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Stereochemistry และ Optical Rotation ในต ารายา

นายสมชย พนธอนกล ส านกยาและวตถเสพตด

กรมวทยาศาสตรการแพทย

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• Isomers

• Stereoisomers

• Chirality

• Enantiomers

• Optical rotation

• Absolute configuration and its notation

• Diastereomers

• Stereochemistry in Pharmacopoeia

Outline

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Isomers

• Molecules that have the same molecular

formula but different arrangements of their

constituent atoms

• There are two forms of isomers:

• Structural isomers

• Stereoisomers

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Structural isomers

• Constitutional isomers

• isomers that have different bonding

arrangements of their atoms (connectivity)

• usually show very marked differences in

physical and chemical properties

• There are 3 forms of structural isomers:

Chain isomers, Positional isomers and

Functional groups isomers

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ตวอยาง: Chain isomers

Pentane, C5H12

CH3 CH2 CH2 CH2 CH3CH3 CH2 CH CH3

CH3

n-pentane isopentane neopentane

CH3 C

CH3

CH3

CH3

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ตวอยาง: Positional isomers

C4H9OH

CH3 CH2 CH2 CH2 OH

CH3 CH2 CH CH3

OH

CH3 CH CH2 OH

CH3 CH3 C CH3

CH3

OH

butan-1-ol butan-2-ol

2-methylpropan-1-ol 2-methylpropan-2-ol

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ตวอยาง: Functional groups isomers

C3H6O

CH3 CH2 C

O

H CH3

CCH3

O

propanal (aldehyde)

propanone (ketone)

CH2 CH CH2 OH

2-propen-1-ol (alcohol)

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Stereoisomers

• isomers with identical connectivity but

different spatial arrangements of their atoms

• There are two forms of stereoisomers:

• Enantiomers

• Diastereomers

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Chirality

• Chirality (Greek: cheir,hand)

• refers to objects which are related as

non–superimposable mirror images

• the term derives from the fact that left and

right hands are examples of chiral objects.

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Chiral molecules

• The most common type of chiral molecule

contains a tetrahedral carbon atom attached

to four different groups (asymmetric carbon).

• Such a molecule can exist as two different

compounds (stereoisomers) that are

nonsuperimposable mirror image of each

other.

• Such stereoisomers are call enantiomers

(Greek: enantio,opposite)

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Enantiomers

• stereoisomers that are nonsuperimposable

mirror images of each other

• Enantiomers have opposite configurations.

• Example: Alanine is a chiral molecule and

exists as a pair of enantiomers

H2N

COOH

CH3H

NH2

COOH

H3C

HEnantiomers of alanine

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• Optical isomers

• have identical chemical and physical

properties in a symmetric environment except

for their ability to rotate plane-polarized light

by equal amounts but in opposite direction

• optically active

Racemic mixture

• 50/50 mixture of two enantiomers

• optically inactive

Enantiomers

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Optical Rotation

• The degree (angle) of rotation is measured

using a polarimeter and has a specific value

for each optically active substance

• If the rotation is to the right (clockwise),

the substance is dextrorotatory, (+) or (d)

(Latin: dexter, right)

• If the rotation is to the left (counterclockwise),

the substance is levorotatory, (-) or (l)

(Latin: laevus, left)

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polarizer

sample

plane-polarized

optically active

optically inactive

dextrorotatory(d ) or (+)

levorotatory(l ) or (-)

analyzer

Polarimeter

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Optical Rotation

• The magnitude of the rotation of an enantiomer

is reported as its specific rotation

• Specific rotation is dependent on:

• the wavelength of the light used

• the length of the polarimeter tube

• the temperature

• the nature of solvent

• the concentration

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• The earliest method of distinguishing between

enantiomers was the sign of optical rotation:

• d- or (+)-form

• l- or (-)-form

• This does not say anything about configuration.

• There is no relationship between a particular

configuration and the direction of rotation.

