Strength from weakness: Conformational divergence between solid and solution states of substituted cyclitols facilitated by CH...O hydrogen bonding

Article

pubs.acs.org/joc

Strength from Weakness: Conformational Divergence between Solid

and Solution States of Substituted Cyclitols Facilitated by CH···O

Hydrogen Bonding

Amol M. Vibhute and Kana M. Sureshan*

School of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram, Thiruvananthapuram, Kerala 695016,

India

S

* Supporting Information

ABSTRACT: We have investigated the conformational

preferences of a series of cyclitol derivatives, namely mono-

and diesters of 1,2:5,6-di-O-isopropylidene-myo-inositol and

1,2:5,6-di-O-cyclohexylidene-myo-inositol, in both solid and

solution states. The solid-state conformations were determined

by single-crystal X-ray analysis. The solution-state conforma-

3

tions were determined by using NMR. The experimental J_HH

values were applied in the Haasnoot−Altona equation to

calculate the dihedral angle (ϕ) between the respective vicinal

protons. By ﬁxing the dihedral angle between diﬀerent sets of

vicinal protons, the molecules were energy-minimized by MM2 method to visualize their conformation in solution. As the solvent

polarities can inﬂuence the conformational preference, we have determined the conformations of these molecules in various

solvents of diﬀerent polarities such as benzene-d₆, chloroform-d, acetonitrile-d₃, acetone-d₆, methanol-d₄, and DMSO-d₆. All of

the compounds adopted boat conformations in solution irrespective of the solvents, acyl groups, or alkylidene protecting groups.

This conformation places H6 and O3 of the cyclitol ring in proximity, such that an intramolecular CH···O hydrogen bond

between them stabilizes this otherwise unstable conformation. However, in the solid state, several intermolecular CH···O

hydrogen bonds force these molecules to adopt the chair conformation. This study uncovers the role of weak noncovalent

interactions in inﬂuencing the molecular conformations diﬀerentially in diﬀerent states.

to the unusual 5a1e (pentaaxial monoequatorial) conformation

through an orthoester lock.¹¹

INTRODUCTION

■

The conformation of molecules present in a substance dictates

the properties of the bulk material.¹For instance, the proper

functioning of biomolecules such as peptides,²proteins,

ligands,³carbohydrates, nucleic acids,⁴lipids, etc. depends on

the conformation of these biomolecules. In addition, the

molecular conformation inﬂuences the physical properties of

materials.⁵In chemistry, the conformation dictates not only the

reactivity but also the selectivity of the reactions. The study of

the role of conformation in deciding the reactivity or selectivity

in chemical transformations⁶and the factors that aﬀect the

conformations is a timely and active area of research. An

important area where the correlation between conformation

and reactivity or selectivity is actively pursued is carbohydrates.⁷

Recently, Bols et al. demonstrated that the conformation of

Apart from covalent conformational locks, conformations can

also be arrested by attractive or repulsive noncovalent

interactions (Figure 1). Strong repulsive steric interactions

between bulky silyloxy groups in trans-vicinal orientation in

cyclohexanes are known to adopt the otherwise unstable diaxial

orientation as a result of conformational ﬂipping.^8,9eThe

classical intramolecular OH···O hydrogen-bonding interactions

are known to stabilize the diaxial conformation of cis-1,3-

cyclohexanedicarboxylic acid.¹²Similarly, intramolecular OH···

O hydrogen bonding is known to stabilize the otherwise

unstable boat conformation (in simple cyclohexane, the boat

conformer is energetically less stable, by 7 kcal/mol, than the

chair conformer) of cis-1,4-cyclohexanediol.¹³As weak

interactions are known to mimic or even overpower relatively

stronger classical hydrogen bonds at times,¹⁴it is, in principle,

possible for weak hydrogen bonds to stabilize the unusual boat

conformations in substituted cyclohexanes. We herein report

that weak CH···O hydrogen bonds¹⁵can also stabilize the

otherwise unstable boat conformation in cyclitols. Though

there are many examples in the literature suggesting that CH···

1

glucopyranosides can be tuned to the C₄conformation by

introducing sterically demanding silyl protecting groups, and as

a consequence, the reactivity can be augmented.⁸In addition,

the inﬂuence of conformation of pyranosides on the selectivity

of glycosylation reactions has been demonstrated.⁹Similarly,

the conformation has been tuned to modulate the reactivity of

cyclitols.¹⁰For instance, the least reactive 2-OH of myo-inositol

could be made most reactive by altering the conformation of

myo-inositol from its normal 5e1a (pentaequatorial monoaxial)

Received: February 27, 2014

Published: May 2, 2014

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NMR spectroscopy is one of the reliable techniques for

studying the solution-state conformations.²⁰As the Karplus

equation relates the dihedral angle (ϕ) between vicinal

3

hydrogens and their J_HHcoupling constants, the dihedral

3

angle can be calculated from the experimental J_HHvalues. We

have used the Haasnoot−Altona equation,²¹which is the most

reliable form of the Karplus equation for studying the solution-

state conformation of cyclitol derivatives,^18,22for the

determination of ϕ values of all sets of vicinal protons. The

solution-state conformations for these compounds were

visualized by energy minimization using MM2 calculations

after ﬁxing the dihedral angles between the vicinal protons as

those obtained from the NMR method.

In a preliminary communication, we reported conformational

studies, in solution and solid states, of di- and monoesters of

1,2:5,6-di-O-isopropylidene-myo-inositol (3−11; Figure 2).^18a

In solution, these molecules adopt a boat conformation due to

intramolecular CH···O hydrogen bonding, but in the solid

state, they adopt a chair conformation as a consequence of

intermolecular CH···O hydrogen bonding. These interesting

and consistent conformational extremities between solid and

solution states prompted us to investigate the generality of this

phenomenon in otherwise diﬀerently protected diketal

derivatives. In the present paper, we extend our conformational

studies to several di- and monoesters of 1,2:5,6-di-O-cyclo-

hexylidene-myo-inositol (12−19) in solution and solid states

and generalize our ﬁndings by comparing with the conforma-

tional preferences of isopropylidene derivatives 3−11.

