‘Cahn-Ingold-Prelog‘, the ‘chiral nature’

Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITY

Consortium members

SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***

**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben

***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.

PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS

UNIVERSITY

Semmelweis University

ORGANIC AND BIOCHEMISTRY New definitions and conventions:

‘normal’, ‘iso’; ‘cis’, ’trans’; chirality and prochirality,

‘Cahn-Ingold-Prelog‘, the ‘chiral nature’

semmelweis-egyetem.hu

(Szerves és Biokémia )

(Újabb fogalmak és konvenciók: „normál”, „izo”; „cisz”,

„transz”; kiralitás és prokiralitás, „Cahn-Ingold-Prelog” a

„királis természet” (és következményei))

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

Table of Contents

World of Molecules: Chirality

1. Constitutional isomerism 3 – 3

2. Tautomerism 4 – 4

3. Stereochemistry 5 – 5

4. Configurational and onformational stereoisomers 6 – 6

5. Chiral molecules 7 – 19

6. Resolution 20 – 29

7. Geometric isomerism in alkenes and related compounds 30 – 33

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Constitutional isomerism

Different physical properties and different therm. stabilities

Positional isomerism

methylcyclopropane cyclobutane

C

H₃ CH₂ CH₂ CH₃ H₃C CH CH₃ CH₃

n-butane i-butane

C H₂

CH CH₂ CH₃

C H₂

C H₂

CH₂ CH₂

H

CH₃ C

H₃

H CH₃

CH₃

World of Molecules: Chirality

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Tautomerism

particular case of constitutional isomerisation, it is a ‘spontaneous’, reversible process

Keto-enol

World of Molecules: Chirality

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CH₂ C H O

R CH₂ C

H O R

N O

H

OH

History

1874 – van’t Hoff (Dutch), Le Bel (French): tetrahedral carbon atom 1901 – van’t Hoff – Nobel-prize

Enantiomers of limonene: one of them has lemon-like odor, the other one has pine-cone odor

Stereochemistry

Contergan (Thalidomide)

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CH₃

H C

H₃

CH₂

CH₃

H C

H₃

CH₂

N

O O

N H

H

O N

O O

N H H

O

R-enantiomer

(sedative, hypnotic)

S-enantiomer (teratogenic)

World of Molecules: Chirality

Configurational isomers:

The particular arrangement of atoms (or goups) in space that is characteristic of a given streoisomer.

The configurational isomers can not be transformed into each other without breaking and making a covalent bond.

- cis-trans; Z-E; geometric isomers - optical isomerism (cf. chirality)

Stereoisomers: configurational and conformational stereoisomers

World of Molecules: Chirality

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H COOH

H COOH

HOOC H

H COOH

Z E

Chiral molecules

‘stereogenic center’ or central chirality: a tetrahedral atom or a pyramidal atom with four ligands, if the interchange of any two ligands leads to a new stereoisomer;

four different ligands are attached to an X central atom, the mirror images can not be superimposed to each other, there are enantiomers.

World of Molecules: Chirality

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L COOH

CH₃ H₂HN

R

D

COOH CH₃ NHH₂

S COOH

CH₃ H NH₂

COOH

CH₃ H₂N H

Symmetry elements

- Plane of symmetry (δ)

It cuts the object into two halves which are mirror images of each other.

- Symmetry axis (C_n)

Rotation around the symmetry axis makes the object superimposable upon itself.

Molecules possessing plane of symmetry are achiral.

World of Molecules: Chirality

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HOOC HOOC COOH COOH

plane axis

Two grip mirror axis of symmetry One grip mirror axis of symmetry

Centre of symmetry Plane of symmetry

Mirror Axis of Symmetry

An object may be defined with S_n, ann-graded mirror axis of symmetry, if any point of the object

rotated about an axis with an 360/n degree angle reflected perpendicular to the plane the original object is get (where n must be 1 or odd).

S₁-axis is equivalent with a plane of symmetry, whereas the S₂-axis is equivalent with the centre of symmetry.

Along any line that crosses the centre of symmetry identical elements are found in equal distances.

