Construction of Two-Component Chemically Reactive Supramolecular Assemblies-Acyl Migration Reactions in Cocrystals of Napthalene-2,3-Diol and Its Diesters

Article abstract of DOI:10.1002/cplu.202100139

Reactions in solids are of contemporary interest due to applications in pharmaceutical industries to environmental sustainability. Although several reactive crystals that support chemical reactions have been identified and characterized, the same cannot be said about reactive cocrystals. Earlier we correlated the facile acyl group transfer reactions in crystals with supramolecular parameters obtained from the crystal structures. The structure-reactivity correlation revealed the requirement of proper juxtaposition of electrophile (C=O) and the nucleophile (OH) with distance (～3.2 ?) and angle (～90°) along the chain structure. The current article describes the preparation of cocrystals that are capable of supporting intermolecular acyl group transfer reactions in a group of structurally similar molecules. The cocrystals of naphthalene 2,3-diol and its corresponding diesters showed a facile solid state acyl transfer reaction, which has been well correlated with their crystal structures.

Full text of DOI:10.1002/cplu.202100139

A Multidisciplinary Journal Centering on Chemistry
Accepted Article
Title: Construction Of Two-Component Chemically Reactive
Supramolecular Assemblies-Acyl Migration Reactions In
Cocrystals Of Napthalene-2,3-Diol And Its Diesters
Authors: Vir Bahadur, Rajesh G. Gonnade, Majid I. Tamboli, Shobhana
Krishnaswamy, and Mysore S. Shashidhar
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ChemPlusChem
10.1002/cplu.202100139
FULL PAPER
Construction
Of
Two-Component
Chemically
Reactive
Supramolecular Assemblies-Acyl Migration Reactions In
Cocrystals Of Napthalene-2,3-Diol And Its Diesters
Vir Bahadur,[a][b] Rajesh Gonnade,*[b][c] Majid I. Tamboli, Shobhana Krishnaswamy, Mysore S.
[a]
[c]
Shashidhar*[a][b]
Abstract: Reactions in solids are of contemporary interest due to
applications in pharmaceutical industries to environmental
sustainability. Although several reactive crystals that support
chemical reactions have been identified and characterized, the same
cannot be said about reactive cocrystals. Earlier we correlated the
facile acyl group transfer reactions in crystals with supramolecular
parameters obtained from the crystal structures. The structure-
reactivity correlation revealed the requirement of proper juxtaposition
of electrophile (C=O) and the nucleophile (OH) with distance (~3.2 Å)
and angle (~90°) along the chain structure. The current article
describes the preparation of cocrystals that are capable of supporting
intermolecular acyl group transfer reactions in a group of structurally
similar molecules. The cocrystals of naphthalene 2,3-diol and its
corresponding diesters showed a facile solid state acyl transfer
reactions which has been well correlated with their crystal structures.
state structure-reactivity correlations that augment the
development of synthetic methods. For instance, even though
crystal structures can be determined with precision, correlation of
crystal structure with reactivity has been realized mainly for
addition to carbon-carbon multiple bonds[
9-12]
and more recently
for acyl transfer reactions.[4] Most other reactions known to occur
in molecular crystals are serendipitously discovered solitary
examples.[13] A large fraction of the organic reactions reported as
reactions in the solid-state includes solvent-less reactions, where
it is not always clear whether the reaction system retains the solid
phase until completion.[ Although these reactions may be useful
in synthesis, they contribute little toward the development of
organized databases that could be used to predict reactivity or
products while designing a synthetic scheme. Hence, we believe
that there is a need for the discovery and systematic enumeration
of reactions in molecular solids for the development of a database,
which could enable (supramolecular) structure-reactivity
correlations that allow prediction of reactivity in condensed
phases and contribute towards the development of functional
3]
Introduction
solids.