Figure 1. Stabilization of unusual conformations of cyclohexane

derivatives by noncovalent interactions and covalent conformational

locks.

O hydrogen bonds play signiﬁcant roles in inﬂuencing the

conformation of small molecules,¹⁶to the best of our

knowledge, stabilization of the boat conformation of cyclo-

hexane rings by CH···O is not known.

Conformation of Dibenzoate 12 in Solution. A

comparison of dibenzoates 3 and 12 revealed that they adopt

identical conformations irrespective of the ketal protecting

groups. For instance, the ¹H NMR spectra of both compounds

showed unusually large coupling constants between H1 and H2

(6.8 Hz in 3 and 7.0 Hz in 12) and unusually small coupling

constants between H3 and H4 (4.4 Hz in 3 nd 3.5 Hz in 12).

RESULTS AND DISCUSSION

■

We have been interested in the chemistry of cyclitols^10,17and

the role of weak interactions in determining the conformation

of cyclitols in solid and solution states.¹⁸The fact that esters of

diketals 1 and 2 are intermediates used for phosphoinositol

synthesis prompted us to study their conformations, especially

in the solution state, as it is more relevant with respect to

reactivity. Though it is easy to study the conformation and the

interactions responsible for the conformation in the solid state

using single crystal X-ray crystallography, conformational

analysis in solution is rather cumbersome. Though the use of

the solid-state conformation (crystal structure) to explain the

solution-state behavior is widely practiced, often the solution-

state conformations diﬀer from the solid-state conformations,

pointing out the danger associated with such a practice.¹⁹¹H

3

The usual J_H1H2and J_H3H4values for the chair conformer of

myo-inositol derivatives are around 2.9 and 9.8 Hz, respectively.

3

All of the other vicinal J_HHvalues were also similar between

identical vicinal hydrogens of 3 and 12. The vicinal H−C−C−

3

H dihedral angles (ϕ) were calculated from the J_HHcoupling

constants using the Haasnoot−Altona equation,²¹and the

conformations of the molecules were mapped by doing energy

minimization after ﬁxing the H−C−C−H dihedral angles. The

cyclitol rings of both molecules adopt the boat conformation. It

Figure 2. myo-Inositol derivatives used for conformational studies.

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is strikingly clear that H6 is approaching O3 in this

conformation, which suggests the possible stabilization of this

conformation by an intramolecular CH···O hydrogen bond

between H6 and O3 (Figure 3). The H6 proton is suﬃciently

solvents very consistently, irrespective of the nature of the

solvent.

Conformation of Dipivaloate 13, Dinaphthoate 14,

and Dipyrenoate 15 in Solution. The conformational

preferences of dipivaloate 13, dinaphthoate 14, and dipyrenoate

15 were also tested in various solvents of diﬀerent polarity, and

their conformations were compared with the conformation of

the corresponding isopropylidene analogues. The coupling

constants and corresponding dihedral angles for various vicinal

protons of dipivaloate 13 are almost similar in all of the solvents

(Table 2). As a representative example, the conformation of

dipivaloate 13 was determined in CDCl₃solution (Figure 4A).

In addition, the conformation of cyclohexylidene derivative 13

was identical with that of the isopropylidene derivative 5 in all

solvents tested. The cyclitol ring of 13 adopted a boat

conformation, wherein H6 and O3 are proximally placed. Both

the distance (2.11 Å) and angle (115.68°) are comparable to

those of 5 (2.19 Å; 119°) and are conducive to CH···O

hydrogen bonding between them. It is interesting to note that

the H6···O3 distances of pivaloates are the smallest among the

compounds studied in this series. As with the dibenzoates and

dipivaloates, both dinaphthoate 14 and dipyrenoate 15 also

exhibited a boat conformation in the solution state. The

coupling constants and dihedral angles for a particular set of

vicinal protons (Tables 3 and 4) of 14 and 15 were identical in

all of the solvents tested. H6···O3 distances of 2.35 and 2.36 Å

were observed in the case of dinaphthoate 14 (in CDCl₃) and

dipyrenoate 15 (in DMSO-d₆), respectively. In addition, the

solution conformations of all of the diesters of 1,2:5,6-di-O-

cyclohexylidene-myo-inositol were identical with the solution

state conformations of the corresponding isopropylidene

derivatives 6 and 7, respectively. This study revealed that the

conformations of similar derivatives (e.g. pivaloates of

isopropylidene and cyclohexylidene) were identical irrespective

of the type of ketal protecting group. In addition, it is clear from

the NMR data (Tables 2−4) that all of the the diesters adopt

boat conformation (for the inositol ring), suggesting that the

nature or bulkiness of the acyl group is unimportant for the

conformation.

