Chemistry 125: Lecture 31

Preparing Single Enantiomers and

Conformational Energy After mentioning some legal implications of chirality, the discussion of configuration concludes using

esomeprazole as an example of three general methods for producing single enantiomers. Conformational

isomerism is more subtle because isomers differ only by rotation about single bonds, which requires

careful physico-chemical consideration of energies and their relation to equilibrium and rate constants.

Conformations have their own notation and nomenclature. Curiously, the barrier to rotation about the C-C

bond of ethane was established by measuring its heat capacity.

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Legal Considerationsof Stereochemistry

McBride Disclosure

I have served as scientific consultant or expert witness to a number of pharmaceutical companies including Eisai.

I take Lipitor and served as an expert witness for a generic competitor in a case involving the validity of a Canadian Lipitor patent of Pfizer.

My only connection to AstraZeneca or Omeprazole is as an occasional consumer of Prilosec OTC.

1267-page“Bible” of

Stereochemistry(1994)

8 pp. on“Biological Properties”

Court Rejects Suit Over AstraZeneca Nexium Marketing

Tuesday November 8, 2005, 4:38 PM EST

WILMINGTON, Del. - (Dow Jones Newswire) - A federal court in Delaware Tuesday dismissed a class-action lawsuit that alleged AstraZeneca PLC's (AZN) misleading marketing of Nexium added billions to health-care costs.

U.S. District Judge Sue Robinson rejected the suit brought by the Pennsylvania Employee Benefit Trust Fund on behalf of entities that foot the bill in health- care plans.

Court Rejects Suit Over AstraZeneca Nexium Marketing

According to the health plan paying organizations, the big difference between the two drugs is not effectiveness, but advertising. By selling doctors and patients on the idea that patented Nexium is better than Prilosec, which faced generic competition, AstraZeneca was able to preserve billions in sales.

Judge Robinson said that the courts should defer to the U.S. Food and Drug Administration in weighing the differences between drugs and that since the FDA cleared Nexium's label, the lawsuit could not stand.

2003 Nexium mass-media advertising budget $260M

2005 advertising budget $226M; Sales $5.8B

Back to Chemistry

To test and manufacture Nexium AstraZeneca had to prepare

the single enantiomer

Resolutiona) Pasteur Conglomerate

b) Temporary Diastereomers

Destroy One EnantiomerReact Racemate with Resolved

Chiral Reagent or Catalyst

Prepare only one Enantiomera) Use resolved starting material

b) Use resolved reagent/catalyst

Resolution of Omeprazole

1) Chromatography on SiO2 coated with trisphenylcarbamoylcellulose (1990)

from Ph-N=C=O and Cellulose

Six Chromatograpy Injections 3 mg (+) , 4 mg (-)

Enough to Measure Racemization t1/2 : 1 hr at 75°C , ~100 hr at 37°C

Ph-N=C=O

Not enough for Human Dose (~20 mg)

n

R

R

R

RR

Ph-N C=O

H

R = R

Ph-N C=O

H

(like urea from NH3 + H-N=C=O)

H2C=O

OH

O

OHH

Resolution of Omeprazole2) Reversible formation of crystalline

mandelate ester (1994)

Hundreds of mg - enough for biological testing.(R) four times as active as (S) in rats. Reversed in humans!

N

SON

N

OCH3

H3CO

H

(S)-mandelic acid separate diastereomers by crystallization

H HC

OR

ORO

OEtO

O CO2Et

RO Ti

O

3) Chiral Catalysis by Titanium/Diethyltartrate

Ti(etc)

+RO

Ligand Exchange

Double Exchange with Diethyltartrate makes catalyst chiral

RO

~ racemic• •

OR

ORO

OEtO

O CO2Et

TiRO

O

3) Chiral Catalysis by Titanium/Diethyltartrate

Ti(etc)

ROO ••

RO+Ti

O

O

O

Ti(etc)

OEtO

CO2Et

O

RO

Ti

O

O

O

Ti(etc)

OEtO

CO2Et94% e.e. (3% R)• •

with added

iPr2NEt(discovered in 2000)

n

*

RSR'

O Ti

O

O

O

Ti(etc)

OEtO

CO2Et

+

(for no obvious reason)

catalyticcycle

RO

ROO

SR R'

Chiral “Oxidizing

Agent”

RSR'

+O

RSR'

O

RSR'

One "C" to Go

Composition

Constitution

"Stereoisomers"

distinction based onbonding model

Change by breakingbonds (van't Hoff)

Change by rotatingabout single bonds

(Paternó)

Isom

ers

Configuration

Conformation

HARD

EASY

All "isomers" representlocal energy minima

(not just differentphases of vibration)

Conformation

19th Century Organic Stereochemistry was

Qualitative.

