236

CHAPTER 5

DIASTEROSELECTIVE GRIGNARD ADDITION TO

(R)-(-)-PHENYLACETYLCARBINOL

5.1 BACKGROUND

Phenylacetylcarbinol (1-phenyl-1-hydroxy-2-propanone) is

manufactured by biotransformation of benzaldehyde to obtain specifically the

‘R’- isomer. The optical purity of R-(-)-phenylacetylcarbinol obtained by this

method is 100%. The (R)-(-)-phenylacetylcarbinol is employed to perform

Grignard reaction to obtain chiral vicinal diols which possess great potential

as drug intermediate and also used as chiral auxiliaries in chiral synthesis.

The mechanism of Grignard addition and absolute configuration of the newly

generated chiral center during the Grignard reaction are discussed in this

chapter.

5.2 ALKYLATION OF (R)-(-)-PHENYLACETYLCARBINOL

(R)-(-)-Phenylacetylcarbinol was subjected to Grignard reaction

with alkyl/aryl magnesium halides. In all these Grignard reactions, excess of

Grignard reagent is employed to neutralize the acidic hydrogen present in the

hydroxyl function of phenylacetylcarbinol. The various Grignard products, 1-

phenyl-2-alkyl/aryl-1,2-dihydroxypropanes, synthesized are shown in Table

5.1. The structures of all Grignard products have been established with the

help of IR,1H NMR,

13C NMR and mass spectra. The yield and physical

constants like melting point, HPLC purity, specific optical rotation and

enantiomeric purity are presented in Table 2.4 (Page No. 75).

237

Table 5.1. 1-Phenyl-2-alkyl/aryl-1,2-dihydroxypropanes synthesized

CC

OHH

CH3

R

OH

Compound

No.

R Compound

No.

R

1 CH3

CHH3C 5

2CH2

CH3

CH36

3 7

F

4 8F

5.3 MACHANISTIC ASPECTS OF GRIGNARD REACTION

The introduction of alkyl/aryl groups at carbon-1 of (R)-(-)-1-

phenyl-1-hydroxy-2-propanone can generate a new chiral center at the

carbonyl carbon, which is the reaction site in these Grignard reactions. The

reason for this assumption is based on the fact that the presence of asymmetry

in the adjacent carbon to the reaction center directs the approach of Grignard

reagent from the least hindered side of the carbonyl carbon. This will lead to

form only one of the diastereomer either erythro or threo isomer of vicinal

diol. The absolute configuration of the Grignard product is predicted by

Cram’s rule and chemical analogy.

238

5.3.1 Absolute Configuration by Cram’s Rule

The absolute configuration of the newly generated chiral center can

be predicted through molecular modeling by making use of Cram’s rule. In

this Newman projection model is viewed through carbon-1 and the carbonyl

carbon. The bulkier groups at both these carbons that is phenyl group at

carbon-1 and methyl group at carbonyl carbon, eclipsing each other (Scheme

5.1). In this conformation (I, Scheme 5.1) the hydroxyl hydrogen is bonded

with the carbonyl oxygen by intramolecular hydrogen bonding.

CH3

C O

C OHR

CH3

C OH

C OHR

H

(Least hindered side)

H

H O

CH3

O H

H O

CH3

O MgBr

RMgBr

R

R

O

CH3

OHH

H

OH3C

R

H OH

H

RR

I II

III

R

C CH3

C OHR

H

HOR

threo-(1R,2R)-1-Phenyl-2-alkyl/aryl-1,2-dihydroxypropane

Scheme 5.1

During the Grignard reaction, one mole of the Grignard reagent

interacted with the active hydrogen of -OH function of (R)-(-)-

phenylacetylcarbinol, thus affording the formation of magnesium complex.