Contemporary literature in chemistry reveals considerable
interest in identifying and preparing functional molecular solids-
solids that possess a particular property, specific use, or
application. One of the properties that interest chemists is the
chemical reactivity of solids[2] since it influences the outcomes of
Earlier work in our laboratory[4] allowed the identification of
crystals capable of supporting intermolecular acyl transfer
reaction between the molecular components in the crystal, based
on three supramolecular structural parameters viz., the relative
orientation of the electrophile (El, ester C=O) and the nucleophile
[
1]
[
3],[4]
stereo- and regio-selective reactions,
affects the stability of
(Nu, OH) – (a) distance of about 3.2 Å and an angle of about 90⁰;
drugs[5],[6] and drug formulations and enables the design of solid
[7]
(b) the presence of channels for the reaction to proceed in a
[
8]
state devices. Even though the fact that organic molecules can
react in the solid state has been known for several decades,
advances in this area of research have been minimal compared
to the corresponding progress pertaining to reactions of organic
molecules in the solution state. Structure-reactivity correlations in
the latter have matured to the extent that allows prediction of
reactivity and products for chemists to be able to design multistep
reaction sequences and processes (retrosynthesis) with
confidence. On the other hand, chemists intending to pursue solid
state synthesis are severely handicapped by the absence of solid
domino fashion and (c) presence of weaker non-covalent
interactions that aid the intermolecular acyl transfer. The current
article describes the preparation of cocrystals that are capable of
supporting intermolecular acyl-transfer reactions. Some of the
reactions previously reported in cocrystals are 2+2
[14]
[15]
[16]
cycloaddition,
decarboxylations,
S
N
2
reactions,
[17]
[18]
asymmetric photocyclization, and isomerization. Cocrystals
find applications in research and industry
[19],[20]
as they exhibit
differences in properties (such as melting point, solubility,
mechanical properties, chemical stability, and reactivity)
[
21]
compared with the individual components. In the context of
chemical reactivity in molecular solids, cocrystals can undergo
heteromolecular reactions (A+B → Products), while crystals
composed of a single molecular entity can only be used to perform
homomolecular reactions (nA → Products).
[a]
Dr. Vir Bahadur, Dr. Majid I. Tamboli, Dr. Mysore S. Shashidhar:
Division of Organic Chemistry CSIR-National Chemical Laboratory,
Pune, 411008, India. E-mail: ms.shashidhar@ncl.res.in
[
b]
c]
Academy of Scientific and Innovative Research (AcSIR), Sector 19,
Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002, India.
Dr. Rajesh G. Gonnade and Shobhana Krishnaswamy: Physical and
Materials Chemistry Division, CSIR-National Chemical Laboratory,
Pune, 411008, India. E-mail: rg.gonnade@ncl.res.in.
[
Results and Discussion
Synthesis and characterization of all diesters, monoesters and
cocrystals are given in supporting information along with single
crystal X-ray diffraction data. Supporting information for this article is
given via a link at the end of the document.
Discovery and characterization of intermolecular acyl transfer
reactions in myo-inositol derivatives[22] provided a conduit for us
to identify other molecular crystals (comprised of molecules that
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ChemPlusChem
10.1002/cplu.202100139
FULL PAPER
bear no structural resemblance to inositol derivatives) that were
capable of exhibiting intermolecular acyl transfer reactions
sodium carbonate, as predicted from their supramolecular
structure (Scheme 3). These thermal reactions were carried out
at least 14 °C below the melting point of the cocrystals and the
yield of the monoesters obtained were 94, 95, 86, 82 and 71% for
the cocrystals 1·4, 1·5, 1·6, 1·7 and 1·8, respectively. The
monoesters 3 and 9-12 were not separated and isolated. Yields
[
23]
(Scheme 1).
OH
+ 2
OH
OCOAr
OH
OH
OH
OCOAr
OCOAr
2
Na CO3
2
Heat
1
given are for the mixture of monoesters obtained. H NMR spectra
of these mixtures clearly showed that the ratio of monoesters was
1
3
1·2
Ar =
1:1, as expected (Figures S7-S10, the supporting information).
CH
3
Scheme 1. Acyl transfer reaction between the ditoluate 2 and diol 1 in 1•2 (2:1
cocrystals identified by a search of the Cambridge Structural Database - CSD).
R1
R1
R2
O
O
O
O
OH
OH
O
O
OH
OH
O
O
Na2CO3
Heat
2
OH
OH
The logical extension of this work was to see if hitherto unknown
cocrystals capable of supporting acyl transfer reactions within
them could be prepared and experimentally tested for the
occurrence of the reaction. The crux of this was to decide which
other compounds containing ester groups could be cocrystallized
with the diol 1. Our earlier work on the correlation of the incidence
of polymorphism with cocrystal formation in disubstituted benzene
derivatives had qualitatively suggested that small organic
molecules that exhibit polymorphism could be more prone to form
cocrystals and that para-disubstituted benzene derivatives had a
R2
2
:1 Cocrystal
diol
1
monoesters
R1 = -CH3 (3) + R2 = -F (9)
(3) + R2 = -Cl (10)
R1 = -CH (3) + R2 = -Br (11)
R1 = -CH (3) + R2 = -I (12)
3
1
2
1.4 (R = CH , R = -F)
3
1
2
R1 = -CH
1
1
1
.5 (R = CH
3
, R = -Cl)
3
1
2
.6 (R = CH
3
, R = -Br)
3
1
2
.7 (R = CH
3
, R = -I)
1
2
R1 = R2 = -I (12)
1.8 (R = R = -I)
Scheme 3. Acyl transfer reaction in cocrystals of the diol 1 resulting in the
formation of monoesters.
