Enhancing intermolecular benzoyl-transfer reactivity in crystals by growing a "reactive" metastable polymorph by using a chiral additive

Article abstract of DOI:10.1002/chem.200801484

Racemic 2,4-di-O-benzoylmyo-inositol-1,3,5-orthoacetate, which normally crystallizes in a monoclinic form (form I, space group P2₁/n) could be persuaded to crystallize out as a metastable polymorph (form II, space group C2/c) by using a small a

Full text of DOI:10.1002/chem.200801484

FULL PAPER
DOI: 10.1002/chem.200801484
Enhancing Intermolecular Benzoyl-Transfer Reactivity in Crystals by
Growing a “Reactive” Metastable Polymorph by Using a Chiral Additive
Chebrolu Murali,[a] Mysore S. Shashidhar,*[a] Rajesh G. Gonnade,[b] and
Mohan M. Bhadbhade*[b]
Abstract: Racemic 2,4-di-O-benzoyl-
myo-inositol-1,3,5-orthoacetate, which
normally crystallizes in a monoclinic
form (form I, space group P21/n) could
be persuaded to crystallize out as a
metastable polymorph (form II, space
group C2/c) by using a small amount of
either d- or l- 2,4-di-O-benzoyl-myo-
inositol-1,3,5-orthoformate as an addi-
tive in the crystallization medium. The
structurally similar enantiomeric addi-
tive was chosen by the scrutiny of pre-
vious experimental results on the crys-
tallization of racemic 2,4-di-O-benzoyl-
myo-inositol-1,3,5-orthoacetate.
1458C. The relative organization of the
molecules in these dimorphs vary
slightly in terms of the helical assembly
of molecules, that is, electrophile
tive and undergo non-specific benzoyl-
group transfer leading to a mixture of
products. The role played by the addi-
tive in fine-tuning small changes that
are required in the molecular packing
opens up the possibility of creating
new polymorphs that show varied phys-
ical and chemical properties. Crystals
À
(El)···nucleophile (Nu) and C H···p in-
teractions, but these minor variations
have a profound effect on the facility
and specificity of benzoyl-group-trans-
fer reactivity in the two crystal forms.
While form II crystals undergo a clean
intermolecular benzoyl-group-transfer
reaction, form I crystals are less reac-
of
d-2,6-di-O-benzoyl-myo-inositol-
1,3,5-orthoformate (additive) did not
show facile benzoyl-group-transfer re-
activity (in contrast to the correspond-
ing racemic compound) due to the lack
of proper juxtaposition and assembly
of molecules.
Keywords: acylation
·
carbohy-
drates · crystal growth · cyclitols ·
solid-state reactions
Form II crystals can be thermally trans-
formed to form I crystals at about
Introduction
matic processes.[1] This is essentially due to the “pre-organi-
zation” of the reacting molecules in crystals and the inability
of the reactant molecules to freely move in the crystalline
state, in contrast to that in the gaseous and solution states.
Wide-ranging areas of interest in organic solid-state chemis-
try include topochemical dimerization or polymerization
that involves addition to C=C double bonds,[2] group-trans-
fer reactions in crystals,[3] mechanistic organic photochemis-
try,[4] generation of chiral products from achiral reactant
molecules in crystalline solids,[5] crystal-to-crystal reac-
tions[5c,6] as tools for the development of green chemistry,[7]
reactions in co-crystals[8] and inclusion crystals,[9] control of
reactivity in the solid state by using linear molecular tem-
plates,[10] reaction between co-crystals,[11] asymmetric synthe-
sis in inclusion crystals by using chiral hosts,[5c,6a,12] solid-
state reaction kinetics,[13] prediction of reactivity by using
computational methods,[14] mechanochemical reactions[3g]
and the development of functional materials.[10c] The ration-
alization, prediction and control of structure and properties
of organic solid phases is difficult due to the complex nature
of weak intermolecular non-covalent bonding.[15] Hence, the
The study of organic reactions in molecular solids and crys-
tals has emerged as a frontier area of research in the recent
past. Although reactions in molecular crystals are less
common than reactions in the gas phase or in solution, the
degree of (regio- and/or stereo-) control exerted by the crys-
talline state is often comparable to that observed in enzy-
[a] Dr. C. Murali, Dr. M. S. Shashidhar
Division of Organic Chemistry, National Chemical Laboratory
Dr. Homi Bhabha Road, Pune, 411 008 (India)
Fax : (+91)20-2590-2642
E-mail: ms.shashidhar@ncl.res.in
[b] Dr. R. G. Gonnade, Dr. M. M. Bhadbhade
Centre for Materials Characterization, National Chemical Laboratory
Dr. Homi Bhabha Road, Pune, 411 008 (India)
Fax : (+91)20-2590-2624
E-mail: mm.bhadbhade@ncl.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801484.
Chem. Eur. J. 2009, 15, 261 – 269
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261

key to carrying out solid-phase bimolecular reactions is to
obtain crystals in which the reacting molecules are arranged
with the required precise distances and relative orientation
between potential reaction centres or to facilitate the inter-
action of reagent molecules with substrate molecules in crys-
tals without disturbing the crystal lattice. Engineering of
molecular crystals with desired physical or chemical proper-
ties has been approached by attempts to control polymorph-
ism,[16] attempts to grow and stabilize metastable poly-
morphs,[17] attempts to gain control over the non-covalent
self-assembly of molecules[10d,18] and the use of templates[19]
and additives[20] for crystallization. Achieving the seemingly
Utopian possibility of breaking and making covalent bonds
in molecular crystals in a predictable manner requires the
identification of suitable reactions, establishing their gener-
ality and developing mechanistic models to engineer other
crystals that exhibit the desired reactions. We have been in-
vestigating acyl-transfer reactions in crystals (Scheme 1)
over the last few years[21] with these goals in mind. Although
acyl-transfer reactions have been investigated[22] for more
than a century in living cells in the laboratory and in indus-
try, their occurrence in the crystalline state was discovered
in our laboratory.[21a]
The present work reports how the acyl-transfer reactivity
was enhanced by the formation of a new highly reactive
metastable crystal form of rac-3 by using a trace of an analo-
gous chiral additive (an enantiomer of the orthoformate rac-
1) in the crystallization medium.[25]
Results and Discussion
The reactive centrosymmetric crystals in which the benzoyl-
group-transfer reaction (Scheme 1)[21] proceeded with high
facility, consistently reinforced a pattern of helical molecular
assembly (see the Supporting Information) of molecules
with the same configuration (R or S).[21,26] In these crystals,
the benzoyl-group-transfer reaction took place among mole-
cules with the same absolute configuration (i.e., either from
R to R or from S to S enantiomers) along the crystallo-
graphic 21 screw axis. Experimental evidence for this came
from the reactive co-crystal[21b] rac-1·rac-3 (1:1) formed from
the reactive orthoformate rac-1 and the less reactive ortho-
AHCTUNGTREGaNNUN cetate rac-3. In this co-crystal, the asymmetric unit consist-
ed of one molecule each of rac-1 and rac-3 containing the
same configuration and related by a non-crystallographic 21-
screw axis. This asymmetric unit then arranged itself helical-
ly around the 21 screw axis in a monoclinic space group Cc
providing a (almost) continuous helical channel for the ben-
zoyl-group-transfer reaction to occur.[21b] We noted that co-
crystals rac-1·rac-3 contained only RR and SS pairs of diben-
zoates rac-1 and rac-3 (of the four possible diastereomeric
pairs). These observations prompted us to attempt crystalli-
zation of rac-3 in the presence of an enantiomer 1 or ent-1.