Figure 3. Conformation of dibenzoate 12 in DMSO-d_6.The

interacting donor (C6−H6) and acceptor (O3) and the resultant

boat form of the cyclitol ring are shown as ball and capped-stick

models, respectively, for clarity. d is the distance between the donor

H6 and acceptor O3, and θ is the C6−H6···O3 angle.

acidic, due to the attachment of an electronegative oxygen to

C6, to be involved in a considerably strong CH···O hydrogen

bond. The separation between the interacting atoms H6 and

the acceptor O3 is 2.30 Å, which is much smaller than the van

der Waals distance (2.72 Å) between them. The angle of

approach of 106.3° is well within the accepted limits for

eﬀective bonding, as CH···O hydrogen bonding is known to be

signiﬁcant even at smaller angles (down to 90°).²³Further

evidence for the CH···O hydrogen bonding was adduced from

the downﬁeld chemical shift of H6 of the cyclitol ring. It is well-

known that, as a consequence of CH···O hydrogen bonding,

the diamagnetic shielding around the donor H decreases and

hence there will be a downﬁeld shift (by Δδ = 0.1−1 ppm) of

the donor H.²⁴Similar downﬁeld shifts of the H6 proton by

0.42 and 0.47 ppm were observed in the case of benzoates 3

and 12, respectively, in comparison to H6 of the tetrol 20,

which adopts a normal chair conformation, in the same solvent

Conformation of Monoesters in Solution. Having

established the fact that diesters of both 1,2:5,6-di-O-

isopropylidene-myo-inositol and 1,2;5,6-di-O-cyclohexylidene-

myo-inositol adopt similar conformations irrespective of the

acyl group and ketal groups, we were curious to know whether

monoesters also adopt such conformations in solution.

Interestingly, the monoesters 16−19 also adopted the boat

conformation in solution as the corresponding monoesters 8−

11 of 1,2:5,6-di-O-isopropylidene-myo-inositol. In addition,

3

(CD₃OD). It is clear from the J_HHvalues of diﬀerent sets of

vicinal hydrogens in various solvents of diﬀerent polarity (Table

1) that molecules 3 and 12 adopt the boat conformation in all

a

3

Table 1. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Dibenzoate 12 and Dibenzoate 3

12

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

6.6 (−8)

CD₃OD

C₆D₆

CD₃CN

3 in DMSO-d₆

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

7.0 (−6)

6.3 (−14)

3.8 (42)

6.3 (−14)

3.9 (43)

6.4 (−12)

4.1 (41)

6.5 (−10)

4.3 (39)

6.3 (−14)

3.9 (43)

3.5 (44)

4.1 (56)

3.6 (45)

4.4 (55)

9.0 (−159)

10.4 (−167)

7.4 (−167)

9.0 (−159)

10.3 (−167)

7.3 (−166)

8.8 (−167)

10.4 (−168)

7.8 (−171)

9.0 (−169)

10.5 (−166)

7.8 (−171)

8.8 (−158)

10.5 (−166)

7.9 (−172)

8.8 (−157)

10.3 (−167)

7.3 (−166)

10.5 (−166)

7.8 (−171)

a

1

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

3

protons of the dibenzoate 12 in solvents of diﬀerent polarities. The J_HHvalues of dibenzoate 3 in DMSO-d₆are given in the last column for easy

comparison.

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a

3

Table 2. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Dipivaloate 13 and Dipivaloate 5

13

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

C₆D₆

CD₃CN

5 in CDCl₃

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

5.9 (−21)

5.0 (33)

6.0 (−19)

4.8 (34)

5.7 (−25)

5.1 (32)

5.7 (−25)

5.1 (32)

5.5 (−26)

5.1 (32)

5.9 (−21)

4.7 (35)

6.3 (−15)

4.7 (35)

6.4 (34)

7.0 (27)

6.9 (38)

7.0 (27)

6.9 (38)

6.5 (34)

5.2 (48)

9.8 (−159)

10.1 (−162)

8.6 (177)

8.8 (−157)

9.7 (−158)

10.1 (−162)

8.6 (177)

10.0 (−160)

10.0 (−162)

8.7 (176)

9.9 (−159)

8.5 (178)

9.9 (−159)

8.6 (177)

9.0 (−152)

10.3 (−165)

8.3 (−177)

a

1

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

3

protons of the dipivaloate 13 in solvents of diﬀerent polarities. The J_HHvalues of dipivaloate 5 in CDCl₃are given in the last column for easy

comparison.

Figure 4. Conformations of (A) dipivaloate 13 in CDCl₃, (B) dinaphthoate 14 in CDCl₃, and (C) dipyrenoate 15 in DMSO-d₆. The interacting

donor (C6−H6) and the acceptor (O3) and the resultant boat form of the cyclitol ring are shown as ball and capped-stick models, respectively, for

clarity. d is the distance between the donor H6 and acceptor O3, and θ is the C6−H6···O3 angle.

Table 3. Comparison of the ³J_HHCoupling Constants and H−C−C−H Dihedral Angles of Dinaphthoate 14 and Dinaphthoate

a

6

14

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

C₆D₆

CD₃CN

6 in CDCl₃

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.7 (4)

6.3 (15)

3.6 (45)

6.3 (15)

5.5 (37)

6.7 (4)

6.6 (5)

6.6 (−9)

4.3 (39)

4.4 (37)

4.7 (39)

5.6 (44)

8.1 (−179)

4.6 (36)

4.5 (36)

4.4 (55)

4.6 (53)

4.3 (56)

9.2(−179)

10.3 (−167)

8.0 (−174)

9.6 (−179)

10.3 (−167)

8.1 (−174)

9.2 (−167)

10.2 (−167)

8.2 (−176)

9.2(−179)

10.2 (−167)

8.0 (−174)

9.4 (−179)

10.2 (−167)

8.3 (−174)

9.4 (−166)

10.2 (−167)

8.0 (−173)

a

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

1

protons of the dinaphthoate 14 in solvents of diﬀerent polarities. The ³J_HHvalues of dinaphthoate 6 in CDCl₃are given in the last column for easy

comparison.

a

Table 4. Comparison of the ³J_HHCoupling Constants and H−C−C−H Dihedral Angles of Dipyrenoate 15 and Dipyrenoate 7

15

H−C−C−H

CDCl₃

6.6 (5)

DMSO-d₆

acetone-d₆

C₆D₆

CD₃CN

7 in DMSO-d₆

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.3 (15)

4.5 (36)

4.5 (54)

8.0 (−179)

6.4 (10)

3.6 (45)

6.9 (2)

6.1 (18)

4.3 (39)

6.1 (−18)

4.7 (35)

4.5 (36)

4.5 (54)

5.4 (46)

9.5 (−179)

9.7 (−167)

9.4 (−155)

10.0 (−167)

8.1 (−179)

9.8 (−159)

9.8 (−167)

7.3 (−179)

9.3 (−165)

10.1 (−167)

8.4 (−179)

8.6 (−154)

8.6 (−179)

6.6 (−164)

7.0 (−164)

a

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

1

protons of the dipyrenoate 15 in solvents of diﬀerent polarities. The ³J_HHvalues of dipyrenoate 7 in DMSO-d₆are given in the last column for easy

comparison.