The electron rich oxygens in this conformation co-ordinate as a bidentate

ligand with the magnesium metal of Mg+Br freezing the conformation of the

239

ketone. In this magnesium complex conformation (II, Scheme 5.1) the

alkyl/aryl groups of the Grignard reagent, attacks carbonyl carbon from less

hindered side leading to exclusive formation of Grignard product with ‘R’

conformation at carbon-2. This preferred diastereomer of the Grignard

product is threo-(1R,2R)-1-phenyl-2-alkyl/aryl-1,2-dihydroxypropane. The

hydrogen bonding between hydrogen of one hydroxyl group bonds and

oxygen of the vicinal hydroxyl function afforded a stable staggered

conformation (III, Scheme 5.1) of the product. The application of Cram’s

rule to (R)-(-)-phenylacetylcarbinol is also showed in Scheme 5.2 by making

use of flying wedge formulae. In this depiction the complexation of

magnesium cation with the electron rich oxygen can be seen more vividly

leading to threo-product (Scheme 5.2). Asymmetric induction during

Grignard reaction has been reported in the synthesis of 1,2-diphenyl-3-

methyl-4-dimethylamino-2-butanol (Shelton 1993, Guo et al 1999 and Finn

2002).

H3C

O

H

O

H

R-MgBr H3C

O

H

O

BrMg

R

H3CH

OR O

HR

RRR

CH3

C OH

C OHR

H

threo-(1R,2R)-1-Phenyl-2-alkyl/aryl-1,2-dihydroxypropane

RR

IV V VI

R

C CH3

C OHR

H

HOR

H

Scheme 5.2

240

5.3.2 Absolute Configuration by Chemical Analogy

In order to secure additional chiral support for stereochemical

consequences of the Grignard alkylation/arylation of (R)-(-)-

phenylacetylcarbinol, benzoin (Adams and Marvel 1941) was subjected to

Grignard reaction with methyl magnesium iodide. The product obtained in

this reaction after work-up is a racemic mixture of 1,2-diphenyl-1,2-

dihydroxypropane (Scheme 5.3).

O

H O

H O

H O

CH 3

H H

R/SR/S

R/S

Racem ic mixture of benzoin Racem ic mixtureof1,2-D iphenyl-l,2 -d ihydrxypropane

CH 3M gI

NH 4Cl

Scheme 5.3

Cram’s rule was applied for the determination of absolute

stereochemistry of 1,2-diphenyl-1,2-dihydroxypropane obtained from the

Grignard reaction of benzoin with methyl magnesium iodide (Scheme 5.4).

It is observed that the two stereochemical compounds obtained

(Scheme 5.4) (A and B) are enantiomers which are seen as two peaks

corresponds to (1R,2S)- and (1S,2R)-isomer in the HPLC chromatograms

using a chiral column. But A and B have the same retention time (RT) in

HPLC when analysed in a non-chiral column. This retention time is different

for the 1,2-diphenyl-1,2-dihydroxypropane obtained by the reaction of (R)-

(-)-phenylacetylcarbinol (compound 3).

241

C6H5

C O

C

C6H5

OHRS

C6H5

C OH

C

C6H5

OHR

H

Mixture of erythro-(1R,2S)-and (1S,2R)-1,2-Dihenyl-1,2-dihydroxypropane

(Least hindered side)

H

H O

C6H5

C6H5

O H

H O

C6H5

C6H5

O MgI

CH3MgI

H3C

H3CS

H3C

O

C6H5

O

C6H5

HH

H

(A)

(RS)-Benzoin

C6H5

C CH3

C

C6H5

HS

HO

(Least hindered side)

O H

C6H5

C6H5

O

CH3

HOR

H

O H

C6H5

C6H5

OIMg

CH3

C6H5

O

C6H5

O H

H

H

(B)

Scheme 5.4

The reason is that the compound 3 is diastereomeric with compound A and B.

Furthermore, Grignard reaction of phenyl magnesium bromide with (RS)-(±)-

phenylacetylcarbinol gave mixture of two enantiomers, (1R,2R)- and (1S,2S)-

1,2-diphenyl-1,2-dihydroxypropane-corresponding to compound C and D

(Scheme 5.5).