Considering the similarities in the arrangement of molecules
in crystals of rac-1, ACTHNUTRGNErNUG ac-3 (form I) and rac-1·rac-3 as well as
similarities in the molecular structure and conformation of
rac-1, rac-3 and enantiomer ent-1 (or 1) we expected one of
the two following outcomes in the crystallization experi-
ment: 1) resolution of ACHTUNRGTNErNUG ac-3 by formation of co-crystals con-
sisting of one of the enantiomers in rac-3 and ent-1 (or 1)[27]
or 2) formation of a new polymorph of rac-3.[17] We envis-
aged the latter possibility since there is precedent in the lit-
erature that additives that mimic the conformation of mole-
cules in stable crystal structures lead to the formation of
polymorphs (Figure 1).
The enantiomeric dibenzoates 1 and ent-1 were prepared
from the enantiomeric ditosylates 10 and ent-10[28] as shown
in Scheme 2. Crystallization of dibenzoates 1 and ent-1 from
chloroform/light petroleum gave crystals suitable for single-
crystal X-ray diffraction studies. We also prepared d-6-O-
and d-4-O-benzyl-myo-inositols 14 and ent-14, which are
precursors for the preparation of enantiomeric myo-inositol-
1,2,3,4,5-pentakisphosphates. The benzyl ethers 14 and
ent-14 have earlier been prepared from myo-inositol[29] as
well as from benzoquinone.[30] The overall yield of enantio-
meric benzyl ethers 14 and ent-14 in these reported proce-
dures is in the range of 3–17%. The method shown in
Scheme 2 provides 14 and ent-14 in an overall yield of
ꢀ25%, which is better than the previously reported proce-
Scheme 1. Solid-state transesterification reactions in crystals of myo-ino-
sitol orthoester derivatives. a) Na2CO3, heat.
A comparison of the structure of crystals[21] in which inter-
molecular acyl-transfer was facile and not so facile revealed
that the following features were necessary in the crystal for
facile acyl-transfer reactions: 1) the properly juxtaposed re-
acting pair of molecules has to make a “reaction channel”
by helically self-assembling itself around a crystallographic
screw axis for the propagation of the intermolecular benzoyl
group-transfer reaction in crystals; 2) good electrophile
(El)···nucleophile (Nu) geometry;[23] and 3) C H···p interac-
À
tions.[24] These interactions made by the migrating benzoyl
group appeared to augment the facility of the intermolecu-
lar benzoyl-group transfer. A crystal form (herein referred
to as form I—space group P21/n) of the orthoacetate deriva-
tive rac-3 had the molecular pre-organization grossly satisfy-
ing all the above criteria, but the acyl-transfer reactivity in
form I crystals was very low yielding and non-specific.[21b]
262
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Chem. Eur. J. 2009, 15, 261 – 269

Enhancing Intermolecular Benzoyl-Transfer Reactivity in Crystals
FULL PAPER
Table 1. Results of the crystallization of rac-3 in the presence of its or-
thoformate analogues.
Entry[a]
Molar ratio of orthoesters
Result
1
2
3
4
5
6
rac-3
form I
rac-1/rac-3 (1:1)
ent-1/rac-3 (1:1)
ent-1/rac-3 (1:9)
ent-1/rac-3 (1:18)
ent-1/rac-3 (9:1)
rac-1·rac-3[b]
form II
form II
form I and II
amorphous solid
[a] Solvent system for all entries: chloroform/light petroleum (vapour dif-
fusion method); [b] 1:1 co-crystals were obtained irrespective of the ratio
of rac-1 and rac-3 present in solution.[21b]
Figure 1. Overlap diagram of molecules present in crystals of ent-1 (light
grey) and rac-3 (black).
crystal rac-1·rac-3 on crystallization with rac-1 from a
chloroform/light petroleum mixture.[21b] Crystallization of
rac-3 in the presence of ent-1 (or 1) gave a new polymorph
(form II) of rac-3 (Figure 2B). The actual outcome of the ex-
Figure 2. Photomicrographs of form I (A) and II (B) crystals of ACHTUNGTRENNUNGrac-3.
periment was dependent on the molar ratio ent-1/rac-3; use
of smaller amounts of ent-1 in the crystallization medium
led to concomitant formation of both the polymorphs
(Table 1, entry 5) of rac-3, whereas the presence of a larger
amount of ent-1 prevented crystal formation completely
(entry 6). Repeated attempts to obtain co-crystals from ACHTUNGTRENNUNGrac-
3 and either 1 or ent-1 were not successful. Form II crystals
could be thermally transformed irreversibly to form I crys-
tals above 1458C as revealed by thermal analysis (Figure 3)
and X-ray crystallography.
