Stereochemistry Optical Rotation

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Stereochemistry ??? Optical Rotation
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Outline

• Isomers
• Stereoisomers
• Chirality
• Enantiomers
• Optical rotation
• Absolute configuration and its notation
• Diastereomers
• Stereochemistry in Pharmacopoeia

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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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???????? Chain isomers Pentane, C5H12
n-pentane
isopentane
neopentane
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???????? Positional isomers C4H9OH
butan-1-ol
butan-2-ol
2-methylpropan-1-ol
2-methylpropan-2-ol
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???????? Functional groups isomers C3H6O
propanal (aldehyde)
propanone (ketone)
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
  nonsuperimposable 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

Enantiomers of alanine
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Enantiomers

• 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

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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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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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Absolute configuration and its notation
Relative configuration

• 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.

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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

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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.

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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.

A
B
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• For example, the configuration of (-)-lactic acid
  can be related to ()-glyceraldehyde.

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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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A
B
Glyceraldehyde
A
(-)-lactic acid
()-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

()-tartaric acid
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• The configuration of (-)-glyceraldehyde was also
  related through reaction of known stereochemistry
  to ()-tartaric acid.

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• This meant that the original arbitrary assignment
  of the configuration of ()- and (-)-
  glyceraldehyde was also correct.

(-)-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.

()-glucose or d-glucose

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• ()-Glucose was degraded by Fischer to
  ()-glyceraldehyde.

()-glyceraldehyde
()-glucose
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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).

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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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.

D-erythrose
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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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Cahn-Ingold-Prelog convention

• Absolute configurations
• R and S nomenclature
• (R) rectus, ???, ?????????????
• (S) sinister, ????, ?????????????

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Cahn-Ingold-Prelog convention

• ???????? priorities ????????????????????????? 4
  ??? Cahn-Ingold-Prelog priority rule
• ???????????????? - 1 lt 2 lt 3 lt 4
• ??????????????????????? priority
  ??????????????????, 1
• ?????????????????????? 3 ??????????????? priority
  ??????? priority ??? 4 gt 3 gt 2
• ??????????? ????????????? (R)-configuration
• ???????????? ????????????? (S)-configuration

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Cahn-Ingold-Prelog priority rule

• ????????????? priority ?????????????????????
• ?????????? atomic number ?????????????????
  asymmetric carbon
• ???????????? atomic number ????????? priority
  ???????
• ?????????? ???????????????????????????
  ????????????????????????
• Look for higher atomic number at the first point
  of difference.

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???????????? Enantiomer

• ??????? configuration ??? chiral center ???????
  (S) ???? (R) ???????????????????????
• ???????? Alanine

(S)-alanine
(R)-alanine
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(S)-alanine
(R)-alanine
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• ????? (R)-alanine ????????????????????????????????
  (-) ---gt (R)-(-)-alanine
• ????? (S)-alanine ???????????????????????????????
  () ---gt (S)-()-alanine
• ???????????????????????? configuration ???
  enantiomers ??? ?????????????????????
  ???????????

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• ()-glyceraldehyde ? R-configuration
• (-)-glyceraldehyde ? S-configuration

(R)
(S)
(R)-()-glyceraldehyde
(S)-(-)-glyceraldehyde
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Fischer projection formulas

• Two-dimensional formulas ?????? chiral molecules
• ??????? 2 ???????????????????? ?????? ??? chiral
  carbon
• ????????????? ????????????????????????????????????
  ???
• ???????????? ?????????????????????????????????????

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????? configuration ?????? Fischer projection
formulas

• (R)-2-butanol
• ?????????????? priority ??????????????????????
  - ???????????
• (S)-2-butanol
• ?????????????? priority ????????????????????? -
  ???????????

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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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(S)-()-alanine
(R)-(-)-alanine
L-alanine
D-alanine
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Diastereomers

• stereoisomers ?????????? mirror images ?????????
• ????????????????????????
• ??????????????????
• ???????????????????????? chiral centers
• ???????? n chiral center ???????????? 2n
  stereoisomers
• ???????? 2 chiral center ???????????? 4
  stereoisomers

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2,3-dibromopentane
1
2
3
4
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Enantiomer
Diastereomer
Diastereomer
Enantiomer
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Meso compounds

• ???????????? 2 chiral centers ????????????? 4
  stereoisomers
• ???? 2,3-dibromobutane ???????????? 3
  stereoisomers

A
B
C
D
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Enantiomer
Diastereomer
Diastereomer
Moso compound
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???????????????????????????????? chiral centers

• ??????? configuration ???? chiral center ???????
  (S) ???? (R) ???????????????????????????????????
• Stereoisomer A ??? 2,3-dibromobutane ?? C-2 ???
  C-3 ???? chiral centers ?? configuration ???????
  (R) ???????

(R)
(2R, 3R)-2,3-dibromobutane
(R)
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(1R,2S)-(-)-Ephedrine
(1S,2R)-()-Ephedrine
(1S,2S)-()-Pseudophedrine
(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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• 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

• d-Ephedrine or ()-Ephedrine
• (1S,2R)-()- Ephedrine
• D-erythro-Ephedrine

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• d-Pseudoephedrine
• (1S,2S)-()-Pseudoephedrine
• L-threo-Pseudoephedrine

• l-Pseudoephedrine
• (1R,2R)-(-)-Pseudoephedrine
• D-threo-Pseudoephedrine

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Stereochemistry ??? Optical Rotation ????????
???????? Chloramphenicol
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(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 gt L()-erythro gt D(-)-erythro
• L(-)-threo form is biologically inactive

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• Chloramphenicol ????????????-
  D(-)-threo-Chloramphenicol
• ??????? Chloramphenicol ???????????????? optical
  rotation ???? (-) ?????? optical rotation
  ???????????? ()
• 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) ?????????? A solution in
  ethanol is dextrorotatory and a solution in ethyl
  acetate is laevorotatory

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• ??????????????? D(-)-threo-Chloramphenicol
• Merck index
• ?27, D 18.6? (c4.86 in ethanol)
• ?25, D -25.5?(ethyl acetate)
• Rebstock et al., 1949
• a 25 D 19.0? in ethanol
• ? 25, D -25.5 ? in ethyl acetate

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