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Figure 5. Conformations of (A) monobenzoate 17 in CDCl₃solution, (B) monopivaloate 16 in CDCl₃solution, (C) mononaphthoate 18 in

DMSO-d₆solution, and (D) monopyrenoate 19 in CDCl₃solution. The interacting donor (C6−H6) and the acceptor (O3) and the resultant boat

form of the cyclitol ring are shown as ball and capped-stick models respectively, for clarity. d is the distance between the donor H6 and acceptor O3,

and θ is the C6−H6···O3 angle.

3

Table 5. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Monopivaloate 16 and

a

Monopivaloate 8

16

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

C₆D₆

CD₃CN

8 in DMSO-d₆

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.2 (16)

5.0 (33)

6.7 (4)

6.5 (10)

4.6 (36)

6.2 (16)

4.7 (35)

6.2 (16)

4.6 (36)

6.7 (−5)

4.2 (40)

4.4 (38)

4.6 (36)

5.1 (48)

4.2 (56)

4.6 (55)

5.4 (46)

5.3 (48)

4.2 (57)

10.1 (−160)

10.2 (−167)

8.6 (−179)

10.4 (−167)

8.0 (−173)

8.8 (−179)

10.3 (−167)

8.1 (−174)

9.0 (−152)

10.2 (−167)

8.3 (−177)

8.6 (−179)

9.8 (−167)

9.0 (−152)

10.3 (−167)

8.3 (−177)

8.4 (−151)

10.5 (−167)

8.0 (−174)

8.2 (−176)

a

1

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

protons of the monopivaloate 16 in solvents of diﬀerent polarities. The ³J_HHvalues of monopivaloate 8 in DMSO-d₆are given in the last column for

easy comparison.

consistent with the diesters, the conformation was uniform and

consistent in all of the solvents tested irrespective of their

polarity. The short H6···O3 contacts were consistent in all the

monoesters and were much less than their van der Waals

distances. Figure 5 shows the conformations of diﬀerent

monoesters in representative solvents. The respective H6···O3

distances and C6H6···O3 angles for monobenzoate 17,

monopivaloate 16, mononaphthoate 18, and monopyrenoate

19 are as follows: 2.32 Å, 107.97°; 2.30 Å, 108.11°; 2.37 Å,

104.95°; 2.28 Å, 107.11°. These are comparable to those of

corresponding isopropylidene derivatives: viz. monobenzoate 9

(2.36 Å, 109°), monopivaloate 8 (2.23 Å, 111°), mononaph-

thoate 10 (2.28 Å, 110°) and monopyrenoate 11 (2.35 Å,

110°) (Tables 5−8).

Conformation of Dibenzoate 12 in the Solid State.

The consistent boat conformation of the mono- and diesters of

ketals in solution prompted us to investigate their conforma-

tional preferences in the solid state. It is possible that, in the

solid state wherein the molecules are closely packed, the

intermolecular interactions dominate over intramolecular

interactions. Hence, the intermolecular interactions will have

major roles in the solid-state conformation and packing. We

obtained good-quality crystals of 12 from a mixture of hexane

and dichloromethane and were analyzed using single-crystal X-

ray diﬀraction. In sharp contrast to the solution-state

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3

Table 6. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Monobenzoate 17 and

a

Monobenzoate 9

17

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

C₆D₆

CD₃CN

9 in DMSO-d₆

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.4 (−10)

3.8 (42)

6.8 (−2)

4.0 (41)

7.0 (−2)

3.6 (45)

6.6 (−6)

3.6 (45)

6.8 (−2)

4.0 (41)

6.7 (−5)

4.0 (42)

3.8 (60)

3.9 (59)

3.6 (62)

4.0 (57)

3.9 (59)

8.6 (−167)

10.5 (−166)

7.8 (−172)

8.6 (−167)

10.3 (−167)

7.8 (−172)

8.2 (−167)

10.6 (−167)

7.4 (−172)

8.6 (−167)

10.2 (−167)

7.3 (−179)

8.1 (−167)

10.5 (−167)

7.9 (−173)

8.6 (−167)

10.6 (−167)

7.7 (−171)

8.5 (−152)

10.6 (−167)

7.8 (−171)

a

³J_HHvalues in Hz obtained from ¹H NMR and dihedral angles ϕ are (in parentheses) calculated for the corresponding set of various vicinal protons

3

of the monobenzoate 17 in solvents of diﬀerent polarities. The J_HHvalues of monobenzoate 9 in DMSO-d₆are given in the last column for easy

comparison.

3

Table 7. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Mononaphthoate 18 and

a

Mononaphthoate 10

18

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

C₆D₆

CD₃CN

10 in CDCl₃

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.1 (18)

4.8 (34)

6.0 (19)

4.1 (41)

6.4 (12)

4.4 (38)

6.0 (19)

4.4 (38)

6.3 (15)

4.4 (38)

6.1 (18)

4.8 (34)

6.1 (−18)

4.7 (35)

4.8 (51)

4.1 (56)

4.4 (55)

5.2(48)

4.7 (52)

4.8 (51)

4.7 (52)

9.2 (−167)

10.1 (−167)

9.2 (−167)

10.1 (−167)

8.1(−173)

8.6 (−167)

10.3 (−166)

8.0 (−174)

8.9 (−167)

10.1 (−167)

8.2 (−176)

8.7 (−167)

10.5 (−166)

8.0 (−173)

9.1 (−167)

10.1 (−167)

8.2 (−176)

9.0 (−164)

10.4 (−167)

8.1(−174)

8.1(−173)

a

1

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

protons of the mononaphthoate 18 in solvents of diﬀerent polarities. The ³J_HHvalues of mononaphthoate 10 in CDCl₃are given in the last column

for easy comparison.