Scheme 2. Preparation of enantiomeric myo-inositol derivatives. a) DMF,
BnBr, NaH, 08C–RT, 30 min, 94–96%; b) NaOMe, MeOH, reflux, 12 h,
92–98%; c) pyridine, BzCl, RT, 20 h, 96–98%; d) ethyl acetate/methanol,
Pd(OH)2/C, H2 (55 psi), RT, 6 h, 94–96%; e) TFA/H2O (4:1 v/v), RT,
24 h, 84–87%. TFA=trifluoroacetic acid.
dures. This procedure can also be adopted to prepare many
other 4-O-substituted myo-inositol derivatives; such deriva-
tives are valuable tools for the study of inositol binding pro-
teins.[31] We had earlier shown[28,32] that inositol derivatives
can be obtained in very good yields from myo-inositol-1,3,5-
orthoformate by using sulfonate groups for the protection of
its hydroxyl groups.
The dibenzoate rac-3 crystallized (Table 1) as form I crys-
tals from most organic solvents, whereas it gave a 1:1 co-
Figure 3. Thermal analysis (DSC) of form I (A) and II (B) crystals of
rac-3.
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M. M. Bhadbhade, M. S Shashidhar et al.
The X-ray diffraction data obtained on the form II crys-
tals (space group C2/c) of rac-3 revealed them to be iso-
structural to the co-crystals rac-1·rac-3 (space group Cc).
À
Similarities were observed in terms of O H···O and El···Nu
interactions. In form II crystals of rac-3, molecules contain-
ing the same configuration assembled helically around the
crystallographic 21 screw axis, with the geometrical parame-
À
À
ters (O H···O, El···Nu and C H···p interactions) favourable
for the intermolecular benzoyl-group-transfer reaction
(Figure 4 and Tables 2 and 3). The conformational differ-
ACHTUNGTRENNUNGences (Figure 5) between the two forms at the singular mo-
lecular level appears to have contributed significantly to the
À
improvement in the El···Nu and C H···p interactions in
form II crystals (Figure 4).
Figure 5. Overlap diagram of molecules present in crystals of form I
(black) and II (light grey) of rac-3.
Since the crystal structural parameters that govern benzo-
yl-transfer reactions and molecular organization were good
in form II crystals of rac-3, we predicted the occurrence of
facile intermolecular benzoyl-transfer reactivity in these
crystals. Indeed, heating them at 1158C with solid sodium
carbonate yielded the tribenzoate 6 and the diol 9 in very
good yields (Scheme 3). The temperature of the reaction
Scheme 3. Acyl-transfer reactions in crystals of rac-3. a) Chloroform/light
petroleum; b) Na2CO3, 1158C.
Figure 4. Comparison of El···Nu geometry and allied weak interactions in
form I (A) and II (B) crystals of rac-3.
mixture was maintained well below the form I to form II
phase transition temperature of 1458C. Form I crystals when
subjected to similar reaction conditions (at 1158C) gave sev-
eral products due to inefficient benzoyl-group transfer.[21b]
The solid-state reactivity of this new polymorph (from II)
was as good as in crystals of rac-1 and rac-2 (Scheme 1) in-
vestigated earlier.[21] This finding reinforces the importance
of the proposed[21] topochemical criterion and overall molec-
ular organization responsible for the efficient intermolecular
acyl-transfer reaction in crystals. It is very intriguing that the
presence of a minor amount of an enantiomer (either 1 or
ent-1) of the orthoformate (without actually being a part of
the crystal) in the crystallization medium can coax mole-
cules of rac-3 to pack in a manner conducive to the benzoyl-
transfer reaction in crystals. We had observed earlier[21b] that
half an equivalent of the racemic orthoformate rac-1 (by
being a part of the co-crystal with rac-3) could coax the mol-
ecules of rac-3 to efficiently participate in the benzoyl-trans-
fer reaction.
Table 2. Hydrogen-bonding parameters in crystals of rac-3 and ent-1.
À
À
D H···A
H···A [ꢁ]
D···A [ꢁ]
D H···A [8]
À
form I
form II
ent-1
O(4) H
C(3) H(3)···Cg(1)
O(4) H
C(3) H(3)···Cg(1)
(4 A)···O(7)[a] 1.93
2.775(2)
4.472
2.822(3)
3.582
2.788(2)
4.086
175
142
176
167
172(2)
139
1
[b]
À
3.67
2.00
2.62
2.02(2)
3.265
À
[d]
À
O(4)-H
A
C(5)-H(5)···Cg(1)[f]
Symmetry code: [a] 1.5Àx, À2+y, 2Àz; [b] 1.5Àx, 12+y, 2Àz; [c] 21Àx, À2+y,
1
1
1
2Àz; [d] 12Àx, 12+y, 21Àz; [e] À2+x, À2Ày, Àz; [f] À2+x, À2Ày, Àz.
1
1
1
1
1
Table 3. Geometry of the reacting groups (El···Nu) in crystals of rac-3
and ent-1.
Distance [ꢁ]/angle [8]
form I
form II
ent-1
[b]
C15···O4
aO4···C15 O8
3.299(2)[a]
84.01
97.20
3.135(4)
87.63
116.46
114.05
1
4.484(2)[c]
50.3(2)
157.3(2)
51.5(1)
1
À
À
aC4 O4···C15
À
aH4A O4···C15
105.8
Symmetry code: [a] 1.5Àx, À2+y, 2Àz; [b] 12Àx, À2+y, 2Àz; [c] À2+x,
1
1
1
Although nucleation is a complex phenomenon, attempts
are made to explain the growth of the reactive polymorph
1
À2Ày, Àz.
264
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Enhancing Intermolecular Benzoyl-Transfer Reactivity in Crystals
FULL PAPER
form II of rac-3. A tentative mechanism for the formation of
form II crystals of rac-3 can be depicted as follows. In princi-
ple, the additive ent-1 (or 1) can play one of two roles
during the crystallization of rac-3. Either ent-1 can just in-
hibit the formation of form I crystals (and form II crystals
grow on their own) or ent-1 can facilitate the growth of
form II crystals. Although the former possibility is supported
by the fact that additives, which mimic the conformation of
molecules in the thermodynamically stable crystal structure,
can kinetically stabilize a metastable polymorph,[17] the
latter possibility cannot be ruled out. The basis for this is
molecular arrangement are obviously very predominant, be-
cause the presence of 50% of rac-1 with rac-3 in co-crystals
rac-1·rac-3 resembled rac-1 organization and not that of
form I crystals of rac-3. This suggests that this inherent
property (crystallographic gene!?) of rac-1 leads to the nu-
cleation of form II crystals of rac-3. Although the enantio-
mer ent-1 is present at 10% concentration, it is enough to
induce the helical assembly to grow in the “right” way, bias-
ing the entire nucleation to yield the reactive form II. This
possibility for the growth of form II crystals is shown as a
cartoon in Figure 7.