C C C

H₃

H CH₃ H

axis

plane

180° C C

C H₃

H H

CH₃

axis

plane

360°

World of Molecules: Chirality

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C

C

H

H H

C

H H H O

H

H

C H

H

O

Cl

C

Cl H

H

C

H H

The plane of symmetry in 2-propanol is defined by the three atoms

H–(C–2)–O

Planes of symmetry in dichloromethane: one plane is defined by the three atoms H–C–H the other by Cl–C–Cl

R S

Absolute configuration can be determined according to the priority order of the substituents (a > b > d > e)

World of Molecules: Chirality

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C e a

d b

C e a

b d

Production of chiral molecules from achiral ones results racemic mixtures very often (except asymmetrical synthesis)

Racemic mixture: equimolar mixture of the enantiomers

Formation of chiral molecules

Example:

Solution:

- Resolution - separation of racemic mixture into its enantiomeric components)

- Asymmetric synthesis - special way of synthesis by the formation one

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C CH₃ O

CH₂ C

H₃ H H

+

OH CH₂

C H₃

butan-2-one (±)-butan-2-ol

racemic mixture World of Molecules: Chirality

Enantiotopic group

Substitution with a new achiral group gives a pair of enantiomers.

enantiomers

OH Me ZH

OH Me HH

OH Me HZ

Me HH

Me ClH

diastereomers Me

HZ

Me ClH

Me ZH

Me ClH

Procirality

Prociral molecule contains enantiotropic and/or diastereotopic group.

Diastereotopic group

Substitution with a new achiral (or chiral) group gives a pair of diastereomers.

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World of Molecules: Chirality

Enantiotopic faces

Attack of achiral reagents from different sides produces enantiomers.

same O^-

A H H

O^- A HH

A A H

C H O

H C

CH₃

A O A O^-

A CH₃

H O^-

A CH₃ H

enantiomers

Et

Me H CN Et H OH

Me H CN HO H

HCN Et

Me H H HCN O

Homotopic faces

Attack from any side pruduces the same product (not prochiral).

Diastereotopic faces

Attack of achiral reagents from different sides produces diastereomers.

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World of Molecules: Chirality

Enantiomers

They are isometric (distances between constitutionally same atoms are the same) but topographically different.

Their chemical and physical properties are the same, except:

- their interactions with chiral molecules are different (hand/gloves) - their interactions with plane polarised light are different (polarimeter),

optical activity; +: clockwise, dextrorotatory;

-: anticlockwise, levorotatory

racemic form: 50-50% 1:1 mixtrure of crystals (mp. does not change) conglomerate (mp. is lower)

Different mixtures of enantiomers can be characterized by the enantiomeric excess (cf, stereoselectivity)

% (S) 100

(R)

(S) -

ee (R) ⋅

= + (optical purity)

World of Molecules: Chirality

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World of Molecules: Chirality

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polarimeter tube

Unpolarized light from source

Polarizer;

fixed Nicol prism

Plane- polarized light

Solution of optically active material

Plane of polarization has undergone a rotation

Analyizer;

movable Nicol prism

Viewer

Determination of optical rotation

Linear polarizer is an optical device which allows the transmission of radiation of which the electric vector is restricted to one plane resulting in linearly polarized

Maximal number of possible stereoisomers of compounds having more than one stereogenic center* :

* if the ligands attached to one stereogenic carbon atom are the identical with those attached to another, the number of the stereoisomers is less, than 2ⁿ

meso form: it is not chiral

2

Diastereomers:

Stereoisomers with non-enantiomeric relationship to each other.

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World of Molecules: Chirality

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H Cl Cl

H

H H

H Cl H

Cl

H H

Cl H Cl

H

H H

meso SS RR

cis trans

World of Molecules: Chirality

Different isomers of 1,2-dichloro-cyclopropane

Achiral form Chiral forms

Even if a molecule possesses a stereogenic center, it is not necessarily chiral.

