Solution-phase racemization in the presence of an enantiopure solid phase

Article abstract of DOI:10.1002/chem.200902983

Solution-phase racemization drives the evolution of single chirality in the solid phase by the "chiral amnesia" process first described by Viedma. The current investigations lay the basis for a better understanding of the mechanism of the solid-phase dera

Full text of DOI:10.1002/chem.200902983

DOI: 10.1002/chem.200902983
Solution-Phase Racemization in the Presence of an Enantiopure Solid Phase
Cristobal Viedma,*[a] Bastiaan J. V. Verkuijl,[b] Josꢀ E. Ortiz,[d] Trinidad de Torres,[d]
Richard M. Kellogg,*[c] and Donna G. Blackmond*[b, e]
Abstract: Solution-phase racemization
drives the evolution of single chirality
in the solid phase by the “chiral amne-
sia” process first described by Viedma.
The current investigations lay the basis
for a better understanding of the mech-
anism of the solid-phase deracemiza-
tion by uncoupling the chemical rate
processes associated with the intercon-
version of enantiomers in the solution
phase from the physical processes asso-
ciated with solution–solid phase trans-
fer via dissolution and reaccretion of
molecules onto crystals. In addition,
the enantiomer concentration profiles
presented in this work, together with
an analytical treatment of the racemi-
zation process in the presence of excess
enantiopure solid, unequivocally recon-
firm the validity of the Meyerhoffer
double solubility rule for systems
under solution racemization conditions.
Keywords: amino acids · chirality ·
deracemization
·
enantioenrich-
ment · racemization
Introduction
scribing how an initial imbalance between enantiomers
might have come about, together with mechanisms for am-
plifying this imbalance, have been proposed as an explana-
tion for the origin of biomolecular single handedness.[3–12]
Most prominent among these are far-from-equilibrium
models that include stochastic symmetry breaking coupled
with autocatalytic amplification associated with crystalliza-
tion phenomena, such as Kondepudiꢀs “Eve crystal”
model,[7] or chemical systems, such as the Soai reaction.[9]
Recent intriguing experimental observations of the evolu-
tion of solid-phase homochirality for mixtures of d and l
crystals offer a new model that is distinct from these mecha-
nisms, representing a near-equilibrium interplay between ki-
netics and thermodynamics in a system that combines physi-
cal phase behavior with chemical reaction processes. The
original observations were made by Viedma,[11] who demon-
strated that a racemic mixture of the two enantiomorphic
crystals of the achiral salt NaClO3 in equilibrium with its sa-
turated solution is driven inexorably over time to a single
chiral solid, aided by the energy input from abrasive grind-
ing of the crystals. Simultaneously, but independently, Black-
mond[13] and Viedma[14] suggested that this phenomenon
could be extended to intrinsically chiral compounds that rac-
emize in solution, and this proposal has since been verified
experimentally for amino acid derivatives,[15] for the pro-
teinogenic amino acid aspartic acid,[16] and for the amine
product of a reversible Mannich reaction.[17]
One of the greatest unsolved problems in chemistry is the
origin of homochirality in the biosphere, that is, the fact that
l-amino acids and d-sugars dominate in nature, while labo-
ratory experiments produce a racemic mixture unless direct-
ed by an added chiral source.[1,2] Several mechanisms de-
[a] Prof. Dr. C. Viedma
Departamento Cristalografia-Mineralogia, Facultad Geologia
Universidad Complutense, 28040 Madrid (Spain)
Fax : (+34)913944872
E-mail: viedma@geo.ucm.es
[b] B. J. V. Verkuijl, Prof. Dr. D. G. Blackmond
Department of Chemistry
Imperial College London, SW7 2AZ London (UK)
[c] Prof. R. M. Kellogg
Syncom B.V., Kadijk 3, 9747 AT Groningen (The Netherlands)
Fax : (+31)505757399
E-mail: r.m.kellogg@syncom.nl
[d] J. E. Ortiz, T. de Torres
Laboratorio de Estratigrafꢁa Biomolecular
EscuelaTꢂcnica Superior de Ingenieros de Minas de Madrid
28040 Madrid (Spain)
[e] Prof. Dr. D. G. Blackmond
Present address:
Department of Chemistry
The Scripps Research Institute
La Jolla, CA 92037 (USA)
Fax : (+1)8587842180
The mechanism of this remarkable process is still under
vigorous discussion.[18–21] One of its most compelling features
lies in a paradox: the key driving force for the evolution of
E-mail: blackmond@scripps.edu
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FULL PAPER
solid-phase homochirality is solution racemization—a pro-
cess that conventionally erodes chiral discrimination—which
in this case provides a conduit between the two chiral solids.