Relative configuration

Absolute configuration and its notation

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H

HOOCOH

CH3

H

COOHHO

H3C

Example: Lactic acid

• There are two enantiomers of lactic acid.

• One rotates the plane-polarized light to the

right and the other to the left and are labeled:

(+)-lactic acid or d-lactic acid

(-)-lactic acid or l-lactic acid

*CH3CHCOOH

OH

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• The two configuration of lactic acid are

shown below, but the question is which

one corresponds to (+)-lactic acid and which to (-)-lactic acid.

H

HOOCOH

CH3

H

COOHHO

H3C

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• Before 1951, only relative configurations of

chiral molecules were known.

• No one had been able to determine the

absolute configuration of an optically active

compound.

• The configurations of chiral molecules were

related to each other through reactions of

known stereochemistry.

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• The configurations of chiral molecules were

established by chemical transformation to an

arbitrarily chosen standard, (+)-glyceraldehyde.

• Glyceraldehyde has one chiral, so it exists as a pair of enantiomers.

C

CHOH

CH2OH

*

O H

C

HOH2COH

H

O H

C

CH2OHHO

H

OH

A B

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• For example, the configuration of (-)-lactic acid can be

related to (+)-glyceraldehyde.

C

C

H

CH2OH

OH C

C

H

CH2OH

OH

O

H

O

OH

(+)-glyceraldehyde (-)-glyceric acid

C

C

H

CH2

OH

O

OH

NH2

C

C

H

CH2

OH

O

OH

Br

C

C

H

CH3

OH

O

OH

(+)-Isoserine

(-)-3-bromo-2-hydroxy-propanoic acid

(-)-lactic acid

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• The stereochemistry of all of these reactions is

known. They all proceed with retention of

configuration.

• If the assumption is made that the

configuration of (+)-glyceraldehyde is as A,

then the configuration of (-)-lactic acid is the

same as that of (+)-glyceraldehyde, A.

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C

HOH2COH

H

O H

C

H3COH

H

O OH

(+)-glyceraldehyde (-)-lactic acid A

C

HOH2COH

H

O H

C

CH2OHHO

H

OH

A B Glyceraldehyde

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• In 1951, the first X-ray determination of the

absolute configuration of an enantiomer was

reported.

• (+)-Tartaric acid had the absolute configuration

shown below:

C

C

O OH

OHH

CCOOH

HO

H(+)-tartaric acid

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• The configuration of (-)-glyceraldehyde was

also related through reaction of known

stereochemistry to (+)-tartaric acid.

C

HOH2COH

H

O H

(+)-glyceraldehyde

C

C

O OH

OHH

CCOOH

HO

H(+)-tartaric acid

C

CH2OHHO

H

OH

(-)-glyceraldehyde

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• This meant that the original arbitrary assignment of

the configuration of (+)- and (-)- glyceraldehyde

was also correct.

C

HOH2COH

H

O H

C

CH2OHHO

H

OH

(-)-glyceraldehyde (+)-glyceraldehyde

It was a lucky guess !!!

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• Fischer convention for the designation of

configuration (in 1919)

• Use the C-5 of the d-enantiomer of glucose

as a starting point.

H OH

HO H

H OH

H OH

CH2OH

H O

(+)-glucose

or

d-glucose

*

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H OH

HO H

H OH

H OH

CH2OH

H O

CHO

CH2OH

OHH

(+)-glyceraldehyde (+)-glucose

• (+)-Glucose was degraded by Fischer to

(+)-glyceraldehyde.

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• Arbitrarily, Fischer assigned the configuration

shown below to (+)-glyceraldehyde and

called it D-(+)-glyceraldehyde,

(due to the position of the OH group on the

right hand side of the chiral center).

CHO

CH2OH

OHH D-(+)-glyceraldehyde

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• All chiral molecules that could chemically be

related to D-(+)-glyceraldehyde were assigned

the configuration D, while molecules related to

L-glyceraldehyde become the L-series.