higher propensity to form polymorphs as compared to ortho-
disubstituted derivatives.[
24]
Hence we prepared several p-
All the cocrystals were isostructural and belonged to the
orthorhombic centrosymmetric Pbcn space group containing one
molecule of naphthalene diol and half molecule of naphthalene
diester in the asymmetric unit resulting in 2:1 stoichiometry
substituted dibenzoates of the diol 1 (Scheme 2) and attempted
their cocrystallization with the diol 1. Symmetric iodo-dibenzoate
8
was prepared by one step acylation of the diol 1 by p-
(
Figure S6, Table S2, the supporting information). The
iodobenzoyl chloride, while the unsymmetric diesters 4-7 were
prepared by the sequential acylation of the diol 1 with two different
acid chlorides.
naphthalene diester molecule occupies a special position (2-fold
symmetry) and hence only half of the molecule is present in the
asymmetric unit. In cocrystals, 1·4, 1·5, 1·6, and 1·7, both ester
groups (halogen and methyl substituted) are statistically
disordered across the two-fold axis, and hence, their occupancies
have been fixed at 50% at the same position. The conformational
analysis of the diester moiety revealed flat geometry for the
naphthalene moiety; however, its difference in the orientation
regarding the ester groups was about 50°. Both the phenyl rings
of the diester groups are locked in parallel displaced π···π
stacking interactions (Cg3···Cg3, see Table S3, the supporting
information for all the intra and intermolecular interactions),
however in opposite directions due to two-fold symmetry
relationship. The naphthalene diol moiety is also flat and both the
vicinal hydroxyl groups are connected through an intramolecular
hydrogen bond, O-H···O (O2-H2A···O1). In the asymmetric unit,
both diol and ester moieties are associated mostly through C-
H···π interactions engaging C-H of the naphthalene diester
molecule and π cloud of the naphthalene ring (Figure 1 and Figure
S6, the supporting information).
OCOR3
OH
3
R COCl
R1 = p-C H F, R2 = p-C H CH
6 4 6 4 3
4
5
TEA, Py-DCM
OCOR3
OH
R1 = p-C H Cl, R = p-C H CH
2
6
4
4
4
6
4
3
8
1
6 R1 = p-C
Br, R2 = p-C
R1COCl
TEA, Py-DCM
6
H
6
H
4
CH
CH
3
7 R1 = p-C
I, R2 = p-C
6
H
6
H
4
3
8
R3 = p-C H I
6 4
OCOR1
OCOR
1
R2COCl
TEA, Py-DCM
OCOR2
OH
3
4-7
Scheme 2. Preparation of the diesters that formed 2:1 cocrystals with the diol 1
(
Table S1, the supporting information).
All the dibenzoates shown in Scheme 2 formed 2:1 cocrystals
with the diol 1 and showed a sharp endotherm in DSC, indicating
no phase transformation during heating until the melting of the
cocrystals (Figures S1-S5, the supporting information). We also
attempted cocrystallization of the diol 1 with chloro and bromo
analogs of 8 as well as unsymmetric dibenzoates not containing
the toluate moiety, but none of these diesters formed cocrystals.
Cocrystal structures were established by single-crystal X-ray
diffraction analysis; all the cocrystals were isostructural with 1·2
H
O
H
O
O1
C3
O
O4
Me/I
O
C16
O
(
Figure S6, Table S2, the supporting information). All the
O
X/I
cocrystals exhibited acyl transfer reactivity in the presence of
(
a)
(b)
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10.1002/cplu.202100139
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Figure 1. (a) Schematic representation of the relative geometry of the El···Nu
interactions in cocrystals 1·4, 1·5, 1·6, 1·7 and 1·8 (X = F, Cl, Br, I). Values for
geometrical parameters for each cocrystal are listed in Table 1. (b) The relative
orientation of the reacting molecules of dihydroxynaphthalene 1 and diester 4 in
cocrystals 1·4 at -173 C.
Table 1. Electrophile···Nucleophile interaction parameters for the
reacting molecules in cocrystals (at 100 (2) K); El and Nu
respectively being ester carbonyl carbon atom and hydroxyl group
oxygen atom (e.g., C16 and O1 in Figure 1a).