242

C6H5

C CH3

C

C6H5

OHR

H

HOR

(C)

CH3

C O

C

C6H5

HRS

HO

C6H5MgBr and

C6H5

C OH

C

C6H5

HS

HO

H3CS

(D)Racemic mixture ofphenylacetylcarbinol (1R,2R)- and (1S,2S)-1,2-Diphenyl-1,2-dihydroxypropane

Scheme 5.5

It is evident from the above Schemes (5.4 and 5.5) that Grignard

reaction of benzoin gave racemic 1,2-diphenyl-1,2-dihydroxypropane having

erythro-configuration. Similarly, Grignard reaction of racemic

phenylacetylcarbinol also gave the racemic product having threo-

configuration. This was further justified by analyzing 1,2-diphenyl-1,2-

dihydroxypropane obtained by Grignard reaction of benzoin (mixture of

compounds A and B, Scheme 5.4) and 1,2-diphenyl-1,2-dihydroxypropane

obtained from racemic phenylacetylcarbinol (mixture of compounds C and D,

Scheme 5.5) in HPLC using non-chiral column. Two peaks with two different

retention times were obtained corresponding to a mixture of A and B and

mixture of C and D. This is because the relationship between (A and B) and

(C and D) is diastereomeric in nature. When mixture of A and B was

analyzed in chiral column, two peaks were obtained at RT 19.7 and 24.8 min

with 50.2% and 48.2% respectively. Similarly mixture of C and D also gave

two peaks at RT 15.82 and 17.82 min with an area percentage of 51.1 and

48.9 respectively. The retention time of one of the peak is found to be the

same as that of compound 3 (RT 15.9 min) (Figure 5.1 a, b and c). This

observation confirmed the fact that the absolute configuration of one of the

stereoisomers of the mixture, namely, (1R,2R)-compound agreed with that of

compound 3 for which (1R,2R)-configuration was predicted. These

experimental observations added support to the predicted R-configuration at

the carbon-2 (reaction center) of phenylacetylcarbinol.

243

Figure 5.1 Chiral HPLC chromatogram of (a) threo-(1R,2R)- (b) threo -(1RS,2RS)- and (c) erythro -(1RS,2RS)-1,2-

diphenyl-1,2-dihydroxypropane

244

The structure of Grignard products, 1-phenyl-2-alkyl/aryl-1,2-

dihydroxypropanes, are confirmed with the help of the spectroscopic data.

5.4 STRUCTURAL ELUCIDATION

5.4.1 threo-(1R,2R)-(-)-1-Phenyl-2-(2-propyl)-1,2-Dihydroxypropane

The IR spectrum (Figure 5.2 a) showed two bands at 3439 and 3314

cm-1

for the presence two hydroxyl groups. The C-CH3 protons in the1H

NMR spectrum (Figure 5.2 b) appeared at H 0.8 ppm as singlet while the

two methyl groups of isopropyl moiety were observed at H 0.92 and 0.99

ppm. It can be noted that the two methyls of isopropyl group are

diastereotopic being bonded to a chiral carbon. The methine proton of

isopropyl group appeared as a septet at H 2.0 ppm. The two hydroxyl groups

appeared at H 2.13 and H 2.86 ppm as broad singlets. The methine proton at

carbon-1 appeared at H 4.63 ppm as sharp singlet. The aromatic signals

appeared as multiplet between H 7.26 and H 7.33 ppm.

The C-CH3 carbon signal in the13

C NMR spectrum (Figure 5.2 c)

appeared at C 16.95 and the two methyl carbons of isopropyl group are

observed at C 17.93 and C 18.12 ppm. The methine carbon of isopropyl

group appeared at C 33.20 ppm. The quaternary carbon and the methine

carbon (carbon-1) have merged with the signals of CDCl3 solvent but

appeared at C 76.5 and c 77.14 ppm. The aromatic signals observed

between C 127.5 and C 144.18 ppm. The [M+H]+ at m/z 195 was not seen

in CI mass spectrum (Figure 5.2d) of the compound 1-phenyl-2-(2-propyl)-

1,2-dihydroxypropane where methanol as CI reagent. The ion at m/z 177

appeared as base peak in the mass spectrum, which corresponds to [MH-

H2O]+. The absence of [M+H]

+ ion can be explained because of exothermic

nature of the formation of [M+H]+ ions of vicinal diols and hence [MH-

H2O]+ ion formation must be energetically facile.

