size and number of crystals12 but simply
represents a kinetic trap accessible on our time scale due to
acceleration of both crystal dissolution/growth and racemization.
Thermodynamics dictates that single chirality may ultimately be
achieved over eons of time, as in a prebiotic scenario, even in the
Supporting Information Available: Details concerning experi-
mental and analytical procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
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