Scheme 1 shows how solution racemization allows intrinsi-
Results and Discussion
The rate of racemization was studied for the two systems
shown in Scheme 2, aspartic acid (1) and N-(2-methylbenzy-
lidene)-phenylglycine amide (2), both of which are com-
pounds that we have previously shown undergo the “chiral
amnesia” process.[15,16] We monitored absolute concentration
profiles of both enantiomers as well as solution phase ee
under two sets of conditions. In one case, we followed race-
mization of the homogeneous enantiopure solution in which
the total number of solution phase molecules is fixed (Sche-
me 3a); in the other case we studied solution phase racemi-
zation in the presence of varying amounts of the enantio-
pure solid phase in equilibrium with the solution phase,
which thus provides a path for either addition or removal of
molecules to or from the solution phase (Scheme 3b).
Scheme 1. Solution–solid equilibrium for molecules forming chiral crys-
tals; a) achiral molecule, such as NaClO3; b) chiral molecules forming
racemic conglomerate crystals, such as aspartic acid.
cally chiral molecules to lose their solid-phase chiral history
and gain the opportunity to choose a new solid-phase chiral
destiny in the same way that an achiral molecule, such as
NaClO3, does when it dissolves from a chiral crystal. For
this reason we have used the term “chiral amnesia” to de-
scribe this enantioenrichment process.
Since solution-phase racemization is the key to the pro-
cess of solid-phase deracemization, our overall mechanistic
understanding will be aided by developing a full understand-
ing of this part of the process. A number of puzzling and
contradictory experimental observations have been made
concerning the relative rates of solution-phase racemization
and the overall deracemization process, suggesting that fur-
ther inquiry is necessary. Kaptein et al. showed that the rate
of solid-phase deracemization was proportional to the con-
centration of the base used to catalyze solution phase race-
mization.[22] This is curious because solution phase racemiza-
tion proceeds much more rapidly than the overall deracemi-
zation process, suggesting that the solution reaction should
not be rate determining. In contrast to this case, Tsogoeva
and colleagues noted that the solution racemization rate ap-
peared to be significantly slower than the solid phase dera-
cemization procecss.[17b] They invoked participation of the
solid in the racemization process to rationalize this result.
We report here solubility and enantiomeric excess meas-
urements in two different systems that help to uncouple the
solution chemical reaction from the physical processes of
dissolution/recrystallization. Our results show that the effect
of the presence of the solid phase on solution-phase racemi-
zation can be described without the need to invoke special
interactions at the solid–solution interface in these systems.
Further, we show that changes in solution phase ee, which is
a relative measurement, may be misleading unless they take
into account the absolute change in each enantiomer con-
centration. This work also reconfirms the validity of the
Meyerhoffer double solubility rule[23] for conglomerate sys-
tems under racemizing conditions.
Scheme 2. Systems employed in studying solution-phase racemization and
solid-phase deracemization.
Plots of ln(ee) versus time
are commonly used to measure
the solution phase racemization
rate constant.[24] Figure 1 shows
results for the racemization of
aspartic acid l-1 carried out in
the
presence
of
varying
Scheme 3. Racemization meas-
urements were carried out
starting from an enantiopure
saturated solution either in:
a) a homogeneous solution, or
b) the presence of the enantio-
amounts of the solid phase l-
amino acid. The rate of change
of solution phase ee shows a
clear dependence on the
amount of solid initially pres- pure solid.
ent.[25] In addition, for lower in-
itial amounts of solid the slope increases by approximately a
factor of two at longer racemization times, and it was ob-
served that less solid remained at the end of the experiment
than at the beginning.
A similar effect of the amount of solid was seen in race-
mization of the Schiff base system of Scheme 2b in the pres-
ence of enantiopure solid 2. The change in solution phase ee
as a function of time was found to be approximately a factor
of two lower in the presence of solid than it is for racemiza-
tion in the homogeneous solution. Decreasing the amount
of solid ultimately resulted in a rate of change of solution
phase ee equaling that measured in homogeneous solution
in the absence of solid (Figure 2).