ACHTUNGTRENNUNGderived from the results of the crystallization experiments
carried out on myo-inositol orthoester derivatives, including
the formation of a co-crystal rac-1·rac-3 with the same unit-
cell parameters as form II crystals of rac-3.[21b] Figure 6
shows the similarities in the arrangement of molecules in
these two crystals.
Since the form II crystals undergo thermal transformation
to form I crystals before melting, it can be concluded that
form I crystals are thermodynamically stable, whereas
form II crystals are a metastable form. As observed in crys-
tallization experiments (Table 1) the appearance of form II
crystals was preferred over that of form I crystals in the
presence of ent-1 (or 1). Molecular organization in crystals
of rac-1 is known to bring about neat benzoyl-transfer reac-
tivity.[21b] The nucleation properties of rac-1 leading to this
Figure 7. Stage 1: Nucleation of the form II crystal (of rac-3), with the aid
of ent-1 (or 1), by the aggregation of molecules of rac-3 with the same
relative configuration as ent-1 (or 1). This molecular assembly is suggest-
ed to be isostructural to that of the co-crystal rac-1·rac-3. Stage 2:
Growth of the helix along the screw axis, by assembly of molecules of
rac-3 with the same configuration (d or l). Stage 3: Complementary heli-
cal assembly (helix constituted by plain molecules) of molecules of rac-3
leading to complete crystal formation and its stabilization. Filled mole-
cules: 1 or ent-1; plain molecules: one of the enantiomers of rac-3;
shaded molecules: enantiomer of rac-3 with a configuration opposite to
that of the plain molecule.
Availability of crystals of ent-1 also allowed us to address
another question. Since we had observed the formation of
the helical assembly of molecules with the same chirality in
crystals of rac-1 (amounting to separation of molecules
along the screw axis in crystals of rac-1), we wondered what
would be the molecular organization in crystals if enantio-
mer ent-1 (or 1) was crystallized separately? Enantiomer
ent-1 crystallized in orthorhombic space group P212121 and
contained a helical organization of molecules along all the
three axes (Figure 8), but none had the molecular assembly
comparable to that observed in crystals of rac-1 (Table 3).
The enatiomer ent-1 did not undergo clean transesterifica-
tion reactions in their crystals, which is consistent with their
crystal structure, which lacks good El···Nu interactions
(Table 3). Hence it appears that interhelical interactions
present in crystals of rac-1 are necessary for the formation
of the helical assembly (of these dibenzoate molecules) ca-
pable of initiating and sustaining intermolecular benzoyl-
transfer reactions in crystals.
Conclusion
The role played by the chiral additive in fine-tuning small
changes required in the molecular packing in crystals opens
Figure 6. Comparison of the molecular organization in A) co-crystal rac-
1·rac-3 and B) form II of rac-3 viewed down the c axis.
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265

M. M. Bhadbhade, M. S Shashidhar et al.
30 min. Excess of sodium hydride was quenched with ice and the solvent
was removed under reduced pressure. The residue was worked up with
dichloromethane and dried over anhydrous sodium sulphate. Evaporation
of the solvent under reduced pressure afforded a gummy residue. The
crude product was purified by column chromatography (eluent: 25%
ethyl acetate/light petroleum) to give 11 as a white solid (1.077 g, 96%).
1
Rf =0.31; m.p. 76–788C; [a]2D9 =À8.85 (c=1 in CHCl3); H NMR (CDCl3,
200 MHz, TMS): d=7.67–7.84 (m, 4H; Ar H), 7.21–7.38 (m, 9H; Ar H),
5.43 (d, 1H, J=1.3 Hz; HCO3), 5.08 (dt, 1H, J=4.1, 1.7 Hz; Ins H), 4.92
(dt, 1H, J=3.27, 1.76 Hz; Ins H), 4.42–4.64 (q, 2H, J=11.6 Hz; CH2),
4.33–4.41 (m, 1H; Ins H), 4.24 (dt, 1H, J=4.2, 1.6 Hz; Ins H), 4.12–4.20
(m, 1H; Ins H), 4.01–4.11 (m, 1H; Ins H), 2.47 (s, 3H; Me), 2.43 ppm (s,
3H; Me); 13C NMR (CDCl3, 50.3 MHz, TMS): d=145.6 (Carom), 145.3
(Carom), 136.7 (Carom), 132.7 (Carom), 132.2 (Carom), 130.0 (Carom), 129.9
(Carom), 128.3 (Carom), 127.8 (Carom), 127.7 (Carom), 127.3 (Carom), 102.4
(HCO3), 72.2 (Ins C), 72.0 (Ins C), 71.2 (CH2), 69.8 (Ins C), 69.6 (Ins C),
68.6 (Ins C), 67.0 (Ins C), 21.5 (CH3), 21.4 ppm (CH3); elemental analysis
calcd (%) for C28H28O10S2: C 57.13, H 4.79, S 10.89; found: C 57.20, H
4.88, S 10.55%.
Figure 8. Helical assembly of molecules in crystals of ent-1 viewed diago-
nal to the bc plane.
d-6-O-Benzyl-myo-inositol-1,3,5-orthoformate (12): A mixture of the di-
tosylate 11 (1.015 g, 1.72 mmol), sodium methoxide (0.931 g, 17.2 mmol)
and dry methanol (10 mL) was refluxed for 12 h. The reaction mixture
was allowed to cool to ambient temperature and methanol was removed
under reduced pressure to give a gummy residue. The residue was puri-
fied by column chromatography (eluent: ethyl acetate/light petroleum
up possibilities of creating new polymorphs of a compound
containing varied physical and chemical properties.[33] It is
pertinent to mention that the metastable form II crystals of
rac-3 was not obtained by random screening of additives for
crystallization experiments, but rather by consideration of
previous experimental results for the selection of the addi-
tive. A comparison of structure and reactivity of form I
and II crystals shows that, for neat intermolecular benzoyl-
group-transfer reactions to occur in the solid state, the ge-
ometry and organization of the molecules as depicted in
Figure 4 is very crucial. It is interesting and important to
note that the presence of a racemic substance and its enan-
tiomer can have a profoundly different influence on the out-
come of the crystallization of substances. Based on these ob-
servations, the possibility of designing and constructing
other molecular systems that show “acyl-transfer activities”
in crystals is being explored in our laboratory.