245

Figure 5.2 (a) IR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-propyl)-

1,2-dihydroxypropane

Figure 5.2 (b)1H NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

propyl)-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(a)

CC

HO H

CH3

OHR

R

(b)

246

Figure 5.2(c) 13

C NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

propyl)-1,2-dihydroxypropane

Figure 5.2(d) Mass spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

propyl)- 1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(c)

CC

HO H

CH3

OHR

R

(d)

247

The elemental analysis of this compound (C12H18O2) gave 74.34

and 9.32 percentage of carbon and hydrogen respectively against the

calculated values of 74.22 and 9.28 percentage for carbon and hydrogen

respectively.

5.4.2 threo-(1R,2R)-(+)-1,2-Diphenyl-1,2-Dihydroxypropane

The IR spectrum (Figure 5.3 a) showed two bands at 3466 cm-1

and

at 3381 cm-1

corresponding to the two hydroxyl functions. The C-CH3

protons in the1H NMR spectrum (Figure 5.3 b) appeared at H 1.39 ppm as a

singlet and the two hydroxyl proton appeared at H 1.58 and H 2.65 ppm as

broad singlets. The methine hydrogen was observed at H 4.87 ppm and also

as a singlet of one proton intensity. The ten aromatic protons are appeared

between H 7.15 and H 7.41 ppm as complex multiplet. The methyl carbon

was noticed at c 23.9 ppm in the13

C NMR spectrum (Figure 5.3 c) while the

quaternary carbon was appeared at C 77.05 ppm (merged with CDCl3

signals). The methine carbon appeared at C 80.75 ppm. All the aromatic

signals appeared between c 125.85 and C 144.96 ppm. The [M+H]+ at m/z

229 was not seen in CI mass spectrum (Figure 5.3 d) of the compound 3,

(Table 5.1) where methanol was used as CI reagent. The ion at m/z 211

appeared as the base peak in the mass spectrum, which corresponds to [MH-

H2O]+.

The elemental analysis of this compound (C15H16O2) gave 79.07

and 7.05 percentages of carbon and hydrogen respectively as against the

calculated values of 78.92 and 7.06 percentages for carbon and hydrogen

respectively.

248

Figure 5.3 (a) IR spectrum of threo-(1R,2R)-(+)-1,2-diphenyl-1,2-

dihydroxypropane

Figure 5.3(b) 1

H NMR spectrum of threo-(1R,2R)-(+)-1,2-diphenyl-1,2-

dihydroxypropane

CC

HO H

CH3

OHR

R

(a)

CC

HO H

CH3

OHR

R

(b)

249

Figure 5.3 (c)13

C NMR spectrum of threo-(1R,2R)-(+)-1,2-diphenyl-1,2-

dihydroxypropane

Figure 5.3 (d) Mass spectrum of threo-(1R,2R)-(+)-1,2-diphenyl-1,2-

dihydroxypropane

The spectroscopic and analytical data for the remaining compounds

are given below.

CC

HO H

CH3

OHR

R

(d)

CC

HO H

CH3

OHR

R

(c)

250

5.5 SPECTROSCOPIC INTERPRETATION OF PRODUCTS OF

THE GRIGNARD REACTIONS

5.5.1 threo-(1R,2R)-(-)-1-Phenyl-2-(2-methylpropyl)-1,2-

Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3412, benzenoid bands at 1602 and 1495, C_

O str. at

1040 and C_H out of plane bending of mono-substituted benzene ring at 745

and 700 (Figure 5.4 a).

2.1H NMR (DMSOd6, 300 MHz) ( H)

0.86 (6H, m, CH3 - CH - CH3), 0.98 (3H, s, C-CH3 ), 1.20 (2H, m,

CH2 – CH – (CH3)2), 1.78 (1H, m, CH2 – CH – (CH3)2), 3.99 (1H, bs, HO – C

- CH3), 4.28 (CH - OH ), 5.17 (1H, s, C6H5 - CH) and 7.20 – 7.34 ( 5H, m,

Harom) (Figure 5.4 b).