• The Fischer convention is widely used in sugar

chemistry and for -amino acids.

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H OH

HO H

H OH

H OH

CH2OH

H O

CHO

CH2OH

OHH

D-(+)-glyceraldehyde D-(+)-glucose

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• The D/L labeling is unrelated to (+)/(−).

• It does not indicate which enantiomer is

dextrorotatory and which is levorotatory.

• Rather, it says that the compound's

stereochemistry is related to that of the

dextrorotatory or levorotatory enantiomer of

glyceraldehyde.

• (+)-glyceraldehyde D-(+)-glyceraldehyde

• (-)-glyceraldehyde L-(-)-glyceraldehyde

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• For sugars and other molecules that contain a

number of chiral center, the Fischer convention

defines a series as D or L according to whether

the configuration at the highest numbered

chiral center is equivalent to D-glyceraldehyde

or L-glyceraldehyde.

CHO

CH OH

CH OH

CH2OH

1

2

3

4

D-erythrose

CHO

CH2OH

OHH

D-glyceraldehyde

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IMPORTANT NOTE:

• Although D-glyceraldehyde is dextrorotatory, the compounds correlated to D-glyceraldehyde do not have to be dextrorotatory, i.e. could rotate light to the left. Therefore, D-prefix is not correlated with the (+) or (-) specific rotation, and the D-compound can be l, (or -), and vice versa L-compound can be d (or +).

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IMPORTANT NOTE:

• This nomenclature system is slowly being abandoned in favor of the Cahn-Ingold-Prelog (CIP) nomenclature, with the exception where the DL-nomenclature has been used traditionally, and is more useful (D-carbohydrates or L-amino acids).

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• Absolute configurations • R and S nomenclature • (R) – rectus, ขวา, ตามเขมนาฬกา • (S) – sinister, ซาย, ทวนเขมนาฬกา

Cahn-Ingold-Prelog convention

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• จดล าดบ priorities ของอะตอมหรอหมอะตอมทง 4 ตาม Cahn-Ingold-Prelog priority rule

เรยงจากต าไปสง - 1 < 2 < 3 < 4 • หมนโมเลกลใหหมทม priority ต าสดชออกนอกตว, 1 • ดทศทางการเรยงตวของ 3 หมทเหลอจาก priority สงไปหา priority ต า : 4 > 3 > 2

• ถาเวยนขวา ตามเขมนาฬกา – (R)-configuration ถาเวยนซาย ทวนเขมนาฬกา – (S)-configuration

Cahn-Ingold-Prelog convention

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Cahn-Ingold-Prelog priority rule

• จดเรยงล าดบ priority ของอะตอมหรอหมอะตอม • พจารณาจาก atomic number ของอะตอมทตอกบ

asymmetric carbon • ใหหมทม atomic number สงกวาม priority สงกวา • ถาเทากน ใหพจารณาอะตอมถดไปเรอยๆ จนกระทงเหนความแตกตาง

• Look for higher atomic number at the first point of difference.

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การเรยกชอ Enantiomer • พจารณา configuration ท chiral center วา

เปน (S) หรอ (R) แลวระบลงในชอสารนน • ตวอยาง: Alanine

H2N

COOH

CH3H

NH2

COOH

H3C

H(S)-alanine (R)-alanine

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COOH

H2NCH3

H1

2

3

4

COOH

NH2H3C4

3

2

NH2

COOH

H3C

H1

2

3

4

COOH

H2N CH34

3

2

(S)-alanine (R)-alanine

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• พบวา (R)-alanine หมนระนาบของแสงโพลาไรซไปทางซาย (-) ---> (R)-(-)-alanine

• พบวา (S)-alanine หมนระนาบของแสงโพลาไรซไปทางขวา (+) ---> (S)-(+)-alanine

• ไมมความสมพนธระหวาง configuration ของ enantiomers กบ ทศทางการหมนระนาบของ แสงโพลาไรซ