1:2) to give 12 as a gummy compound (0.445 g, 92%). Rf =0.28; [a]D27
=
À14.9 (c=0.01 in ethanol) (lit.:[35] [a]D25 =À16.6 (c=1 in EtOH));
1H NMR (CDCl3, 200 MHz, TMS): d=7.28–7.45 (m, 5H; Ar H), 5.44 (d,
1H, J=1.3 Hz; HCO3), 4.61–4.73 (q, 2H, J=11.6 Hz; CH2), 3.39–4.45
(m, 2H; Ins H), 4.18–4.32 (m, 3H; Ins H), 4.09 (d, 1H, J=9.5 Hz; Ins
H), 3.74 (d, 1H, J=10.2 Hz; OH), 3.21 ppm (d, 1H, J=11.2 Hz; OH);
13C NMR (CDCl3, 50.3 MHz, TMS): d=135.8 (Carom), 128.7 (Carom), 128.6
(Carom), 127.9 (Carom), 102.5 (HCO3), 74.6 (Ins C), 74.0 (Ins C), 72.8
(CH2), 72.1 (Ins C), 67.7 (Ins C), 67.1 (Ins C), 60.4 ppm (Ins C); IR
(neat): n˜ =3300–3650 cmÀ1; elemental analysis calcd (%) for C14H16O6: C
59.99, H 5.75; found: C 59.84, H 5.84.
d-2,4-Di-O-benzoyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate
(13):
Benzoyl chloride (1.053 g, 7.49 mmol) was added dropwise over a period
of 10 min to an ice-cooled solution of the diol 12 (0.35 g, 1.25 mmol) and
4-dimethylaminopyridine (DMAP; 0.02 g) in dry pyridine (6 mL). The re-
action mixture was stirred for 20 h at ambient temperature and then the
pyridine was removed under reduced pressure. The residue was worked
up with dichloromethane and dried over anhydrous sodium sulfate. The
crude product obtained was purified by column chromatography (eluent:
20% ethyl acetate/light petroleum) to afford 13 as a white solid (0.596 g,
98%). Rf =0.33; m.p. 140–1438C; [a]2D5 =+25.6 (c=1 in CHCl3);
1H NMR (CDCl3, 200 MHz, TMS): d=8.13–8.22 (m, 2H; Ar H), 7.87–
7.96 (m, 2H; Ar H), 7.43–7.65 (m, 4H; Ar H), 7.21–7.32 (m, 7H; Ar H),
5.80 (dt, 1H, J=3.9, 1.6 Hz; Ins H), 5.64–5.70 (m, 2H; Ins H, HCO3),
4.70–4.75 (m, 1H; Ins H), 4.52–4.69 (m, 4H; CH2, Ins H), 4.48 ppm (dt,
1H, J=3.8, 1.7 Hz); 13C NMR (CDCl3, 50.3 MHz, TMS): d=166.1 (C=
O), 165.3 (C=O), 136.7 (Carom), 133.4 (Carom), 133.3 (Carom), 129.9 (Carom),
129.5 (Carom), 128.9 (Carom), 128.43 (Carom), 128.37 (Carom), 128.0 (Carom),
127.9 (Carom), 103.2 (HCO3), 73.4 (Ins C), 72.1 (CH2), 69.9 (Ins C), 69.6
(Ins C), 68.1 (Ins C), 67.4 (Ins C), 64.2 ppm (Ins C); IR (CHCl3): n˜ =
1724 cmÀ1; elemental analysis calcd (%) for C28H24O8: C 68.84, H 4.95;
found: C 68.93, H 4.89.
Experimental Section
General: All the solvents were purified according to literature proce-
dures[34] before use. 60% dispersion of sodium hydride in mineral oil was
used for O-alkylation reactions. TLC was performed on E. Merck pre-
coated 60 F254 plates and the spots were rendered visible either by shining
UV light or by charring the plates with concd H2SO4. Workup implies
the washing of the organic layer successively with water, dilute HCl
A
brine. Column chromatographic separations were carried out on silica gel
(60–120 mesh or 230–400 mesh) with the solvent system as mentioned in
experimental procedures. TLC Rf values reported are with the same
eluent as that used in column chromatography. The compounds previous-
ly reported in the literature were characterized by comparison of their
d-6-O-Benzyl-myo-inositol (14):
A mixture of the orthoformate 12
(0.07 g, 0.25 mmol), trifluoroacetic acid (0.8 mL) and water (0.1 mL) was
stirred at room temperature for 24 h. The solvents were removed under
reduced pressure and the residue was co-evaporated with dry toluene.
The white solid obtained was crystallized from methanol/dichlorome-
thane 1:4 at ꢀ08C to give 14 as white needle-type crystals (0.059 g,
87%). m.p. 175–1768C (lit.:[29a] m.p. 176–1788C); [a]2D9 =6.4 (c=1 in
MeOH) (lit.:[29a] [a]2D2 =À6.4 (c=1 in MeOH))).
melting points and/or H NMR spectra with reported data. All the asym-
metrically substituted racemic myo-inositol derivatives (numbered with
the prefix rac-) are represented in the schemes by one of the enantiomers
without numbering of the inositol ring carbon atoms.