3

Table 8. Comparison of the J_HHCoupling Constants and H−C−C−H Dihedral Angles of Monopyrenoate 19 and

a

Monopyrenoate 11

19

H−C−C−H

CDCl₃

DMSO-d₆

acetone-d₆

CD₃OD

6.3 (15)

C₆D₆

CD₃CN

11 in DMSO-d₆

H1−C1−C2−H2

H2−C2−C3−H3

H3−C3−C4−H4

H4−C4−C5−H5

H5−C5−C6−H6

H6−C6−C1−H1

6.4 (10)

4.6 (36)

6.3 (15)

4.2 (41)

6.5 (11)

4.5 (35)

6.4 (10)

4.4 (37)

6.2 (16)

4.8 (34)

6.3 (−15)

4.4 (38)

4.6 (53)

4.5 (55)

5.0 (49)

4.4 (55)

4.8 (51)

4.5 (54)

9.6 (−179)

10.1 (−167)

8.3 (−177)

8.9 (−167)

10.1 (−167)

8.0 (−173)

8.6 (−154)

10.4 (−167)

8.0 (−173)

9.0 (−167)

10.1 (−167)

8.2 (−176)

8.6 (−167)

10.3 (−167)

7.7 (−172)

9.1 (−153)

10.3 (−167)

8.2 (−176)

8.9 (−161)

10.3 (−167)

8.0 (−173)

a

³J_HHvalues in Hz obtained from H NMR and dihedral angles ϕ in deg (in parentheses) calculated for the corresponding set of various vicinal

protons of the mononaphthoate 19 in solvents of diﬀerent polarities. The J_HHvalues of mononaphthoate 11 in DMSO-d₆are given in the last

1

3

column for easy comparison.

Figure 6. Conformations of (A) dibenzoate 12 and (B) dipivaloate 13 in the solid state. The interacting atoms and the resultant chair form of the

cyclitol ring are shown as ball and capped-stick models, respectively, for clarity.

conformation, the cyclitol ring of dibenzoate 12 adopted a chair

conformation in the solid state (Figure 6A). In the solution

conformation, the C3 end of the cyclitol ring approaches the

C6 end, which facilitates an intramolecular CH···O hydrogen

bond between H6 and O3. In the solid state, the C3 end of the

cyclitol ring is held in an orientation opposite to the C6 end.

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Figure 7. Conformations of (A) monobenzoate 17 and (B) monopivaloate 16 in the solid state. The interacting atoms and the resultant chair form

of the cyclitol ring are shown as ball and capped-stick models, respectively, for clarity.

The main interaction responsible for this conformation is the

C3−H3···O7 hydrogen bond with the carbonyl oxygen of the

C4-benzoate of a neighboring molecule. Also, it is worth noting

that this is the strongest CH···O bonding in the crystal with the

shortest H···O distance of 2.37 Å. This interaction is further

supplemented by three other CH···O contacts made by the

carbonyl oxygen (O8) of C3-benzoate (C6H6···O8,

C14H14B···O8, and C8H8B···O8). Apart from these inter-

actions, many other CH···O hydrogen bonds are involved in

the stabilization of the crystal (Table S1, Supporting

Information). It is clear that, as in the case of dibenzoate

3,^18athe solid-state conformation of 12 is dictated by several

intermolecular CH···O hydrogen bonds.

Conformation of Dipivaloate 13 in the Solid State.

Dipivaloate 13 crystallizes in the Cc space group with four

molecules in the asymmetric unit. In all of the conformers, the

cyclitol rings adopted a chair conformation. In all of these

conformers H1, H2, and H3 of the inositol ring are in CH···O

hydrogen bonds with the carbonyl oxygen of a diﬀerent

neighboring conformer (Figure 6B). It should be noted that the

H3···OC contact is the shortest in all of the conformers,

suggesting that the main function of the carbonyl oxygen is to

arrest the conformation of the cyclitol ring of a neighboring

molecule as a chair by pulling the C3 end of the cyclitol ring

opposite to the C6 end. In conformer A, the C3 is held by a

C3AH3A···O7B (2.46 Å) hydrogen bond to a neighboring B

conformer, as a result of which the cyclitol ring is held in a chair

conformation. In the B conformer, C3 is held by C3BH3B···

O8A (2.47 Å) hydrogen bond to the carbonyl oxygen of a

neighboring A conformer. Conformers C and D show disorders

in the tert-butyl groups of the pivaloyl unit at C3. The

conformer C adopts a chair conformation as a result of the

intermolecular C3CH3C···O8D hydrogen bond (2.45 Å), and

conformer D adopts a chair conformation as a result of the

C3DH3D···O8C (2.49 Å) hydrogen bond. The intermolecular

CH···O hydrogen bonding (Table S2, Supporting Information)

and the chair conformation adopted by the dipivaloate 13 is

identical with those of dipivaloate 5 in the solid state.

and with their solution conformation, we have done single

crystal X-ray analysis of several monoesters as well.

Conformation of Monobenzoate 17 in the Solid State.

