Chemistry 125: Lecture 29November 13, 2009

“Absolute” ConfigurationX-ray and CIP Nomenclature

Preparing Single Enantiomers Determination of the actual atomic arrangement in tartaric acid in 1949 motivated a

change in stereochemical nomenclature from Fischer’s 1891 genealogical convention (D,L)

to the CIP scheme (R,S) based on conventional group priorities. Methods of resolution are

described. 3D visualization of omeprazole. The chemical mode of action of omeprazole is

expected to be insensitive to its stereochemistry, making clinical trials of the proposed

virtues of a chiral switch crucial.

For copyright notice see final page of this filePRELIMINARY

d-(+) l-(-)

How does Optical Activity work?

COOH

COOH

H

OH

HO

H

COOH

COOH

OH

H

H

HO

COOH

COOH

H

OH

HO

H

COOH

COOH

OH

H

H

HO ?

Chirality and Circularly Polarized Light

In order to detect molecular chirality, some sort of chiral probe must be used.

Right- and left-circularly polarized light beams are mirror-image chiral systems and so can act as chiral probes:

Chiral molecules respond slightly differently to right- and left-circularly polarized light. A difference in absorption corresponds to circular dichroism; a difference in refractive index leads to optical rotation.

The instantaneous electric field vectors of right- and left-circularly polarized light beams propagating along z.

right

left

z

z

Changing Time

at Fixed Position

counter-clockwise

Fixed Time

clockwise

Circular Differential Refraction

Linearly polarized light can be described as a coherent superposition of right- and left-circularly polarized waves of equal amplitude.

From P.W. Atkins, Physical Chemistry (OUP)

θΔ A difference in refractive index for the right- and left-circularly polarized beams means a difference in velocity. So the phase relation between the two contrarotating electric vectors will change, resulting in a rotation of the plane of polarization.

Go to Google Images for animations (Google ‘circularly polarized light’ and open the www.enzim.hu site).

)( RL nnl

−=λπθΔ

A Scattering Picture of Optical Rotation

A circularly polarized light wave ‘bouncing’ from one group to the other as it scatters from a simple two-group chiral molecular structure will sample the chirality. The scattered intensity of right- and left-circularly polarized waves will be slightly different for a given handedness of the chiral structure.

The Rotational Strength

The optical rotation angle is given by

Using quantum-mechanical perturbation theory this becomes

The molecular quantity responsible for optical rotation (and circular dichroism) is the rotational strength:

and m are electric and magnetic dipole moment operators, respectively, so the optical activity ultimately originates in interference between electric and magnetic dipole transitions during the light scattering process!€

R j ← n( ) = Im n μ j • j m n( ) .

)( RL nnl

−=λπθΔ

€

Δθ =2μolN

3h

ω2

ω jn2 −ω2

Im n μ j • j m n( )j≠n

∑ πc/λ

The Carbonyl Chromophore

The carbonyl chromophore is an important source of optical activity in many organic compounds. The carbonyl group itself has a plane of symmetry so is not chiral/optically active. Optical activity is induced in its electronic transitions via perturbations from the chiral environment provided by the rest of the molecule.

n←∗π transition at ~ 290 nm

linear displacement of charge(electric)

helical motionof charge

(both)

n

π*

n

π* n transition is magnetic dipole-allowed, electric dipole-forbidden. Electric dipole character is induced by mixing of the oxygen dYZ orbital into

the π orbital:

€

R π ∗+ λ dYZ( ) ← n( ) = Im n μZ π ∗+ λ dYZ( ) π ∗+ λ dYZ( ) mZ n( )

This generates a ZmZ component (from .m) of the rotational strength:

C O

C O

C O

C O

C OC O

rotation of charge(magnetic)

π* n dXZ n π + dXZ) n

x

z

y

mix

mixed by environment asymmetry

Quantum-Chemical Calculations

€

Δθ =2μolN

3h

ω2

ω jn2 −ω2

Im n μ j • j m n( )j≠n

∑

The optical rotation can be calculated using ab initio quantum-chemical programs (Gaussian, Dalton). Often sufficiently good to determine absolute configuration from the sign and magnitude.