El···Nu
C16···O1 (Å)
1·4
3.179(2)
1·5
3.1529(1
1·6
3.151(2)
1·7
3.158(3)
1·8
3.261(
9)
8)
<
O4=C16···
86.08(10
85.83(9)
85.40(1
0)
84.33(14
82.4(4)
°
O1 ( )
)
)
<
H1A-
O1···C16 ( )
C2-
O1···C16 ( )
82(2)
82.8(15)
78.3(19)
82(2)
80(6)
°
<
102.80(1
2)
102.55(9
)
102.04(
9)
100.99(1
3)
99.4(4)
°
Further, there is a short contact between the carbonyl carbon of
the ester moiety and hydroxyl oxygen (H-O···C=O) as observed
[
23]
in the cocrystal 1·2. The closely associated naphthalene diols
form a dimeric unit across the inversion center using classical O-
H···O (O2-H2A···O1) hydrogen bonds. Two such dimeric units
sandwich the naphthalene diester moiety through the C-H···π
(C12-H12···Cg5, C14-H14···Cg6) contacts and the aromatic
stacking π···π (Cg3···Cg5) interactions engaging diester phenyl
rings and the phenyl ring of the naphthalene (diol) moiety (Figure
Figure 2. (a) The layered arrangement of the naphthalene diester and diol
molecules along the ac-diagonal in cocrystal 1·4. (b) The discrete packing of the
naphthalene diester and diol molecules viewed down the layered structure
2a; for similar molecular association in cocrystals, 1·5, 1·6, 1·7
and 1·8, see Figure S11, the supporting information).
(
down ac-diagonal) in cocrystal 1·4. A similar molecular association is observed
There also exist the X···π (X = halogen atom, π = Cg5, Cg6) and
C-H···π interactions between the halogen and toluoyl H atoms of
the diester moiety and π electron cloud of the naphthalene rings
of the diol 1. The sandwiched units are extended along the ac-
diagonal to reveal a one-dimensional layered structure wherein
the reactive functional groups OH (O1-H1A) and C=O (C16=O4)
are in close proximity (Figure 2a, for similar molecular association
in cocrystals, 1·5, 1·6, 1·7 and 1·8, see Figure S11, the supporting
information). The presence of C-H···π and halogen···π
interactions between the naphthalene diesters and the diol 1
strengthen the association of molecules within the layered
assembly. The adjacent layers are connected through strong O-
H···O (O2-H2A···O4) hydrogen bonds involving the hydroxyl
group of the naphthalene diol and carbonyl oxygen of the ester
moiety parallel to the ac-diagonal. This association is further
supported by a linear C-H···O (C22-H22···O2) contacts between
C-H of the benzene ring of ester group and hydroxyl oxygen
in the other isostructural cocrystals 1·5, 1·6, 1·7 and 1·8 (see Figures S11 and
S12, the supporting information).
Figure 3. The view of molecular packing in cocrystals 1·4 down the b-axis
showing the discrete packing of adjacent layers along the ac-diagonal. A similar
molecular association is observed in the other isostructural cocrystals 1·5, 1·6,
(Figure 2b; for similar molecular association in cocrystals, 1·5, 1·6,
1
·7 and 1·8, see Figure S12, the supporting information). Both
1
·7 and 1·8 (see Figure S13, the supporting information).
these O-H···O and C-H···O interactions not only help to build well
directed and separated channels but also assist in tightly holding
them together along the ac-diagonal. These channels can be
clearly seen when viewed down the b-axis (Figure 3, for similar
molecular association in cocrystals, 1·5, 1·6, 1·7 and 1·8, see
Figure S13, the supporting information).
Pertaining to efficient acyl transfer reaction in the crystalline state
and its correlation with the crystal structure, we carried out a
detailed analysis of the supramolecular features of all the
cocrystals. All the cocrystals revealed short contact between
nearest–OH group (nucleophile, Nu) of the diol 1 and ester C=O
(electrophile, El) of diesters, which lay in the range 3.151(2) Å to
3
.261(9) Å and the angle of approach of Nu towards El was found
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10.1002/cplu.202100139
FULL PAPER
to be between 82.4(4) and 86.08(10) degrees (Table 1, Figure 1,
Figure S6, the supporting information) which are within the limits
of the required metric parameters for the solid-state acyl transfer
reaction. This supramolecular motif is further extended to form a
one-dimensional channel parallel to the ac-diagonal. Moreover,
the neighbouring channels are discretely held to each other
through strong O-H···O and linear C-H···O hydrogen bonds to
reveal a well-defined reaction pathway throughout the crystal
lattice, thereby satisfying all the essential requisites for the acyl
group migration. The relatively lower yield (71%) of the monoester
in the case of the diiodo cocrystal 1·8 is understandable due to
larger El···Nu distance 3.261(9) Å and greater deviation in the
corresponding angle 82.4(4)° as compared to the optimum values
required (3.2 Å and 90°) for efficient acyl transfer reaction.
Generally, reactions in crystals are influenced by steric as well as
electronic factors. El···Nu interactions enumerated above reveal
the effect of electronic factors (Table 1). Although the El···Nu
distances and angles have not changed significantly, there is a
monotonous decrease in the distance and increase in the angle
on proceeding from iodobenzoate 1.8 to fluorobenzaote 1.4. That
this change indeed represents better El···Nu interactions is
reflected by the increase in yield of the products on going from
iodobenzoate 1.8 to fluorobenzaote 1.4.
supported intermolecular acyl-transfer reactivity. The proposed
mechanism for the facile solid-state acyl transfer is shown in
scheme 4,[ which displays the possible initiation of the solid-
state reaction by solid sodium carbonate at the base of a channel
followed by the propagation of the reaction by successive H-atom
and acyl group transfers.