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C

HOH2COH

H

O H

C

CH2OHHO

H

OH

• (+)-glyceraldehyde R-configuration

• (-)-glyceraldehyde S-configuration

(R)-(+)-glyceraldehyde (S)-(-)-glyceraldehyde

(R) (S)

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Fischer projection formulas A

C

BD

A

C

BD

A

DB

C= =

• Two-dimensional formulas ส าหรบ chiral molecules • เสนตรง 2 เสนตดกนเปนมมฉาก จดตด แทน chiral carbon • เสนในแนวตง แทนพนธะทยนเขาไปหลงระนาบของกระดาษ • เสนในแนวนอน แทนพนธะทยนออกมาจากระนาบของกระดาษ

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A

C

BD

A

C

BD

A

DB

C= =

A

B

C

D

A

B

C D

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การหา configuration โดยใช Fischer projection formulas

CH3CHCH2CH3

OH

*

H

CH2CH3

OHCH3(R)-2-butanol • เมอหมทม priority ต าทสดอยใน

แนวตง - อานตามปกต (S)-2-butanol • เมอหมทม priority ต าทสดอยใน

แนวนอน - อานตรงขาม

CH3

CH2CH3

OHH

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L- and D- Nomenclature

• It is also used for amino acids to define the

configuration at the –center.

• When drawn as a Fischer projection:

• The D-isomer has the higher priority group on

the right hand side.

• The L-isomer has the higher priority group on the left hand side.

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COOH

CH3

H2N H

L-alanine

COOH

CH3

NH2H

D-alanine

COOH

H2NCH3

HNH2

COOH

H3C

H(S)-(+)-alanine (R)-(-)-alanine

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Diastereomers • stereoisomers ทไมเปน mirror images กนและกน • มสมบตทางกายภาพตางกน • เปนสารตางชนดกน • โมเลกลทมมากกวาหนง chiral centers • สารทม n chiral center มไดทงหมด 2n stereoisomers • สารทม 2 chiral center มไดทงหมด 4 stereoisomers

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2,3-dibromopentane CH3CHCHCH2CH3

Br Br

**

C BrH

CH3

C

C2H5

BrH

1

CBr H

CH3

C

C2H5

Br H

2

C HBr

CH3

C

C2H5

BrH

CH Br

CH3

C

C2H5

Br H

3 4

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C BrH

CH3

C

C2H5

BrH

1

CBr H

CH3

C

C2H5

Br H

2

C HBr

CH3

C

C2H5

BrH

3

CH Br

CH3

C

C2H5

Br H

4

Enantiomer

Enantiomer

Diastereomer Diastereomer

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Meso compounds • โมเลกลทม 2 chiral centers อาจจะมไมครบ 4 stereoisomers • เชน 2,3-dibromobutane มไดทงหมด 3 stereoisomers

CH3CHCHCH3

Br Br

* *

C HBr

CH3

C

CH3

BrH

CH Br

CH3

C

CH3

Br H

C BrH

CH3

C

CH3

BrH

CBr H

CH3

C

CH3

Br H

A B C D

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C HBr

CH3

C

CH3

BrH

A

CH Br

CH3

C

CH3

Br H

B

C BrH

CH3

C

CH3

BrH

C

Enantiomer

Moso compound

Diastereomer Diastereomer

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การเรยกชอสารทมมากกวาหนง chiral centers • พจารณา configuration ทละ chiral center วาเปน (S) หรอ

(R) แลวระบต าแหนงลงในชอเรยกสารนน • Stereoisomer A ของ 2,3-dibromobutane ม C-2 และ C-3

เปน chiral centers ม configuration เปนแบบ (R) ทงค

(2R, 3R)-2,3-dibromobutane C HBr

CH3

C

CH3

BrH(R)