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4933

D. G. Blackmond, R. M. Kellogg, C. Viedma et al.
(R)-2 concentration rises—behavior that is characteristic of
racemization in homogeneous solution in which the sum of
((R)-2+(S)-2) in solution is necessarily constant over the
course of the racemization. In the case of a large excess of
solid, however, we observe that while the (R)-2 concentra-
tion rises as expected during racemization, the concentration
of (S)-2 does not decrease, but remains essentially constant
over time (Figure 3b). This results in an overall increase—in
fact a doubling—of the total concentration of enantiomers
((R)-2+(S)-2) in solution when the system is fully equili-
brated. Thus, the solid phase rapidly replenishes the solution
phase with (S)-2 molecules to compensate for the loss of
those that are converted to (R)-2 molecules via racemiza-
tion. Figure 3 thus presents clear kinetic evidence of the val-
idity of the Meyerhoffer double solubility rule in the case of
racemizing enantiomers.
Figure 1. Log plot of the change in solution phase ee over time as a func-
&
*
^
tion of the amount of solid aspartic acid l-1 ( : 0.8 g, : 0.5 g, : 0.2 g) in
acetic acid at 758C (Scheme 2a).
Our observation of a factor of two difference in the slope
of plots of ln(ee) versus time for racemizing homogeneous
solution compared to systems containing excess solid de-
serves further discussion. The results of Figure 3 show simi-
lar initial rates of increase in solution phase (R)-2 concen-
tration, indicating that the rate of conversion from one
enantiomer to the other in solution does not depend on the
presence of solid. Solution ee, however, is a function of the
absolute concentrations of both R and S. Because the abso-
lute temporal solution concentrations of R and S are influ-
enced differently depending on whether solid is present or
absent, the interpretation of the change in solution enantio-
meric excess becomes more complicated. Solution enantio-
meric excess profiles for the two cases with enantiopure
solid present, in which only one enantiomer concentration is
changing, and in homogeneous solution, in which both enan-
tiomer concentrations are changing, cannot be directly com-
pared as a means to monitor racemization rate.
Figure 2. Log plot of the change in solution phase ee over time as a func-
tion of the amount of solid N-(2-methylbenzylidene)-phenylglycine
amide in MeCN with DBU (Scheme 2b); DBU concentration was 2 mm.
These results appear to suggest that the rate of racemiza-
tion in solution is dependent on the amount of solid present
in the system, giving rise to speculation about mechanisms
through which the solid phase might play a role in the solu-
tion racemization process. However, under closer examina-
tion of the racemization pro-
We may rationalize the observed ee profiles through an
analytical treatment of the rate of solution racemization for
the two cases shown in Figure 3. In the case of racemization
in a homogeneous solution as shown in Equation (1), where
cess, we find that a different
picture emerges.
Monitoring the absolute con-
centrations of enantiomers of 2
in solution as racemization pro-
ceeds, provides the data shown
in Figure 3 for the system of
Scheme 2b. Solution concentra-
tions over the time course of
racemization for a system con-
taining a large excess of enan-
tiopure solid (S)-2 were com-
pared with those in a homoge-
neous saturated solution of (S)-
Figure 3. Time-course profiles for the absolute solution concentrations during racemization of the amino acid
derivative 2 (Scheme 2) at ambient temperature starting with saturated solutions of enantiopure (S)-2 in:
2. In the case of the homogene-
ous solution, Figure 3a shows
that the (S)-2 concentration in
~
!
a) homogeneous solution; and b) the presence of excess solid (S)-2. : solution concentration of (S)-2; : solu-
&
tion concentration of (R)-2; : sum of the solution concentrations of the two enantiomers (total: (R)-2+(S)-
solution decreases while the 2). DBU solution concentration was 6 mm in both cases.
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Solution-Phase Racemization
FULL PAPER
d½Rꢀ
the total concentration of [R]+[S] remains constant, plots
of ln(ee) versus time are routinely employed to measure the
racemization rate constant for
ð5bÞ
þ krac½Rꢀ ¼ krac½Sꢀ0
dt
½Rꢀ ¼ ½Sꢀ0ð1 ꢁ eꢁk
½Sꢀ ¼ ½Sꢀ0
Þ
ract
ð6aÞ
ð6bÞ
the case in homogeneous solu-
tion.[24,26]
Such plots derive from the solution of the first order
linear differential Equation (2) describing the increase in so-
lution concentration of R as racemization proceeds in an
enantiopure solution of concentration [S]0, where [R]+[S]=
constant=[S]0 and krac is the forward and reverse racemiza-
tion rate constant.