23]
O
O
O
O
H
H
O
H
H
O
H
H
O
H
H
O
O
O
O
O
O
O
naphthalene moity of diester
naphthalene moiety of diol
O
H
H
H
O
O
H
O
H
O
H
O
O
O
O
O
O
=
CH /X
3
O
O
O
Step 2
O
O
H
H
H
H
O
O
O
O
H
H
H
O
O
O
Step 1
ONa
ONa
O
O
O
H
H
O
H
H
O
O
O
H
H
H
O
H
O
O
O
O
O
O
O
O
O
Step 4
Since the cocrystals are isostructural, we compared the unit cell
parameters and volumes to see if there are differences due to
steric effects (Table S2, Figure S14, the supporting information).
The lengths of the a-axis have increased slightly (0.02 to 0.06 Å)
from cocrystal 1·4 to 1·7 whereas cocrystal 1·8 showed a
substantial increase (0.28 Å). The length of the b-axis also
showed a similar trend, but the increase in the b-edge length was
considerable (up to 0.9 Å from 1·4 to 1·7) and for cocrystal 1·8, it
is 1.33 Å. Conversely, the c-axis length revealed a slight decrease
O
H
O
H
O
H
H
O
O
O
H
H
O
H
O
Step 3
O
OH
O
O
O
O
O
H
H
O
O
H
O
H
O
H
O
H
O
O
O
O
Scheme 4. Plausible mechanism for the intermolecular acyl transfer in
cocrystals of the diol 1.
(
up to 0.14 Å for cocrystals 1·4 to 1·8). The unit cell volume also
3
Our experience while carrying out acyl transfer reactions in
molecular crystals showed that the use of fewer than eight
equivalents of sodium carbonate resulted in a lesser yield of
products. We are of the opinion that the initiation of the acyl
transfer reaction in crystals by sodium carbonate happens at the
surface of the crystal. Perhaps large excess of sodium carbonate
is necessary to activate the acyl transfer reaction in individual
crystals simultaneously since we do not stir the reaction mixture
and achieve a high rate of conversion of starting material to
products. However, further work is essential to understand these
interfacial chemical activation phenomena. We also attempted
preparation of cocrystals of the diol 1 with diesters containing
substituents on the benzene ring (of the benzoate) as well as on
the naphthalene ring, as the reaction in these cocrystals could
provide additional evidence for the acyl transfer mechanism
showed a slight increase (up to ~92 Å ) from 1·4 to 1·7; however,
the increase in the cell volume of cocrystal 1·8 was very
significant (~242 Å ). This indicated that the steric bulk of iodine
could have played a role in lowering the yield of the monoester
due to intermolecular acyl transfer in the diiodo cocrystal 1·8.
Hence as expected, both electronic and steric factors contribute
to the overall reactivity and yield of products.
3
To compare the acyl transfer reactivity in the solid and solution
states (and hence to demonstrate the importance of
supramolecular assembly of reacting molecules in cocrystals), we
carried out the acyl transfer reaction in dry p-xylene solution at
comparable temperatures (100-135 °C). As expected, the yield of
the monoesters was much lower (37-51%) and most of the diester
remained unreacted. The acyl-transfer reaction did not occur in
the molten state owing to the loss of topochemical control. TLC
analysis revealed the formation of several products in small
amounts, including monoesters and free carboxylic acids. No
effort was made to isolate or characterize the products. A
comparison of the results of acyl transfer reactions in the
crystalline, solution and molten states clearly indicated the
importance of molecular packing and lattice constraints in these
reactions. Hence from the foregoing, it is clear that we were able
to construct supramolecular assemblies (cocrystals) that
(Scheme 4); but such cocrystals were not obtained.
It is interesting to note that the diester molecule needed at least
one toluate ester group to form a cocrystal (except 1·8) with the
diol 1, as it did not form cocrystals with p-substituted halo-diesters
(F, Cl and Br). The crystal structure analysis also revealed that
the presence of the methyl group helped in establishing the C-
H···π interaction between the hydrogen of the methyl group of
diester and naphthalene ring of the diol 1 in cocrystals (Table S3,
the supporting information) in addition to the halogen···π
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10.1002/cplu.202100139
FULL PAPER
interaction. However, the formation of cocrystals of diol 1 with p-
iodo-substituted diester (8) could be due to relatively stronger I···π
interaction compared to other halogen···π interactions.