3.13

C NMR (DMSOd6, 75 MHz) ( C)

22.55 (CH3 – CH - CH3), 23.33 (CH3 – CH - CH3), 24.53 (C-CH3),

25.18 (CH2 – CH – (CH3)2), 45.71 (CH2 – CH – (CH3)2), 74.16 ( C - CH3),

79.58 (C6H5 - CH ) and 26.49 – 142.65 (aromatic carbons) (Figure 5.4 c).

4. Mass spectrum (CI, methanol)

[M+H]+ at m/z 209 (absent) and [MH-H2O]

+ at m/z 191(100)

(Figure 5.4 d).

The elemental analysis of this compound, C13H20O2, gave 75.17 and

9.26 percentage of carbon and hydrogen respectively as against the calculated

values of 74.96 and 9.6 percentage for carbon and hydrogen respectively.

251

Figure 5.4 (a) IR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

methylpropyl)-1,2-dihydroxypropane

Figure 5.4(b)1H NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

methylpropyl)-1,2-dihydroxypropane

CC

HO H

CH3

H2C

OHR

R

(a)

CH

H3C

CH3

CC

HO H

CH3

H2C

OHR

R

(b)

CH

H3C

CH3

252

Figure 5.4 (c)13

C NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

methylpropyl)-1,2-dihydroxypropane

Figure 5.4 (d) Mass spectrum of threo-(1R,2R)-(-)-1-phenyl-2-(2-

methylpropyl)-1,2-dihydroxypropane

CC

HO H

CH3

H2COH

R

R

(c)

CH

H3C

CH3

CC

HO H

CH3

H2C

OHR

R

(d)

CH

H3C

CH3

253

5.5.2 threo-(1R,2R)-(+)-1-Phenyl-2-Benzyl-1,2-Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3420 and 3297, benzenoid bands at1603 and 1495, C_

O

str. at 1040 and C_H out of plane bending of mono-substituted benzene ring at

735 and 700 (Figure 5.5 a).

2.1H NMR (CDCl3, 300 MHz) ( H)

0.93 (3H, s, C-CH3), 2.01 (1H, bs, HO – C - CH3), 2.72 (CH -

OH), 2.90 (2H, m, C6H5 - CH2), 4.57 (1H, s, CH - OH) and 7.23 – 7.37 (10H,

m, Harom) (Figure 5.5 b).

3.13

C NMR (CDCl3, 75 MHz) ( C)

21.82 (C - CH3), 45.11 (C6H5 - CH2), 75.19 (C - CH3), 79.13 (CH -

OH) and 126.51–140.25 (aromatic carbons) (Figure 5.5 c).

4. Mass spectrum (ESI)

[M+H]+ at m/z 243 (absent), [MH-H2O]

+ at m/z 225(82) and

[MH-2H2O]+ at m/z 207(100) (Figure 5.5 d).

The elemental analysis of this compound (C16H18O2) gave 78.95

and 7.51 percentage of carbon and hydrogen respectively as against the

calculated values of 79.37 and 7.49 percentage for carbon and hydrogen

respectively.

254

Figure 5.5 (a) IR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-benzyl-1,2-

dihydroxypropane

Figure 5.5(b)1H NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

benzyl-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(b)

CC

HO H

CH3

OHR

R

(a)

255

Figure 5.5(c)13

C NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

benzyl-1,2-dihydroxypropane

Figure 5.5 (d) Mass spectrum of of threo-(1R,2R)-(+)-1-phenyl-2-

benzyl-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(c)

CC

HO H

CH3

OHR

R

(d)

256

5.5.3 threo-(1R,2R)-(+)-1-Phenyl-2-(2-phenylethyl)-1,2-

Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3445 and 3362, benzenoid bands at1603 and 1493, C_

O

str. at1043 and C_H out of plane bending of mono-substituted benzene ring at

735 and 698 (Figure 5.6 a)

2.1H NMR (CDCl3, 300 MHz) ( H)

1.15 (3H, s, C-CH3), 1.84 (2H, m, C6H5 - CH2 – CH2), 2.20 (1H, bs,

OH – C - CH3), 2.76 (3H, m, C6H5 - CH2 – CH2 & CH - OH), 4.57 (1H, s,

C6H5 - CH) and 7.18 – 7.36 (10H, m, Harom) (Figure 5.6 b).