From Equation (6), the relationship for solution enantio-
meric excess as a function of time during racemization in
the presence of excess solid is given by Equation (7).
ract
½Sꢀ ꢁ ½Rꢀ
½Sꢀ þ ½Rꢀ
eꢁk
ð7aÞ
ð7bÞ
% ee ¼ 100
¼
2 ꢁ eꢁk
ract
d½Rꢀ
ð2aÞ
ð2bÞ
¼ krac½Sꢀ ꢁ krac½Rꢀ ¼ kracð½Sꢀ0 ꢁ ½RꢀÞ ꢁ krac½Rꢀ
þ 2krac½Rꢀ ¼ krac½Sꢀ0
dt
lnð%eeÞ ¼ ꢁkract ꢁ lnð2 ꢁ eꢁk Þ þ 4:6 ¼ ꢁkractþ ꢂ 4:0
ract
d½Rꢀ
dt
Thus, it may be seen by comparing Equations (4) and (7),
the initial rate of change in solution ee as a function of time
will be decreased by about twofold when racemization is car-
ried out in the presence of an excess of the enantiopure
solid in rapid exchange with its solution phase. This finding
is a consequence of the combination of the Meyerhoffer
double solubility rule, which tells us that molecules will be
driven from the solid to the solution phase during racemiza-
tion so that [R]+[S]¼[S]0, with the fact that solution–solid
phase transfer is rapid compared to solution racemization,
which results in [S]=[S]0 throughout the process. Plots of
ln(solution ee) versus time for systems under these condi-
tions will approach a twofold difference in slope for racemi-
zation in the presence of a solid phase compared to homo-
geneous solution. Figure 4 shows the general case in theoret-
ical plots of ln(ee) versus the function (kract) on the x axis
for Equations (4) and (7).
The analytical solution of this equation, employing the in-
itial condition of enantiopure solution with [S]=[S]0 and
[R]=0 at t=t0, is given by Equations (3a) and (3b) to de-
scribe the R and S concentrations as a function of time.
½Sꢀ0
ract
½Rꢀ ¼
½Sꢀ ¼
ð1 ꢁ eꢁ2k
Þ
ð3aÞ
2
½Sꢀ0
ract
ð1 þ eꢁ2k
Þ
ð3bÞ
2
Substituting these relationships into the equation for
enantiomeric excess, defined with [S] excess as positive,
gives Equation (4) for ee as a function of time during the
racemization process. Thus, the slope of a plot of ln(ee)
versus time is given by 2krac
.
½Sꢀ ꢁ ½Rꢀ
ract
¼ 100eꢁ2k
ð4aÞ
ð4bÞ
% ee ¼ 100
½Sꢀ ꢁ ½Rꢀ
lnð%eeÞ ¼ ꢁ2kract þ 4:6
However, when racemization is carried out in the pres-
ence of the enantiopure solid, these relationships can no
longer be employed. As our data show, and as the Meyer-
hoffer double solubility rule predicts, the total quantity
[R]+[S] in solution is no longer constant. As racemization
proceeds, the solution concentration increases over time as
the loss of S by conversion to R is compensated for by disso-
lution of S from the S solid. For the case of a large amount
of solid, we may assume that replenishment is rapid and the
solution concentration of S remains constant at [S]0 over the
course of the racemization, as was found for the case shown
in Figure 3b. This provides a new differential equation de-
scribing the racemization [Eq. (5)]. This equation may be
solved by using the same initial conditions as previously em-
ployed, giving Equation (6) for the temporal concentrations
of R and S enantiomers.
Figure 4. Plot of ln(solution ee) versus time as a function of (kract) for the
case of a homogeneous solution (c) according to Equation (4) and in
the presence of a solid phase (a) according to Equation (7).
The experimental confirmation of Equations (4) and (7)
was shown in Figure 2, where the difference in slope for rac-
emization in homogeneous solution by using 2 mm DBU
(slope=0.045 minꢁ1) compared to racemization in the pres-
ence of a solid (slope=0.028 minꢁ1) is an apparent effect
due to the presence of the solid; the intrinsic kinetic racemi-
zation rate constant remains unchanged, and the chemical
process of racemization continues to be described solely by
d½Rꢀ
ð5aÞ
¼ krac½Sꢀ0 ꢁ krac½Rꢀ
dt
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D. G. Blackmond, R. M. Kellogg, C. Viedma et al.
solid phase. Solution phase enantiomeric excess was measured by using
chiral HPLC methods as previously described.[16]
solution phase interactions even in the presence of the solid
phase.