NMR (Acetone-D6,
ppm; Elemental analysis calculated for C17
.93; found C, 72.08; H, 3.67 %.
C
6
F
6
as reference, 376.5 MHz): -162.90 (C
6 6
F ), -104.95
H11FO
3
(282.27): C, 72.34; H,
3
Reaction of 1·4 in solution
Conclusions
The cocrystals 1·4 (0.030 g, 0.042 mmol), sodium carbonate (0.035 g, 0.33
mmol) and dry p-xylene (2.5 mL) were heated at 100-105 ºC for 72 h. The
reaction mixture was concentrated under reduced pressure and the
residue worked up as above (as in the solid-state reaction). Column
chromatographic separation yielded a mixture of 3 and 9 (0.012 g, 51%),
the diol 1 (0.08 g,) along with a minor amount of the diester 4 (0.002 g).
We have presented a rational approach for the construction of
cocrystals capable of supporting intermolecular acyl transfer
reactions in them. Variation in the yield of the products obtained
(
in reactions in cocrystals of the diol 1) with respect to the El···Nu
parameter supports the supramolecular structure-reactivity
Solid-state reactivity of cocrystals 1·5
[
22]
correlations that we had enumerated earlier. Despite numerous
reports of cocrystals in the CSD, cocrystals with desired
properties are not routinely realized. The work presented here
illustrates that concerted efforts towards the development of
cocrystals, even by qualitative understanding and analysis of
supramolecular assemblies, can lead to property (in the present
case, acyl transfer reactivity) oriented supramolecular (cocrystals)
synthons and augment the pace of research directed towards the
development of functional assemblies.
The reaction was carried out as described for 1·4 using 1·5 (0.100 g, 0.14
mmol) and activated sodium carbonate (0.117 g, 0.92 mmol) at 125 ºC for
7
2 h to obtain a 1:1 mixture (Figure S8, the supporting information) of
monoesters 3 and 10 (0.074 g, 95%) and the diol 1 (0.020 g). Column
chromatography of the mixture of monoesters 3 and 10 (silica gel 100-200
mesh; eluent, ethyl acetate:light petroleum 1:9, v/v), yielded 10 (0.022 g,
46%) and a mixture of 3 and 10.
Data for 10. TLC R
f
: 0.6 (1:9 ethyl acetate: light petroleum); Mp. 211 o
plate shaped crystals obtained from chloroform; IR (Nujol): ꢀ 3396, 2923-
C
(
2
7
-
1 1
858, 1720 cm ; H NMR (400 MHz, Acetone-D6) δ 7.32-7.49 (m, 3 H),
13
.66-7.86 (m, 5 H), 8.23-8.29 (d, 2 H), 9.06 (s, 1 H) ppm. C NMR (101
Experimental Section
MHz, Acetone-D
6
) δ 112.0, 121.6, 124.6, 126.9, 128.2, 129.2, 129.3 129.9,
+
1
2
32.7, 134.0, 140.3, 141.2, 164.5 ppm; HRMS calculated for C17
99.0475 found 299.0457.
3
H11ClO H
Solid-state reactivity of cocrystals 1·4
Reaction of 1·5 in solution
A mixture of freshly grown crystals 1·4 (0.050 g, 0.07 mmol) and activated
sodium carbonate (0.059 g, 0.6 mmol) was ground into a fine powder using
a mortar and pestle. The mixture was transferred to a test tube filled with
argon and heated in an oil bath (100-105 ºC) for 72 h. The reaction mixture
was cooled to ambient temperature; the solid was extracted with
dichloromethane (DCM) and the residue was separated by filtration. The
The cocrystals 1·5 (0.100 g, 0.14 mmol), sodium carbonate (0.117 g, 0.92
mmol) and dry p-xylene (4 mL) were heated at 120 ºC for 48 h. The
reaction mixture was concentrated under reduced pressure and the
residue worked up as above (as in the solid-state reaction). Column
chromatographic separation yielded a mixture of 3 and 10 (0.039 g, 50%),
the diol 1 (0.033 g) along with a minor amount of the diester 7 (0.020 g).
2 4
DCM solution was washed with water, dried over anhydrous Na SO and
evaporated to dryness. TLC analysis of the residue showed it to be a
mixture of monoesters 3 and 9 and a minor amount of the unreacted
diester 4. The mixture of monoesters 3 and 9 (0.036 g, 94%) was
separated by column chromatography (silica gel 100-200 mesh; eluent,
ethyl acetate:light petroleum 1:9, v/v). The monoesters 3 and 9 were
Solid-state reactivity of cocrystals 1·6
The reaction was carried out as described for 1·4 using 1·6 (0.110 g, 0.141
mmol) and activated sodium carbonate (0.119 g, 1.12 mmol) at 135 ºC for
7
2 h to obtain a 1:1 mixture (Figure S9, the supporting information) of
1
obtained in a 1:1 ratio, as revealed by H NMR spectroscopy (Figure S7,
monoesters 3 and 11 (0.074 g, 86%) and the diol 1 (0.026 g). Column
chromatography of the mixture of monoesters 3 and 11 (silica gel 100-200
mesh; eluent, ethyl acetate:light petroleum 1:9, v/v), yielded 11 (0.018 g,
the supporting information). Our attempts to separate monoesters 3 and 9
by column chromatography (silica gel 100-200 mesh; eluent, ethyl
acetate:light petroleum 1:9, v/v), yielded 9 (0.011g, 56%) and a mixture of
3
4%) and a mixture of 3 and 11.