(R)

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(1R,2S)-(-)-Ephedrine

C(R )

HHO

C(S )

HCH3NH

CH3

C(S )

H OH

C(R )

H NHCH3

CH3

C(S )

OHH

C(S )

HCH3NH

CH3

C(R )

HO H

C(R )

H NHCH3

CH3

(1S,2S)-(+)-Pseudophedrine

(1S,2R)-(+)-Ephedrine

(1R,2R)-(-)-Pseudophedrine

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Erythro- and Threo- Nomenclature

• Erythro- and Threo- are applied to system

containing two chiral carbons when two of the

groups are the same and the third is different.

• Erythro- describes adjacent stereocenter

possessing similar group on the same side of the

vertical axis of the Fischer projection.

• Threo- describes adjacent stereocenter

possessing similar group on the opposite side of

the vertical axis of the Fischer projection.

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Y

Z

X W

X W

Erythro-stereocenters

CHO

CH2OH

H OH

H OH

D-Erythrose

Y

Z

W X

X W

Threo-stereocenters

CHO

CH2OH

HO H

H OH

D-Threose

CHO

CH2OH

HHO

HHO

L-Erythrose

CHO

CH2OH

OHH

HHO

L-Threose

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• The ambiguity arises from the question what should be used as the main chain.

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• l-Ephedrine or (-)-Ephedrine

• (1R,2S)-(-)-Ephedrine

• L-erythro-Ephedrine

C(R )

HHO

C(S )

HCH3NH

CH3

C(S )

H OH

C(R )

H NHCH3

CH3

• d-Ephedrine or (+)-Ephedrine

• (1S,2R)-(+)- Ephedrine

• D-erythro-Ephedrine

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C(S )

OHH

C(S )

HCH3NH

CH3

C(R )

HO H

C(R )

H NHCH3

CH3

• d-Pseudoephedrine

• (1S,2S)-(+)-Pseudoephedrine

• L-threo-Pseudoephedrine

• l-Pseudoephedrine

• (1R,2R)-(-)-Pseudoephedrine

• D-threo-Pseudoephedrine

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Stereochemistry และ Optical Rotation ในต ารายา

ตวอยาง: Chloramphenicol

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NO2

CHO H

C

CH2OH

NHCCHCl2H

O

1

2

(R)

(R)

NO2

C OHH

C

CH2OH

Cl2HCCHN H

O

1

2

(S)

(S)

NO2

CH OH

C

CH2OH

H NHCCHCl2

O

1

2

(R)

(S)

NO2

C HHO

C

CH2OH

HCl2HCCHN

O

1

2

(S)

(R)

(1R,2R)-D(-)-threo

(1S,2S)-L(+)-threo-

(1R,2S)- D(-)-erythro-

(1S,2R)- L(+)-erythro-

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Chloramphenicol

• D(-)-threo isomer is biologically active

• Biological activity:

D(-)-threo > L(+)-erythro > D(-)-erythro

• L(-)-threo form is biologically inactive

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Chloramphenicol ในเภสชต ารบ:- D(-)-threo-Chloramphenicol

• ชอของ Chloramphenicol ในเภสชต ารบระบ optical rotation เปน (-) แตคา optical rotation ทก าหนดเปน (+)

• USP 30: Specific rotation: between +17.0 and +20.0.

(in dehydrated alcohol)

• BP 2007: Specific optical rotation is +18.5 to +20.5. (in

ethanol) แตระบวา “A solution in ethanol is

dextrorotatory and a solution in ethyl acetate is laevorotatory”

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ขอมลเพมเตม D(-)-threo-Chloramphenicol

• Merck index:

[]27, D +18.6 (c=4.86 in ethanol)

[]25, D -25.5(ethyl acetate)

• Rebstock et al., 1949

[α] 25 D = +19.0 in ethanol

[] 25, D = -25.5 in ethyl acetate

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