Experimental procedure for N-(2-methylbenzylidene)-phenylglycine
amide (2): Two reaction mixtures were prepared, the first (a) with (S)-
Schiff base (50 mg) in acetonitrile (1.5 mL) and the second (b) with (S)-
Schiff base (50 mg) in acetonitrile (1.0 mL). A magnetic stirrer and 1.0 g
of glass beads (2.5 mm) were added and the reaction mixtures were
stirred, overnight. Both reaction mixtures were white suspensions. Reac-
tion mixture (a) was taken up in a syringe and filtered over a 0.45 mm
filter and 1.0 mL of the filtrate was put in a new flask. A stock solution
of DBU (60.0 mm) in acetonitrile was prepared and 0.1 mL of stock solu-
tion was added to both reaction mixtures. The mixtures were stirred vigo-
rously and the conversion was monitored over time by taking samples.
The absolute concentrations of the Schiff base enantiomers were deter-
mined according to a method previously described.[20]
These findings may be considered in the context of exper-
imental observations that have been made for different sys-
tems that undergo the chiral amnesia process. One clear
conclusion is that the rationale of surface-aided racemiza-
tion invoked by Tsogoeva for their Mannich system does
not apply to either aspartic acid (1) or phenylglycine amide
Schiff base 2 studied in this work, since the presence of the
solid has no effect on intrinsic racemization rate in these
systems. Our work also indicates that the enhancement in
overall deracemization rate for 2 that has been observed
with increasing [DBU] cannot be explained simply by a cat-
alytic effect on solution racemization, since solid–solution
equilibration is much more rapid than solution racemization,
and solution racemization is much faster than the overall de-
racemization process at all levels of DBU. These studies,
which involve uncoupling the rates of the different physical
and chemical processes, will aid us in developing the de-
tailed mechanistic understanding of the chiral amnesia pro-
cess that continues to elude us.
Acknowledgements
D.G.B. acknowledges funding from Merck & Co. and a Royal Society
Wolfson Research Merit Award. C.V. acknowledges helpful discussions
with members of the European COST Action CM0703 “Systems Chemis-
try”.
Conclusion
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mogeneous conditions and in the presence of excess enan-
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solution phase ee will be lower by twofold for the former
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Experimental Section
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Chemicals: (S)-N-(2-Methylbenzylidene)-phenylglycine amide was kindly
provided by DSM Pharma and Syncom. DBU and aspartic acid were ob-
tained from Aldrich. Acetonitrile was obtained at Riedel-de Haꢄn, dried
prior to use with Na2SO4 and stored over 4 ꢅ mol sieves under Argon at-
mosphere.
Experimental procedure for aspartic acid (1): Solution–solid mixtures of
l-aspartic acid at various amounts (0.2, 0.5, 0.8 g in 8 mL of acetic acid)
were magnetically stirred (900 rpm) for four days at ambient temperature
in the presence of 1 mm glass beads (6 g) forming a slurry. After estab-
lishing solution–solid equilibrium, solution-phase racemization was initi-
ated in the absence of glass beads by adding salicylaldehyde (0.05 mL) as
catalyst at room temperature (258C) in some experiments and by increas-
ing the temperature to 758C without salicylaldehyde in other experi-
ments. Samples were collected over time and centrifuged to separate the
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Solution-Phase Racemization
FULL PAPER
[25] In all solution racemization experiments carried out in the presence
of the enantiopure solid, the solid phase remains enantiopure while
the solution phase undergoes racemization. This has been shown
previously (see refs. [15,16]) and is attributed to the fact that pri-
mary nucleation to form the first crystals of the enantiomeric solid
is a much more activated process and is highly disfavored under
these conditions.
[26] The mathematical derivation of enantiomeric excess as a function of
time during racemization in homogeneous solution that is given in
Equations (2)–(4) is derived in ref. [24], however, repeated here in
order to contrast this with the expressions obtained for racemization
in the presence of enantiopure solid, which to our knowledge have
not been presented previously.
Received: October 28, 2009
Published online: March 31, 2010
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