3.13

C NMR (CDCl3 , 75 MHz) ( C)

21.27 (C - CH3), 29.87 (C6H5 - CH2 – CH2), 40.71 (C6H5 - CH2 –

CH2), 75.12 (C - CH3), 79.76 (CH - OH) and 125.78–142.42 (aromatic

carbons) (Figure 5.6 c).

4. Mass spectrum (ESI)

[M+H]+ at m/z 257 (absent), [MH-H2O]

+ at m/z 239(82) and [MH-

2H2O]+ at m/z 221(100) (Figure 5.6 d).

The elemental analysis of this compound, C17H20O2, gave 80.10 and

7.82 percentage of carbon and hydrogen respectively as against the calculated

values of 79.65 and 7.86 percentage for carbon and hydrogen respectively.

257

Figure 5.6 (a) IR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(2-

phenylethyl)-1,2-dihydroxypropane

Figure 5.6 (b)1H NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

(2-phenylethyl)-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(a)

CC

HO H

CH3

OHR

R

(b)

258

Figure 5.6 (c)13

C NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(2-

phenylethyl)-1,2-dihydroxypropane

Figure 5.6 (d) Mass spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(2-

phenylethyl)-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(c)

CC

HO H

CH3

OHR

R

(d)

259

5.5.4 threo -(1R,2R)-(-)-1-Phenyl-2-Cyclohexyl-1,2-Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3431 and 3277, benzenoid bands at1493 and 1452, C_

O

str. at 1042 and C_H out of plane bending of mono-substituted benzene ring at

743 and 700 (Figure 5.7 a).

2.1H NMR (CDCl3, 300 MHz) ( H)

0.84 (3H, s, C-CH3), 1.00 – 1.34 (4H, m, CH – CH2 – CH2 – CH2 -

CH2 ), 1.72 (2H, m, CH – CH2 – CH2 – CH2 - CH2), 1.81 – 2.01 ( 7H, m, CH2

– CH – CH2 , HO – C - CH3 & CH - OH), 4.71 (1H, s, CH - OH) and 7.26 –

7.35 ( 5H, m, Harom) (Figure 5.7 b).

3.13

C NMR (CDCl3, 75 MHz) ( C)

19.34 (C - CH3), 26.63 (CH – CH2 – CH2 – CH2 - CH2), 26.93 (CH

– CH2 – CH2 – CH2 - CH2), 28.03 (CH2 – CH – CH2), 43.72 (CH2 – CH –

CH2), 76.25 (C - CH3), 76.71 (C6H5 - CH) and 127.65–141.16 (aromatic

carbons) (Figure 5.7 c).

4. Mass spectrum (CI, methanol)

[M+H]+ at m/z 235 (absent), [MH-H2O]

+ at m/z 217(100) and

[MH-2H2O]+ at m/z 199(30) (Figure 5.7 d).

The elemental analysis of this compound, C15H22O2, gave 76.43 and

8.98 percentage of carbon and hydrogen respectively as against the calculated

values of 76.84 and 9.46 for carbon and hydrogen respectively.