3
and 9.
Data for 11: TLC R
f
: 0.6 (1:9 ethyl acetate: light petroleum); Mp. 230 o
C
The solid residue (left behind after extraction with DCM) was extracted with
ethyl acetate (2 20 mL). The combined ethyl acetate extract was washed
with water, dried over sodium sulfate and evaporated under reduced
pressure to obtain a solid. The solid was purified over a short column of
silica gel (100-200 mesh, eluent: 1:4 ethyl acetate:light petroleum) to
obtain the diol 1 (0.011 g); Mp. 162 ºC. Literature Mp. 162 ºC.[23] This
represents the diol 1 formed due to transacylation reaction, as well as that
present in unreacted cocrystals.
(
plate shaped crystals obtained from ethyl acetate; IR (Nujol)ꢁ ꢀ 3396,
-
1 1
2
923-2858, 1718 cm ; H NMR (400 MHz, Acetone-D
6
) δ 7.23-7.40 (m, 3
13
H), 7.67-7.79 (m, 5 H), 8.06-8.11 (d, 2 H), 8.99 ppm (s, 1 H) C NMR (101
MHz, Acetone-D ) δ 111.6, 121.2, 124.4, 126.7, 128.0, 128.9, 129.1, 129.8,
32.5, 133.9, 140.2, 141.2, 164.6 ppm; HRMS calculated for
6
1
C
+
17 3
H11BrO H 342.9970 found 342.9993.
Reaction of 1·6 in solution
Data for 9: TLC R
f
: 0.6 (35% ethyl acetate in light petroleum); Mp. 228-230
The cocrystals 1·6 (0.110 g, 0.14 mmol), sodium carbonate (0.119 g, 1.12
mmol) and dry p-xylene (6 mL) were heated at 120 ºC for 72 h. The
reaction mixture was concentrated under reduced pressure and the
residue worked up as above (as in the solid-state reaction). Column
chromatographic separation yielded a mixture of 3 and 11 (0.040 g,
46%),the diol 1 (0.030 g) along with diester 6 (0.036 g).
o
C (crystals from Ethyl acetate); IR (Nujol): ꢀ 3350-3450, 1738 cm-1; 1
H
NMR (500 MHz, Acetone-D
.81 (d, J = 8.5 Hz, 1 H), 8.25 – 8.35 (m, 2 H), 9.12 ppm (s, 1 H, D
exchangeable, OH); 13C NMR (126 MHz, Acetone-D
) δ 112.0, 116.5,
6
) δ 7.31 - 7.45 (m, 5 H), 7.70 - 7.76 (m, 2 H),
7
2
O
6
1
1
16.7, 121.5, 124.5, 126.80, 126.84, 127.0, 128.1, 129.2, 133.7, 133.8,
33.9, 141.3, 149.2, 164.4, 166.9 ppm( JC-F 253 Hz); H-decoupled 19F
1
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Solid-state reactivity of cocrystals 1·7
X-ray data acquisition (unit–cell measurements and data collection) was
controlled and monitored by the APEX3 program suite of Bruker-AXS
(
polarization and absorption effects (multi-scan method) by using SAINT
and SADABS programs with the transmission coefficients. Using the
APEX3 (Bruker, 2016) program suite, the structure was solved with the
ShelXS-97 structure solution program, using direct methods.[26] The model
The reaction was carried out as described for 1·4 using 1·7 (0.110 g, 0.13
mmol) and activated sodium carbonate (0.112 g, 1.06 mmol) at 130 ºC for
Bruker, 2016).[25] The complete data sets were corrected for Lorentz-
7
2 h to obtain a 1:1 mixture (Figure S10, the supporting information) of
monoesters 3 and 12 (0.081 g, 82%) and the diol 1 (0.023 g). Column
chromatography of the mixture of monoesters 3 and 12 (silica gel 100-200
mesh; eluent, ethyl acetate:light petroleum 1:9, v/v) yielded 12 (0.023 g,
was refined with
minimization based on F .
a
version of ShelXL-2013 using Least Squares
4
4%) and a mixture of 3 and 12.