d-2,4-Di-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate
Sodium hydride (0.087 g, 2.18 mmol) was added to an ice-cooled solution
of d-2,4-di-O-tosyl-myo-inositol-1,3,5-orthoformate (10, 0.951 g,
(11):
d-2,4-Di-O-benzoyl-myo-inositol-1,3,5-orthoformate (1):
A solution of
1.91 mmol) and benzyl bromide (0.34 mL, 2.86 mmol) in dry DMF
(10 mL), and the reaction mixture was stirred at ambient temperature for
the benzyl ether 13 (0.489 g, 1.0 mmol) in methanol (3 mL) and ethyl ace-
tate (3 mL) was hydrogenolyzed in the presence of 20% Pd(OH)2/C
266
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 261 – 269

Enhancing Intermolecular Benzoyl-Transfer Reactivity in Crystals
FULL PAPER
(0.040 g) at 50 psi. After 6 h, the reaction mixture was filtered over a
short bed of Celite, which was subsequently washed with ethyl acetate
(10 mL). Evaporation of the solvents from the filtrate and washings
under reduced pressure followed by column chromatography (eluent:
ethyl acetate/light petroleum 1:2) afforded 1 as a white solid (0.380 g,
95%). The dibenzoate 1 could be crystallized for single-crystal X-ray dif-
fraction studies by slow diffusion of light petroleum into a chloroform so-
m.p. 175–1778C); [a]D30 =+6.4 (c=1 in MeOH) (lit.:[29a] [a]D22 =+6 (c=1
in MeOH)).
d-2,6-Di-O-benzoyl-myo-inositol-1,3,5-orthoformate (ent-1): A solution
of ent-13 (0.3 g, 0.61 mmol) was hydrogenolyzed in methanol (2 mL) and
ethyl acetate (3 mL) in the presence of 20% Pd(OH)2/C (0.025 g) as in
the preparation of 1 to give ent-1 as a white solid (0.234 g, 96%). The di-
benzoate ent-1 could be crystallized for single-crystal X-ray diffraction
studies by slow diffusion of light petroleum into a chloroform solution of
ent-1 in a closed container at RT. Rf =0.28; m.p. 163–1658C; [a]2D7 =À65.1
(c=1 in CHCl3); 1H NMR (CDCl3, 200 MHz, TMS): d=8.10–8.20 (m,
2H; Ar H), 7.99–8.09 (m, 2H; Ar H), 7.54–7.66 (m, 2H; Ar H), 7.40–
7.52 (m, 4H; Ar H), 5.84 (dt, 1H, J=4.0, 1.8 Hz; Ins H), 5.63–5.70 (m,
2H; Ins H, HCO3), 4.69–4.81 (m, 1H; Ins H), 4.56–4.67 (m, 2H; Ins H),
4.45–4.54 (m, 1H; Ins H), 2.65 ppm (d, 1H, J=5.4 Hz; OH); 13C NMR
(CDCl3, 50.3 MHz, TMS): d=166.3 (C=O), 165.3 (C=O), 133.7 (Carom),
133.5 (Carom), 129.9 (Carom), 129.8 (Carom), 129.3 (Carom), 128.8 (Carom), 128.6
(Carom), 128.5 (Carom), 102.9 (HCO3), 71.7 (Ins C), 69.6 (Ins C), 68.5 (Ins
C), 68.4 (Ins C), 67.3 (Ins C), 63.8 ppm (Ins C); IR (CHCl3): n˜ =3412,
1722, 1703 cmÀ1; elemental analysis calcd (%) for C21H18O8: C 63.31, H
4.55; found: C 63.01, H 4.41.
lution of 1 in a closed container at RT. Rf =0.27; m.p. 162–1648C; [a]D22
=
+66.0 (c=1 in CHCl3); 1H NMR (CDCl3, 200 MHz, TMS): d=8.02–8.20
(m, 4H; Ar H), 7.55- 7.70 (m, 2H; Ar H), 7.39–7.54 (m, 4H; Ar H), 5.83
(dt, 1H, J=3.7, 1.6 Hz; Ins H), 5.62–5.75 (m, 2H; Ins H, HCO3), 4.70–
4.82 (m, 1H; Ins H), 4.56–4.67 (m, 2H; Ins H), 4.45–4.55 (m, 1H; Ins H),
2.69 ppm (d, 1H, J=5.8 Hz; OH); 13C NMR (CDCl3, 50.3 MHz, TMS):
d=166.3 (C=O), 165.3 (C=O), 133.6 (Carom), 129.9 (Carom), 129.8 (Carom),
129.3 (Carom), 128.8 (Carom), 128.6 (Carom), 128.5 (Carom), 102.9 (HCO3),
71.7 (Ins C), 69.6 (Ins C), 68.5 (Ins C), 68.4 (Ins C), 67.2 (Ins C),
63.8 ppm (Ins C); IR (CHCl3): n˜ =3540–3240, 1701, 1728 cmÀ1; elemental
analysis calcd (%) for C21H18O8: C 63.31, H 4.55; found: C 63.21, H 4.29.
d-2,6-Di-O-tosyl-4-O-benzyl-myo-inositol-1,3,5-orthoformate (ent-11): d-
2,6-Di-O-tosyl-myo-inositol-1,3,5-orthoformate
(ent-10,
0.701 g,
Crystallization of rac-2,4-di-O-benzoyl-myo-inositol-1,3,5-orthoacetate
(rac-3) in the presence of d-2,6-di-O-benzoyl-myo-inositol-1,3,5-orthofor-
mate (ent-1): The orthoacetate rac-3 (0.052 g, 0.13 mmol) and the ortho-
formate ent-1 (0.005 g, 0.01 mmol) were dissolved in chloroform (3 mL).
Light petroleum was diffused into this solution in a closed container over
4–5 days at RT. Clusters of sharp needles (0.044 g) were obtained. The
sharp needles were separated and collected (0.037 g). Use of a larger
amount of ent-1 (0.010 g or 0.050 g) for the crystallization experiment (as
above) did not make any difference in the yield of form II crystals. How-
ever, the use of a lesser amount of ent-1 (0.002 g) for the crystallization
experiment (as above) resulted in concomitant formation of both form I
and II crystals of rac-3. Form I crystals appeared faster than the form II
crystals. Crystallization of rac-3 in the absence of ent-1 in chloroform re-
sulted in form I crystals (2–3 days) alone. Similar results were obtained
on crystallization of the racemic orthoacetate rac-3 in the presence of 1.