260

Figure 5.7 (a) IR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-cyclohexyl-

1,2-dihydroxypropane

Figure 5.7 (b)1H NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-

cyclohexyl-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(a)

CC

HO H

CH3

OHR

R

(b)

261

Figure 5.7 (c)1H NMR spectrum of threo-(1R,2R)-(-)-1-phenyl-2-

cyclohexyl-1,2-dihydroxypropane

Figure 5.7 (d) Mass spectrum of threo-(1R,2R)-(-)-1-phenyl-2-

cyclohexyl-1,2- dihydroxypropane

CC

HO H

CH3

OHR

R

(c)

CC

HO H

CH3

OHR

R

(d)

262

5.5.5 threo-(1R,2R)-(+)-1-Phenyl-2-(3-fluorobenzyl)-1,2-

Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3416 and 3296, benzenoid bands at 1607 and 1508,

C_

O str. at 1042, C_H out of plane bending of para-di-substituted benzene

ring at 814 and mono-substituted benzene ring at 764 and 702 (Figure 5.8 a).

2.1H NMR (CDCl3, 300 MHz) ( H)

0.91 (3H, s, C-CH3), 2.03 (1H, bs, HO – C - CH3), 2.68 (1H, bs,CH

- OH), 2.87 (2H, m, F - C6H4 - CH2), 4.55 (1H, s, CH - OH) and 6.96 – 7.36

(9H, m, Harom) (Figure 5.8 b).

3.13

C NMR (CDCl3, 75 MHz) ( C)

21.70(C - CH3), 44.16 (F - C6H4 - CH2), 75.14 ( C - CH3), 79.06

(CH - OH) and 114.75–163.39 (aromatic carbons) (Figure 5.8 c).

4. Mass spectrum (CI, methanol)

[M+H]+ at m/z 261 (absent), [MH-H2O]

+ at m/z 243(100) and

[MH-2H2O]+ at m/z 225(45) (Figure 5.8 d).

The elemental analysis of this compound (C16H17FO2) gave 74.16

and 6.54 percentage of carbon and hydrogen respectively as against the

calculated values of 73.83 and 6.58 percentage for carbon and hydrogen

respectively.

263

Figure 5.8 (a) IR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(3-

fluorobenzyl)-1,2-dihydroxypropane

Figure 5.8 (b)1H NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(3-

fluorobenzyl)-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(b)F

CC

HO H

CH3

OHR

R

(a)F

264

Figure 5.8 (c)13

C NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

(3-fluorobenzyl)-1,2-dihydroxypropane

Figure 5.8 (d) Mass spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

(3-fluorobenzyl)-1,2-dihydroxypropane

CC

HO H

CH3

OHR

R

(c)F

CC

HO H

CH3

OHR

R

(d) F

265

5.5.6 threo-(1R,2R)-(+)-1-Phenyl-2-(4-fluorobenzyl)-1,2-

Dihydroxypropane

1. IR (cm1) (KBr)

O-H str. at 3420 and 3312, benzenoid bands at 1614 and 1585, C_

O str. at 1144 and C_H out of plane bending of mono-substituted benzene ring

at 762 and 700 (Figure 5.9 a).

2.1H NMR (CDCl3, 300 MHz) ( H)

0.92 (3H, s, C-CH3), 2.09 (1H, bs, HO – C - CH3), 2.70 (1H, bs,CH

- OH), 2.84 (2H, m, F - C6H4 - CH2), 4.55 (1H, s, CH - OH) and 6.96 – 7.36

(9H, m, Harom) (Figure 5.9 b).

3.13

C NMR (CDCl3, 75 MHz) ( C)

21.74(C - CH3), 44.76 (p-F - C6H4 - CH2), 75.16 (C - CH3), 79.05

(CH - HO) and 113.21 – 164.21 (aromatic carbons) (Figure 5.9 c).

4. Mass spectrum (ESI)

[M+H]+ at m/z 261 (absent), [MH-H2O]

+ at m/z 243 (45) and

[MH-2H2O]+ at m/a 225(100) (Figure 5.9 d).

The elemental analysis of this compound, C16H17FO2, gave 73.60

and 6.62 percentage of carbon and hydrogen respectively as against the

calculated values of 73.83 and 6.58 percentage for carbon and hydrogen

respectively.