Conformationinvolving rotational

isomerism about single bonds is more subtle,requiring quantitative

thought about equilibria, rates, & energies.

GenealogyBottomPhysical-Organic

Chemistry

Genealogy TopPhysical-Organic

Chemistry

In the late 19th Century organic chemists focused their efforts on molecular structure ,

while physical chemists focused on energy.

(sometimes to the exclusion of structure)

Principles of Chemistry

An Introduction to all Chemical Textbooks

by

Wilhelm Ostwald

1907

In all 554 pages Ostwald used the word “atom” only this once

- in the subordinate clauseof a footnote!

Footnote, p. 421

“Dalton, who developed the law of combining weights on the basis of an hypothesis he had pro-posed about the composition of matter from atoms, at first took hydrogen as unity, since it had the smallest ‘atomic weight’, i.e. combining weight.”

Dedication ofSterling Chemistry Laboratory

April, 1923

G. N.Lewis

(Student of Richards)

T. W.Richards

WilderBancroft

Students ofOstwald

“ Ostwald's gift for leadership showed itself in the wayhis pupils regarded him all through their lives.

Ostwald obituary by Wilder Bancroft (1933)

They usually believed whatOstwald said even when theyknew that he was not right.”

High St. Gibbs

Ostwald became fixated on energy because he was so impressed by

the man who lived here.

JosiahWillardGibbs

(1839-1904)

~1855

Physical Chemists were (and are)

Quantitativeabout

Equilibrium Constant (K)

Rate Constant (k)

Energy (E, or H, or G)

Energy determines what can happen (equilibrium)

K = e-E/kT

and how fast (kinetics) 10-(3/4)E kcal/mole

@ room Temp

k (/sec) = 1013e-E /kT‡

‡ 1013-(3/4)E kcal/mole@ room Temp

“activation” energy

Conformationinvolves

rotational isomerism about single bonds.

How Free is Single-Bond Rotation?Paternó (1869)

Not at allvan't Hoff (1874)

Entirely

(Note that all are shown eclipsed)

(Count Isomers) (Don’t Count Isomers)

as are both versions of the ACS

“molecule of the week” L-(+)-Tartaric Acid

H

H HH

H H

Eclipsed

H

H H

H

H H

The Newman Projection (1952)

Melvin Newman1908-1993

Yale '29, Ph.D. '32

YX

Y

X

Y

X

H

HH

H

H H

Staggered

Y

X

Anti

YX

Syn (or fully eclipsed)

YX

Gauche(+)(-)

H

H H

(+)(-)

conventional

by p

erm

issi

on J

. D. R

ober

ts

IUPAC "Basic Terminology of Stereochemistry"

Pure Appl. Chem. 68, 2193-2222 (1996)

prettypedantic

Is 3-Fold Barrier to Rotation Significant?

H

H HH

H HH

H HH

H H

H

HH

H

H H

H

HH

H

H H

H

HH

H

H HH

H HH

H H

H

HH

H

H H

0° 120° 240° 360°Torsional Angle

Ene

rgy

Is Energy Quantized in Triple Minimum?

Absorption of Heat by Ethane (1936)

cal /

mol

e / d

egre

e

Depends on how much Heat is absorbed,

For T = 298.1 K

Barrier (kcal/mole) SCalculated

0.0 56.40.3 56.33.1 54.6

SExperimental

54.8 0.2

€

∫0

T

CP

Td T

S "entropy"

and on the Temperature at which it is absorbed.

With larger quantized spacings, less Heat is

absorbed, and at higher T, smaller S.

1Kcal Harmonic Oscillator at RT

81.9%

2.7%14.8%

0.5% 0.1%

average

Equilibrium ratio of 0:1 quantum (or 1:2, etc.)?

103/4 = 5.6

1Kcal Harmonic Oscillator at RT

364 cal/mol

1.2 cal/mol K@ 300 K

(of 1.8)

average

at 1 kcal

0.8%

4.2%lowest level

33%

59%

6%

2.7%14.8%

81.9%

End of Lecture 31Nov. 19, 2008

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