Monobenzoate 17 forms a centrosymmetric hydrogen-bonded

dimer with a neighboring molecule. The cyclitol ring of

monobenzoate 17 also adopts a chair conformation in the solid

state. The carbonyl oxygen (O7) forms trifurcated CH···O

hydrogen bonds with C1−H1, C3−H3, and C5−H5 hydro-

gens, which collectively assist to pull the C3 end away from the

C6 end of the cyclitol ring, preventing its boat conformation

(Figure 7A). In addition, these weak interactions facilitate the

formation of another centrosymmetric dimer. It is worth noting

that a C3H3···O7 hydrogen bond consistent with that in

diesters is present, which assists in the chair conformation in

the solid state (Table S4, Supporting Information). Though the

monobenzoate 17 adopts a chair conformation, similar to that

of 9 in the solid state, their intermolecular hydrogen-bonding

patterns are diﬀerent. While trifurcated CH···O hydrogen

bonds are responsible for the chair conformation of

monobenzoate 17, the OH···O hydrogen bond also plays a

signiﬁcant role in pulling the C3 end of the cyclitol ring

opposite to the C6 end in case of monobenzoate 9.

Conformation of Monopivaloate 16 in the Solid State. As

in the case of dipivaloate 13, the monopivaloate 16 also

crystallizes with four molecules in the asymmetric unit. The

cyclitol ring of each of these conformers adopts a chair

conformation, in line with other esters and dipivaloate 13. The

hydroxyl group of each conformer is involved in intermolecular

OH···O hydrogen bonds. In each of the four conformers, the

carbonyl oxygen is involved in a CH···O hydrogen bond with

H3 of a neighboring conformer, forming a pseudocentrosym-

metric dimer. These two mutually complementing CH···O

hydrogen bonds force the C3 end opposite to the C6 end,

arresting the conformation of the cyclitol ring in chair form.

Other noncovalent interactions involved in stabilizing the

crystal structure are given in Table S3 (Supporting

Information).

Conformation of Monopyrenoate 19 in the Solid State.

Monopyrenoate 19 crystallizes in the P1 space group with two

symmetrically independent molecules of 19 and two molecules

of dichloromethane in the asymmetric unit (Figure 8). The

cyclitol ring in both conformers of 19 adopts a chair

conformation. Each of the conformers makes centrosymmetric

OH···O hydrogen bonds with an identical conformer. As with

solid-state structures of other esters, the C3H3···O7 hydrogen

bonding is intact in both the conformers. Thus, the mutually

complementary CH···O hydrogen bonds between carbonyl

oxygen and H3 of two neighboring molecules stabilize the chair

Conformation of Monoesters in the Solid State. While

the solid-state conformations of diesters are dictated by several

intermolecular CH···O hydrogen bonds, the presence of one

free hydroxyl group in monoesters, which can form strong

intermolecular OH···O hydrogen bonds, can mask any weak

interaction such as CH···O hydrogen bonding. Though such

intermolecular interactions are less likely in dilute solutions,

they can be powerful in the solid state. In order to compare the

solid state conformations of monoesters with that of diesters

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EXPERIMENTAL SECTION

■

General Methods. Chromatograms were visualized under UV

light and by dipping plates into either phosphomolybdic acid in

MeOH or anisaldehyde in ethanol, followed by heating. H NMR,

1

COSY, NOESY, and HMQC spectra were recorded on a 500 MHz

NMR spectrometer. Proton chemical shifts are reported in ppm (δ)

relative to the internal standard tetramethylsilane (TMS, δ 0.0 ppm) or

to the solvent reference relative to TMS employed as the internal

standard (CDCl₃, δ 7.26 ppm; D₂O, δ 4.79 ppm). Data are reported as

follows: chemical shift (multiplicity (singlet (s), doublet (d), doublet

of doublets (dd), triplet (t), quartet (q), and multiplet (m)), coupling

constants (Hz), integration, and peak identiﬁcation). All NMR signals

were assigned on the basis of ¹H NMR, ¹³C NMR, COSY, and HMQC

experiments. ¹³C spectra were recorded with complete proton

decoupling. Carbon chemical shifts are reported in ppm (δ) relative

to TMS with the respective solvent resonance as the internal standard.

All NMR data were collected at 25 °C. The concentration of the

1

compounds for H NMR was 5 mg per 0.5 mL, and for ¹³C NMR it

was 20 mg per 0.5 mL. Melting points were determined using a

melting point apparatus and are uncorrected. Flash column

chromatography was performed using 200−400 mesh silica gel. All

reactions were carried out under an argon or nitrogen atmosphere

employing oven-dried glassware.

Figure 8. Conformation of monopyrenoate 19 in the solid state. The

interacting atoms in intermolecular CH···O hydrogen bonding and the

chair form of the cyclitol ring are shown in ball and capped-stick

models respectively, for clarity.

X-ray intensity data measurements of freshly grown crystals of 12,

13, 16, and 17 were carried out at 293−296 K and those of 19 at 110

K on a Bruker-KAPPA APEX II CCD diﬀractometer with graphite-

monochromated (λ(Mo Kα) = 0.71073 Å) radiation. The X-ray

generator was operated at 50 kV and 30 mA. Data were collected with

a scan width of 0.3° at diﬀerent settings of φ (0, 90, and 180°),

keeping the sample to detector distance ﬁxed at 40 mm and the

detector position (2θ) ﬁxed at 24°. The X-ray data collection was

monitored by the SMART program. All data were corrected for

Lorentzian, polarization, and absorption eﬀects using SAINT and

SADABS programs. SHELX-97 was used for the structure solution and

full-matrix least-squares reﬁnement on F². Molecular and packing

diagrams were generated using Mercury 3.1. Geometrical calculations

were performed using SHELXTL and PLATON.

conformation. As with other structures of this series, several

intermolecualr interactions stabilize the chair conformation of

19 in the solid state (Table S5, Supporting Information).

However, its isopropylidene derivative 11 adopts a boat

conformation in the solid state.