Calculated specific rotation of 2,3-hexadiene as a function of the number of excited states considered.

J. P

hys.

Che

m. A

, 200

8, 1

12, 2

415-

2422

Must sum >1500 excitations to get steady value!

Absolute Configuration

J. M. Bijvoetvan't Hoff Laboratory, Univ. Utrecht

(1949-51)

Na Rb d-(L)-TartrateX-ray anomalous

dispersion

60 year old

Fischer Guessfor

(L)-Tartrate “The question of nomenclature is beyond the scope of our investigation... The problem of nomenclature now concerns given configurations, and requires a notation which denotes these configurations in an unambiguous and if possible self-explanatory way.” (Bijvoet, 1951)

Naming Double Bond ConfigurationMalic Acid

(HO2C)CH(OH).CH2. (CO2H)Maleic & Fumaric Acids

(HO2C)HC=CH(CO2H)Δ

H

HOOC COOH

H H

HOOC

COOH

H

cis(on this side of)

trans(across)

H3C

H

CH3

COOH

cis or trans?

Absolute nomenclatureis hard to generalize

O OO

+ H2O

cistrans

(though relative is fine)

Δ

Double Bond Configuration

H3C

H

CH3

COOH

H3C

H CH3

COOH

Assign groups at either end "priority"by atomic number (or weight for isotopes)

at first difference

H3C

H

C

C

HOO

O

HH

H

H3C

H

C

C

HH

H

HOO

OO

O

(E)ntgegen (Opposed) (Z)usammen (Together)The names trans and cis are "polluted" by previous usage.

In Assigning PriorityProceed One "Shell" at a Time

(respecting previous decisions)

C

C

OO

O

HH

H

H

C

C

OO

O

CH

H

H

Cl

H3CCl

Tie

Win

Tie

Win

Cl is highin priority,

but irrelevant;the decision

is already made.

Cl

Cl

Robinson: "Hello Katchalsky. What are you doing here in Zurich?"

from V. Prelog, My 132 semesters of chemistry studies (1981)

The 1950s "CIP" Priority Scheme is Conventional

R. S.Cahn

C. K.Ingold

V.Prelog

Robinson: "Well then, if it is not wrong, it is absolutely unnecessary."

Robinson: "You know, Prelog, your and Ingold's configurational notation is all wrong."

Prelog: "Excuse me, Sir Robert, I am only Prelog, and I live here."

Prelog: "Sir Robert, it can't be wrong. It is just a convention. You either accept it or not."

R. Robinson R. B.Woodward

by p

erm

issi

on J

. D. R

ober

ts

Exercise for Monday:

Eadfrith’s Error

(Click here & create your very own chiral conventions)

http

://w

ww

.bl.u

k/on

line

gall

ery/

them

es/e

urom

anus

crip

ts/l

indi

sfar

ne.h

tml

CIP (R/S) Nomenclaturefor Stereogenic Centers

(S)inister (left)

COOH

COOH

OH

H

H

HO4

3

2

1

1

3

4

2

(2R,3R)-2,3-dihydroxybutanedioic

acid

rightturn

H

(R)ectus (right)

H

HO D

CH3

H

leftturn

HO CH3

D

H

14

2

3

CH3 CH3

HO HODHHD

Bloomer Gate

Organic

:B

Racemization

CH3

HO CO

OH

CH3

HO CO

OH

HOMO

π*LUMO

(R) (RS)

easy

harder(occasional)

CH3

HO CO

OH

dianionvery rare

planarachiral!

(R)-Lactic Acid

HCOOH

CH3

HO

(S)-Lactic Acid

COOHH

CH3

HO

H

HCOO

CH3

HO

End of Lecture 29Nov. 13, 2009

Copyright © J. M. McBride 2009. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).

Use of this content constitutes your acceptance of the noted license and the terms and conditions of use.

Materials from Wikimedia Commons are denoted by the symbol .

Third party materials may be subject to additional intellectual property notices, information, or restrictions. 

The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0