266

Figure 5.9 (a) IR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(4-

fluorobenzyl)-1,2-dihydroxypropane

Figure 5.9 (b)1H NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-

(4-fluorobenzyl)-1,2-dihydroxypropane

CC

H O H

C H 3

O HR

R

F(a )

CC

H O H

CH 3

O HR

R

F(b)

267

Figure 5.9 (c)13

C NMR spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(4-

fluorobenzyl)-1,2-dihydroxypropane

Figure 5.9 (d) Mass spectrum of threo-(1R,2R)-(+)-1-phenyl-2-(4-

fluorobenzyl)-1,2-dihydroxypropane

These spectroscopic data and the analytical values amply confirmed

the structures of compounds 1 to 8.

CC

H O H

C H 3

O HR

R

F(c)

CC

HO H

CH3

OHR

R

F(d)

268

5.6 ENANTIOMERIC PURITY

The chiral purity of all the compounds prepared by Grignard

reactions have been determined using chiral HPLC method. The chiral

column used was CHIRALPAK AD H-250 X 4.6 mm, 5 m (COL/CH /014).

It is pertinent to mention here that the enantiomeric purity determined by the

above mentioned method was found to be 100% in the case of all the

compounds prepared in this work.

In order to establish the enantiomeric purity of Grignard products

by chiral HPLC, the other isomer (1S,2S)- compounds could not be prepared

since it was not possible to obtain (S)-(+)-phenylacetylcarbinol by any

reported fermentation process. But racemic phenylacetylcarbinol was

prepared and performed the Grignard reaction with phenyl magnesium

bromide and 4-fluorobenzylmagnesium bromide. The HPLC chromatogram

of (1R,2R)-1,2-diphenyl-1,2-dihydroxyproane (Figure 5.1a) showed a peak at

a retention time of 15.9 min. (100%) and racemic 1,2-diphenyl-1,2-

dihydroxyproane showed two peaks at retention time of 15.82 and 17.82 min

(Figure 5.1 b) corresponding to (1R,2R)-isomer (51.1%) and (1S,2S)-isomer

(49.9%) respectively. Similarly, retention time of (1R,2R)-(+)-1-phenyl-2-(4-

fluorobenzyl)-1,2-dihydroxy propane was observed at 5.10 min with a purity

of 100% (Figure 5.10 a). Whereas the racemic (1RS,2SR)-(±)-1-phenyl-2-(4-

fluorobenzyl)-1,2-dihydroxypropane showed two peaks, one corresponding to

(1R,2R)-isomer at 5.11 min and other corresponding to (1S,2S)-isomer at 4.45

min with a purity of 50 % each (Figure 5.10 b).

The HPLC chromatograms showing the enantiomeric purity

determined for each compound are depicted in Figures 5.11 to 5.17.

269

Figure 5.10 (a) Chiral HPLC chromatogram of threo-(1R,2R)-(+)-1-

phenyl-2-(4-fluorobenzyl)-1,2-dihydroxy propane

Figure 5.10 (b) Chiral HPLC chromatogram of threo-(1RS,2SR )-(±)-1-

phenyl-2-(4-fluorobenzyl)-1,2-dihydroxy propane

270

Figure 5.11 Chiral HPLC chromatogram of threo-(1R,2R)-(-)-1-phenyl-

2-(2-propyl)-1,2-dihydroxypropane

Figure 5.12 Chiral HPLC chromatogram of threo-(1R,2R)-(-)-1-phenyl-

2-(2-methylpropyl)-1,2-dihydroxypropane

271

Figure 5.13 Chiral HPLC chromatogram of threo-(1R,2R)-(+)-1-phenyl-

2-benzyl-1,2-dihydroxypropane

Figure 5.14 Chiral HPLC chromatogram of threo-(1R,2R)-(+)-1-phenyl-

2-(2-phenylethyl)-1,2-dihydroxypropane

272

Figure 5.15 Chiral HPLC chromatogram of threo-(1R,2R )-(-)-1-phenyl-

2-cyclohexyl-1,2-dihydroxypropane

Figure 5.16 Chiral HPLC chromatogram of threo-(1R,2R)-(+)-1-phenyl-

2-(3-fluorobenzyl) -1,2-dihydroxy propane