CONCLUSION

■

We have successfully shown the consistent conformational

extremities between solution and solid states of a series of

cyclitol derivatives. While in the solution state these molecules

adopt a boat conformation irrespective of the nature of the

solvent and the nature and number of acyl groups, in the solid

state all of these molecules adopt a chair conformation. The

solution conformation is stabilized by a lone intramolecular

CH···O hydrogen bond, but the solid-state conformation is

dictated by several intermolecular CH···O hydrogen bonds.

Though our evidence suggests that intramolecular CH···O

hydrogen bonds are involved in the solution conformation,

whether this CH···O bond is a cause or consequence of the

boat conformation is a question yet to be resolved. The

inherent nature of these molecules to adopt the boat

conformation in isolation (dilute solution) by virtue of

intramolecular CH···O or other structural constraints is

challenged by several intermolecular hydrogen bonds, and

thus the compound is compelled to adopt the chair

conformation in the solid state. Hence, undoubtedly the

conformation is dictated by intermolecular CH···O hydrogen

bonds in the solid state. Knowledge of molecular conformations

and the factors aﬀecting the conformation are important, as

properties, reactivities, etc. depend on the conformations of

molecules. Our study shows that even a weak noncovalent

interaction can inﬂuence the conformation of molecules

diﬀerently in diﬀerent states: viz., solution and solids. This

study also cautions against the practice of depending on the

crystal structure to explain the solution-state behavior of

molecules.

Determination of the Structure in Solution. ³J_HHvalues for the

1

cyclitol ring protons were measured from H NMR spectra. By using

the Haasnoot−Altona equations the corresponding ϕ values were

calculated. The structures were then energy minimized after ﬁxing the

ϕ values to the vicinal protons by the MM2 method using the

ChemBio3D Ultra 12.0 platform.

( )-3,4-Di-O-benzoyl-1,2:5,6-di-O-isopropylidene-myo-inositol

(3). To a cooled solution of ( )-1,2:5,6-di-O-isopropylidene-myo-

inositol (1;²⁵0.26 g, 1 mmol) in dry pyridine (5 mL) were added

benzoyl chloride (0.24 mL, 2.1 mmol) and a catalytic amount of

DMAP (10 mg). The reaction mixture was stirred for 2 h at room

temperature. When TLC showed the complete disappearance of the

starting material, the reaction was quenched by adding a few drops of

water and the mixture was concentrated under reduced pressure. The

resulting residue was dissolved in ethyl acetate (50 mL), and this

solution was then washed successively with 10% ascorbic acid solution,

saturated sodium bicarbonate solution, water, and ﬁnally brine. The

organic layer was dried over anhydrous MgSO₄and concentrated

under reduced pressure. The crude product thus obtained was puriﬁed

by ﬂash column chromatography using 25% ethyl acetate in petroleum

ether (R_f0.34) as eluent, to give ( )-3,4-di-O-benzoyl-1,2:5,6-di-O-

isopropylidene-myo-inositol (3)²⁶as a white solid (0.402 g, 86%),

which was crystallized from a mixture of dichloromethane and hexane

(2/1, v/v) by slow evaporation.

1

Mp: 186−188 °C. H NMR (400 MHz, CD₃OD): δ 1.337 (s, 3H,

CH₃), 1.343 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 1.48 (s, 3H, CH₃), 4.01

(dd, J = 10.2, 8.8 Hz, H-5), 4.18 (dd, J = 10.2, 7.8 Hz, H-6), 4.55 (dd, J

= 7.8, 6.3 Hz, H-1), 4.78 (dd, J = 6.3, 3.9 Hz, H-2), 5.56−5.59 (m, 2H,

H-3 and H-4), 7.47−8.02 (m, 10H, Ar-H). ¹H NMR (400 MHz,

C₆D₆): δ 1.13 (s, 3H, CH₃), 1.29 (s, 3H, CH₃), 1.34 (s, 3H, CH₃),

1.35 (s, 3H, CH₃), 3.67 (dd, J = 9.9, 9.0 Hz, H-5), 4.19 (dd, J = 7.4, 6.9

Hz, H-1), 4.40−4.47 (m, 2H, H-2 and H-6), 5.82 (t, J = 4.4, H-3), 6.09

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(dd, J = 9.0, 4.4 Hz, H-4), 6.90−8.18 (m, 10H, Ar-H). ¹H NMR (400

MHz, CDCl₃): δ 1.33 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.48 (s, 3H,

CH₃), 1.52 (s, 3H, CH₃), 3.89 (dd, J = 10.3, 8.0 Hz, H-5), 4.32 (dd, J =

10.3, 7.3 Hz, H-6), 4.53 (dd, J = 7.3, 6.8 Hz, H-1), 4.73 (dd, J = 6.8, 3.9

Hz, H-2), 5.60−5.70 (m, 2H, H-3 and H-4), 7.26−8.10 (m, 10H, Ar-

2), 5.08 (dd, J = 9.1, 5.0 Hz, H-4), 5.13 (dd, J = 5.0, 4.5 Hz, H-3). ¹H

NMR (500 MHz, CD₂Cl₂): δ 1.25 (s, 3H, CH₃), 1.34 (s, 3H, CH₃),

1.36 (s, 3H, CH₃), 1.38 (s, 3H, CH₃), 1.99 (s, 3H, COCH₃), 2.01 (s,

3H, COCH₃), 3.52 (dd, J = 10.5, 8.7 Hz, H-5), 3.93 (dd, J = 10.5, 7.9

Hz, H-6), 4.26 (dd, J = 7.9, 6.7 Hz, H-1), 4.39 (dd, J = 6.7, 4.1 Hz, H-

2), 5.05 (dd, J = 4.1, 3.9 Hz, H-3), 5.08 (dd, J = 8.7, 3.9 Hz, H-4). ¹H

NMR (500 MHz, CD₃CN): δ 1.33 (s, 3H, CH₃), 1.41 (s, 3H, CH₃),

1.43 (s, 3H, CH₃), 1.47 (s, 3H, CH₃), 2.06 (s, 3H, COCH₃), 2.07 (s,

3H, COCH₃), 3.69 (dd, J = 10.5, 9.3 Hz, H-5), 3.98 (dd, J = 10.5, 8.1

Hz, H-6), 4.38 (dd, J = 8.1, 6.4 Hz, H-1), 4.51 (dd, J = 6.4, 3.6 Hz, H-

2), 5.16−5.18 (m, 2H, H-3 and H-4). ¹³C NMR (125 MHz, CD₂Cl₂):