2 [27]
The hydroxyl group H-atoms for all the
cocrystals were located in the difference map and refined isotropically,
while all other H-atoms were placed in a geometrically idealized position
and constrained to ride on their parent atoms. An ORTEP III view of all the
cocrystals was drawn at the 50% probability displacement ellipsoids, and
H atoms are shown as small spheres of arbitrary radii.[28] The molecular
packing diagrams were generated using the Mercury program.[29]
Geometrical calculations were performed using SHELXTL and
PLATON.[30] Crystal data, data collection and structure refinement for all
the cocrystals are summarized in Tables S2, the supporting information.
Deposition Number(s) 2064852 (for cocrystal 1·4), 2064853 (for cocrystal
1·5), 2064854 (for cocrystal 1·6), 2064855 (for cocrystal 1·7) and 2064856
Data for 12: TLC R
C (plate shaped crystals obtained from ethyl acetate); IR (Nujol)ꢁ ꢀ 3400,
f
: 0.6 (1:9 ethyl acetate:light petroleum); Mp. 225-227
o
-
1 1
2
6
923-2858, 1717 cm ; H NMR (400 MHz, Acetone-D ) δ 7.35-7.37 (m,
J=8.13, 1.13 Hz, 1 H) 7.40 - 7.45 (m, 2 H) 7.73 - 7.75 (m, 2 H) 7.81 (d,
J=8.13 Hz, 1 H) 7.98 - 8.01 (m, 2 H) 8.02 - 8.05 (m, 2 H) 9.03 ppm (s, 1
H); 13C NMR (101 MHz, Acetone- D
6
) δ 101.94, 112.12, 121.61, 124.68,
1
1
26.97, 128.23, 129.31, 130.26, 132.56, 134.03, 139.11, 141.31, 149.20,
65.04 ppm; HRMS calculated for C17H11IO H 390.9831, found 390.9826.
3
+
Reaction of 1·7 in solution
(
for cocrystal 1·8) contains the supplementary crystallographic data for this
The cocrystals 1·7 (0.090 g, 0.11 mmol), sodium carbonate (0.094 g, 0.89
mmol) and dry p-xylene (6 mL) were heated at 135 ºC for 72 h. The
reaction mixture was concentrated under reduced pressure and the
residue worked up as above (as in the solid-state reaction). Column
chromatographic separation yielded a mixture of 3 and 12 (0.034 g, 47%) ,
the diol 1 (0.013 g) along with diester 7 (0.030 g ).
paper. These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service www.ccdc.cam.ac.uk/structures.
Acknowledgements
Solid-state reactivity of cocrystals 1·8
This work was supported by an emeritus scientist grant
The reaction was carried out as described for 1·4 using 1·8 (0.118 g, 0.12
mmol) and activated sodium carbonate (0.106 g, 0.96 mmol) at 135 ºC for
(21(1090)/19/EMR-II) to MSS from CSIR, New Delhi. VB and MT
7
2 h to obtain the monoester 12 (0.07 g, 71%) and the diol 1 (0.026 g).
received fellowships from CSIR, New Delhi.
Reaction of 1·8 in solution
Keywords: acylation • domino reactions • intermolecular
interactions • Reaction in Cocrystal • solid-state reactions • X-ray
diffraction
The cocrystals 1·8 (0.235 g, 0.25 mmol), sodium carbonate (0.212 g, 1.94
mmol) and dry p-xylene (12 mL) were heated at 130 ºC for 72 h. The
reaction mixture was concentrated under reduced pressure and the
residue worked up as above (as in the solid-state reaction). Column
chromatographic separation yielded monoester 12 (0.073 g, 37%), the diol
[
[
[
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(0.061 g) along with diester 8 (0.089 g).
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4
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(
2
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.71073 Å) at 100(2) K temperature for all the cocrystals. A preliminary set
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matrix, three runs, each run comprised of 12 frames). The full intensity
[
(
[16] M. C. Etter, G. M. Frankenbach, J. Bernstein, Tetrahedron Lett. 1989, 30,
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depending on the diffraction power of the crystals. The whole process of
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Entry for the Table of Contents
FULL PAPER
Understanding the crystal structure-
reactivity correlation and insights into
cocrystal formation helped us
construct cocrystals that support
intermolecular acyl transfer reactions.
The cocrystals of naphthalene 2,3-diol
and its diesters facilitated the benzoyl
group transfer from the diester
molecules to the diol in their
Vir Bahadur, Rajesh Gonnade,* Majid I.
Tamboli, Shobhana Krishnaswamy,
Mysore S. Shashidhar*
Page No. – Page No.
Construction of two-component
chemically reactive supramolecular
assemblies-Acyl migration reactions
in cocrystals of naphthalene-2,3-diol
and its diesters
cocrystals to yield the corresponding
monoester.
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