Note: The 1H NMR spectrum of the clusters of from II crystals showed
that they contained rac-3 and ent-1 in the ratio 11:1. The ratio of the two
dibenzoates in manually separated needles (from clusters) was 20:1. The
variation in the relative amount of the two dibenzoates present in form II
crystals suggested that the form II crystals are a polymorphic modifica-
tion of the racemic orthoacetate (rac-3) contaminated with the enatio-
meric orthoformate rather than co-crystals of the two dibenzoates. This
was confirmed by single-crystal X-ray diffraction data of form II crystals
and the thermal transformation of form II crystals to form I crystals.
Washing of the crystals of rac-3 to free them from the adhering ent-1 is
not practical because both the dibenzoates have a similar solubility in or-
ganic solvents.
1.41 mmol) was benzylated with benzyl bromide (0.25 mL, 2.1 mmol) in
dry DMF (8 mL) and sodium hydride (0.068 g, 1.70 mmol) as in the prep-
aration of 11 to give ent-11 as a white solid (0.778 g, 94%). Rf =0.29;
m.p. 75–788C; [a]2D5 =+8.8 (c=1 in chloroform); 1H NMR (CDCl3,
200 MHz, TMS): d=7.68–7.83 (m, 4H; Ar H), 7.21–7.40 (m, 9H; Ar H),
5.43 (d, 1H, J=1.3 Hz; HCO3), 5.08 (dt, 1H, J=3.9, 1.64 Hz; Ins H),
4.89–4.96 (m, 1H; Ins H), 4.42–4.65 (q, 2H, J=11.6 Hz; CH2), 4.35–4.41
(m, 1H; Ins H), 4.24 (dt, 1H, J=4.1, 1.65 Hz; Ins H), 4.12–4.20 (m, 1H;
Ins H), 4.01–4.10 (m, 1H; Ins H), 2.47 (s, 3H; CH3), 2.43 ppm (s, 3H;
CH3); 13C NMR (CDCl3, 50.3 MHz, TMS): d=145.6 (Carom), 145.3 (Carom),
136.7 (Carom), 132.9 (Carom), 132.3 (Carom), 130.0 (Carom), 129.9 (Carom), 128.4
(Carom), 127.9 (Carom), 127.8 (Carom), 127.4 (Carom), 126.8 (Carom), 102.5
(HCO3), 72.3 (Ins C), 72.1 (Ins C), 71.3 (CH2), 69.9 (Ins C), 69.6 (Ins C),
68.7 (Ins C), 67.1 (Ins C), 21.6 (CH3), 21.5 ppm (CH3); elemental analysis
calcd (%) for C28H28O10S2: C 57.13, H 4.79, S 10.89; found: C 57.4, H
4.53, S 11.03.
d-4-O-Benzyl-myo-inositol-1,3,5-orthoformate (ent-12): Methanolysis of
ent-11 (0.589 g, 1.0 mmol) with sodium methoxide (0.541 g, 10.02 mmol)
in dry methanol (8 mL) as in the preparation of 12 gave ent-12 as a gum
(0.275 g, 98%). Rf =0.28; [a]2D7 =+15.3 (c=1 in ethanol); 1H NMR
(CDCl3, 200 MHz, TMS): d=7.23–7.50 (m, 5H; Ar H), 5.44 (d, 1H, J=
1.3 Hz; HCO3), 4.67 (q, 2H, J=11.6 Hz; CH2), 4.38–4.55 (m, 2H; Ins H),
4.18–4.35 (m, 3H; Ins H), 4.09 (s, 1H; Ins H), 3.75 (d, 1H, J=10.2 Hz;
OH), 3.23 ppm (s, 1H; OH); 13C NMR (CDCl3, 75.48 MHz, TMS): d=
135.8 (Carom), 128.9 (Carom), 128.8 (Carom), 128.0 (Carom), 102.7 (HCO3),
74.7 (Ins C), 74.2 (Ins C), 73.0 (CH2), 72.2 (Ins C), 67.8 (Ins C), 67.3 (Ins
C), 60.6 ppm (Ins C); IR (neat): n˜ =3200–3550 cmÀ1; elemental analysis
calcd (%) for C14H16O6: C 59.99, H 5.75; found: C 60.11, H 5.70.
Thermal analysis: The thermal behaviour of dimorphs of rac-3 was inves-
tigated by measuring the enthalpy change on a Mettller differential scan-
ning calorimeter instrument. About 3–5 mg of crystals were placed on an
aluminium pan (5 mm diameter) and were analysed from room tempera-
ture to 2008C by using an empty pan as the reference. The heating rate
was 108CminÀ1 and nitrogen gas was used for purging. DSC analysis
(Figure 3) of form II crystals of rac-3 indicated a phase change around
145–1508C. Analysis of the crystals by X-ray diffraction revealed that
this polymorph underwent crystal-to-crystal transformation on heating at
1458C to give form I crystals.
d-2,6-Di-O-benzoyl-4-O-benzyl-myo-inositol-1,3,5-orthoformate (ent-13):
Compound ent-12 (0.25 g, 0.89 mmol) was benzoylated with benzoyl chlo-
ride (0.75 g, 5.33 mmol), dry pyridine (4 mL) and DMAP (0.01 g) as in
the preparation of 13 to give ent-13 as a white solid (0.418 g, 96%). Rf =
0.35; m.p. 140–1428C; [a]D27 =À25.02 (c=1 in CHCl3); 1H NMR (CDCl3,
200 MHz, TMS): d=8.13–8.21 (m, 2H; Ar H), 7.87–7.97 (m, 2H; Ar H),
7.43- 7.68 (m, 4H; Ar H), 7.20–7.33 (m, 7H; Ar H), 5.80 (dt, J=4.0,
1.8 Hz 1H; Ins H), 5.64–5.70 (m, 2H; Ins H, HCO3), 4.69–4.76 (m, 1H;
Ins H), 4.52–4.68 (m, 4H; Ins H), 4.48 ppm (dt, 1H, J=3.8, 1.6; Ins H);
13C NMR (CDCl3, 50.3 MHz, TMS): d=166.1 (C=O), 165.3 (C=O), 136.7
(Carom), 133.4 (Carom), 133.3 (Carom), 129.9 (Carom), 129.5 (Carom), 128.9
(Carom), 128.4 (Carom), 128.3 (Carom), 128.0 (Carom), 127.9 (Carom), 103.2
(HCO3), 73.4 (Ins C), 72.1 (CH2), 69.9 (Ins C), 69.6 (Ins C), 68.1 (Ins C),
67.4 (Ins C), 64.2 ppm (Ins C); IR (CHCl3): n˜ =1722 cmÀ1; elemental
analysis calcd (%) for C28H24O8: C 68.84, H 4.95; found: C 68.57, H 4.61.