δ 19.48, 19.57, 19.92, 20.00, 20.06, 20.44, 20.53, 23.72, 24.35, 25.76,

26.20, 26.44, 71.15, 72.07, 72.85, 73.63, 75.18, 76.01, 76.43, 77.26,

110.25 (ketal carbon), 111.99 (ketal carbon), 168.37 (CO), 168.76

(CO). Anal. Calcd for C₁₆H₂₄O₈: C, 55.81; H, 7.02. Found: C, 55.51;

H, 7.26.

( )-3,4-Di-O-pivaloyl-1,2:5,6-di-O-isopropylidene-myo-inositol

(5). To a cooled solution of diketal 1 (0.26 g, 1 mmol) in dry pyridine

(5 mL) were added pivaloyl chloride (0.61 mL, 5 mmol) and a

catalytic amount of DMAP (10 mg). The reaction mixture was stirred

for 2 h at room temperature. When TLC showed complete

disappearance of the starting material, the reaction was quenched by

adding a few drops of water and the mixture was concentrated under

reduced pressure. The resulting residue was dissolved in ethyl acetate

(50 mL), and the solution was then washed successively with 10%

ascorbic acid solution, saturated sodium bicarbonate solution, water,

and ﬁnally brine. The organic layer was dried over anhydrous MgSO₄

and concentrated under reduced pressure. The crude product thus

obtained was puriﬁed by ﬂash column chromatography using 25%

ethyl acetate in petroleum ether (R_f0.30) as eluent, to give ( )-3,4-di-

O-pivaloyl-1,2:5,6-di-O-isopropylidene-myo-inositol (5) as a white

solid (0.35 g, 82%), which was crystallized from a mixture of

chloroform and petroleum ether (1/4 v/v).

1

H). H NMR (400 MHz, acetone-d₆): δ 1.31 (s, 3H, CH₃), 1.32 (s,

3H, CH₃), 1.42 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 4.11 (dd, J = 10.5, 8.8

Hz, H-5), 4.30 (dd, J = 10.5, 7.8 Hz, H-6), 4.65 (dd, J = 7.8, 6.6 Hz, H-

1), 4.86 (dd, J = 6.6, 3.9 Hz, H-2), 5.63−5.67 (m, 2H, H-3 and H-4),

1

7.49−7.99 (m, 10H, Ar-H). H NMR (400 MHz, DMSO-d₆): δ 1.28

(s, 6H, 2 × CH₃), 1.41 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 4.08 (dd, J =

10.3, 8.8 Hz, H-5), 4.14 (dd, J = 10.3, 7.3 Hz, H-6), 4.57 (dd, J = 7.3,

6.3 Hz, H-1), 4.78 (dd, J = 6.3, 3.9 Hz, H-2), 5.51 (dd, J = 8.8, 4.4 Hz,

1

H-4), 5.5 (dd, J = 4.4, 3.9 Hz, H-3), 7.52−8.32 (m, 10H, Ar-H). H

NMR (400 MHz, CD₂Cl₂): δ 1.23 (s, 3H, CH₃), 1.26 (s, 3H, CH₃),

1.38 (s, 3H, CH₃), 1.41 (s, 3H, CH₃), 3.80 (dd, J = 10.5, 8.3 Hz, H-5),

4.19 (dd, J = 10.5, 7.8 Hz, H-6), 4.42 (dd, J = 7.8, 6.8 Hz, H-1), 4.63

(dd, J = 6.8, 3.9 Hz, H-2), 5.47−5.53 (m, 2H, H-3 and H-4), 7.36−

1

7.97 (m, 10H, Ar-H). H NMR (500 MHz, CD₃CN): δ 1.22 (s, 3H,

CH₃), 1.23 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.39 (s, 3H, CH₃), 3.90

(dd, J = 10.5, 8.8 Hz, H-5), 4.12 (dd, J = 10.5, 7.9 Hz, H-6), 4.42 (dd, J

= 7.9, 6.5 Hz, H-1), 4.65 (dd, J = 6.5, 4.1 Hz, H-2), 5.47−5.52 (m, 2H,

H-3 and H-4), 7.40−7.95 (m, 10H, Ar-H). ¹³C NMR (100 MHz,

CDCl₃): δ 24.82 (CH₃), 26.62 (CH₃), 26.96 (CH₃), 27.01 (CH₃),

72.67 (C-3 or C-4), 73.64 (C-4 or C-3), 74.04 (C-2), 76.37 (C-5),

76.43 (C-1), 77.64 (C-6), 111.34 (ketal carbon), 113.14 (ketal

carbon), 128.34, 128.44, 129.25, 129.87, 129.97 (aromatic C), 133.35

(C-ipso), 164.86 (CO), 165.06 (CO). Anal. Calcd for C₂₆H₂₈O₈: C,

66.66; H, 6.02. Found: C, 66.45; H, 6.27.

( )-3,4-Di-O-acetyl-1,2:5,6-di-O-isopropylidene-myo-inositol (4).

To a cooled solution of diketal 1 (0.26 g, 1 mmol) in dry pyridine (5

mL) were added acetic anhydride (0.28 mL, 3 mmol) and a catalytic

amount of DMAP (10 mg). The reaction mixture was stirred for 2 h at

room temperature. When TLC showed complete disappearance of the