Solid-state transesterification reaction of form II crystals of rac-3:
Form II crystals of rac-3 (0.032 g, 0.08 mmol) and anhydrous sodium car-
bonate (0.07 g, 0.7 mmol) were mixed together and ground to a fine
powder by using a pestle and mortar. This mixture was heated in a glass
stoppered test tube at 1158C under an argon atmosphere for 195 h. The
reaction mixture was cooled to room temperature and the products were
extracted with chloroform/methanol 1:1 (2ꢂ10 mL). The mixture of
d-4-O-Benzyl-myo-inositol (ent-14): Compound ent-12 (0.021 g,
0.08 mmol) was treated with trifluoroacetic acid and water (0.4+0.1 mL)
at room temperature for 24 h (as in the preparation of 14) to give ent-14
as white needle-type crystals (0.017 g, 84%). M.p. 175–1768C (lit.:[29a]
products obtained on evaporation of the solvent was separated by preACHTUNGTRENNUNGpar-
AHCTUNGTREGaNNUN tive TLC to give the tribenzoate 6 (0.017 g, 42%; m.p. 153–1558C
(lit.:[36] m.p. 154–1558C)) and the diol 9 (0.01 g, 42%; m.p. 158–1598C
(lit.:[37] m.p. 1608C)) as white solids.
Chem. Eur. J. 2009, 15, 261 – 269
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
267

M. M. Bhadbhade, M. S Shashidhar et al.
Note: We have observed earlier that the crystal structure of dibenzoates
analogous to rac-3 remains unaffected on grinding with sodium carbon-
ate. For details see reference [21].
CCDC-690376 (rac-3) and -690375 (ent-1) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
Solid-state transesterification reaction of form I crystals of rac-3: The re-
action was carried out as above by using form I crystals of the orthoace-
tate rac-3 (0.103 g, 0.25 mmol) and anhydrous sodium carbonate (0.212 g,
2.0 mmol) at 1158C for 195 h. The tribenzoate 6 (0.017 g, 13%) and the
starting material rac-3 (0.024 g, 23%) were separated from the mixture
of products formed[21b] by column chromatography using a mixture of
ethyl acetate/dichloromethane/petroleum ether 1:1:8 as the eluent.
Acknowledgements
X-ray crystallography: Single-crystal X-ray structures were determined
for form II crystals of rac-3 and the enatiomeric orthoformate ent-1. All
the crystals were stable at room temperature and the intensity data mea-
This work was supported by the Department of Science and Technology,
New Delhi (India). C.M. is the recipient of a Senior Research Fellowship
of the Council of Scientific and Industrial Research (India). Help by Dr.
S. Mule in recording the DSC runs is acknowledged.
ACHTUNGTRENNUNGsureACHTUNGTRENNUNGments were carried out at room temperature (297 K) on a Bruker
SMART APEX CCD diffractometer with graphite-monochromatized
(MoKa =0.71073 ꢁ) radiation. The X-ray generator was operated at
50 kV and 30 mA. Data were collected with a w scan width of 0.38 at four
different settings of f (0, 90, 180 and 2708) keeping the sample-to-detec-
tor distance fixed at 6.145 cm and the detector position (2q) fixed at
À288. X-ray data collection was monitored by the SMART program
(Bruker, 2003). All the data were corrected for Lorentzian, polarization
and absorption effects by using SAINT and SADABS programs (Bruker,
2003). SHELX-97 was used for structure solution and full-matrix least-
squares refinement on F2. Hydrogen atoms for the enantiomer ent-1
were located from a difference Fourier map, and their positional coordi-
nates and isotropic thermal parameters were refined. H atoms in form II
crystals of rac-3 were included in the refinement as per the riding model.
Molecular and packing diagrams were generated by using ORTEP-32
and Mercury-1.5. Geometrical calculations were performed by using
SHELXTL (Bruker, 2003) and PLATON. Table 4 summarizes the crystal-
lographic data for form II crystals of rac-3 and ent-1.
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Table 4. Summary of crystal data, data collection, structure solution and
refinement details for form II crystals of rac-3 and ent-1.
Crystal data
rac-3 (form II)
ent-1
formula
Mr
C22H20O8
412.38
C21H18O8
398.35
crystal size [mm]
T [K]
0.78ꢂ0.10ꢂ0.08
297(2)
0.69ꢂ0.19ꢂ0.12
297(2)
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
monoclinic
C2/c
orthorhombic
P212121
5.914(2)
16.229(6)
18.957(7)
90
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Soc. 1999, 121, 11930–11931.
27.591(7)
9.383(3)
16.938(4)
117.346(4)
3895.0(18)
8
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4391; Angew. Chem. Int. Ed. 2001, 40, 4256–4261; b) B. Hatano, S.-
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b [8]
V [ꢁ3]
1819.3(12)
4
Z
F
G
1728
832
]
1.406
1.454
]
0.108
0.113
absorption
correction
Tmin
multiscan
multiscan
0.9205
0.9912
13715
3422
2857
0.9265
0.9862
11640
3200
Tmax
reflns. collected
unique reflns.
observed reflns.
index range
2956
À32ꢁhꢁ32,
À6ꢁhꢁ7,À19ꢁkꢁ19,
À11ꢁkꢁ11,À20ꢁlꢁ19 À22ꢁlꢁ22
R1 [I>2s(I)]
wR2
0.0693
0.1468
0.0344
0.0779
R1 (all data)
wR2 (all data)
goodness-of-fit
D1max, D1min [eꢁÀ3
0.0834
0.1534
1.214
0.178, À0.259
0.0379
0.0797
1.099
0.127, À0.119
]
268
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Chem. Eur. J. 2009, 15, 261 – 269

Enhancing Intermolecular Benzoyl-Transfer Reactivity in Crystals
FULL PAPER
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Received: July 22, 2008
Published online: November 26, 2008
Chem. Eur. J. 2009, 15, 261 – 269
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
269