Not each chiral molecule has a stereogenic center, it may possesses other stereogenic unit:

ƒ axial chirality 1,3-disubstituted alleneatropisomerism

ƒ planar chirality rare

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World of Molecules: Chirality

mirror

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C C C

CH₃ H H

C H₃

C C

C C

H₃ H

H CH₃

N H

NH

NH NH

World of Molecules: Chirality

Resolution

Separation of the enantiomers of the racemic mixture e.g. with a chiral reagent,

e.g., through formation of diastereomeric pairs of a salt (crystallization)

(+)B (-)B S*

S*(+)B

S*(-)B separation

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World of Molecules: Chirality

A common way of separation of enantiomers

uses the conversion into diastereomers, that are not mirror images of each other.

Enantiomorphus (mirror images) crystals of sodium ammonium tartarate have been separated by hand-picking.

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1. Mechanical separation (Pasteur, 1848)

H HOOC

H

COOH OH

OH HO

HOOC

O H

COOH H

H

(2R,3R)-tartaric acid [α] = +12

(2S,3S)-tartaric acid [α] = -12

World of Molecules: Chirality

Used for resolution of chiral acids or bases.

Racemic carboxylic acids (mixture of enantiomers) forms salt with chiral base producing diastereomeric mixture.

The diastereomeric salts can be separated (e.g. fractional crystallization).

The carboxylic acid can be recovered from the salt.

Similarly racemic bases can be separated.

Frequently used chiral bases:

(-)-brucine, (-)-strychnine

Frequently used chiral acids:

(+)-tartaric acid

(+)-camphor sulfonic acid (+)- or (-)-mandelic acid

2. Formation of diastereomeric salts

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(R)-acid + (S)-acid ^{2 (S)-base} (R)-acid-(S)-base + (R)-acid-(S)-base

World of Molecules: Chirality

Synthesis of rac-amphetamine

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CH₃

O

H₂N-OH CH₃

N OH

* CH₃ NH₂ NaBH₄

Phenylacetone Phenylacetone-oxime 1-Phenylpropane-2-amine β-Phenylpropylamine

Amphetamine World of Molecules: Chirality

Formation of diastereomeric salt (resolution of racemic amphetamine)

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CH₃

NH₂ H

+

CH₃

N H₂

H

+

H HOOC

H

COOH OH OH

2x

CH₃

NH₃⁺ H

CH₃

+H₃N H

+

H

-OOC H

COOH OH

OH H

HOOC H

COO^- OH OH

R,R,R-tartarate S,R,R-tartarate

diastereomers

World of Molecules: Chirality

Condition:

- Reversible reaction.

- Formation and recovery of the compound should not involve racemization.

- Racemic alcohols can be transfered into diastereomeric esters with chiral acid.

- Oxo-compounds can be converted into diastereomeric hydrazones.

- Formation of diastereomeric complex:

Example: resolution of trans-cycloocten as a chiral amin containing Pt-complex

3. Formation of diastereomeric compound

World of Molecules: Chirality

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CH₂ H

(CH₂)₄ NH₂ C Ph Me Pt H

Cl

Cl

Solution of the chiral mixture is adsorbed on an optically-active stationary phase; the different enantiomers interact in a

physically diferent manner with the adsorbent molecules;

different chromatographic mobility; different adsorption.

Example: racemic mandelic acid has been resoluted by column chromatography on starch adsorbent.

4. Chromatography

World of Molecules: Chirality

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Chromatography

It is a separation method based on the selective distribution of the components of a mixture between the stationary and the mobile phase.

The components of the mixture move by different rate along the stationary phase, the component having stronger interaction with the stationary phase remains behind (retention).

Mobile phase

World of Molecules: Chirality

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Chiral HPLC

Single enantiomer is immobilized onto the stationary phase Resolution:

The enantiomers of racemic mixture form diasereomers with rhe chiral compound of the statiobary phase; different elution (more stable

diastereomers are eluted slowly than the less stable ones) Stationary phase:

-proton acceptor or proton donor stationary phases (proton acceptor: N-(3,5- dinitrobenzoyl)-phenilglycin) on silica gel

-celluose derivatives -cyclodextrines

-proteins

-crown ethers -macrocycles

World of Molecules: Chirality

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5. Chiral recognition

World of Molecules: Chirality

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Chiral crown

C NH₃⁺ Me

H

Ph PF₆^-

O O

O

O

O

O

6. Kinetic resolution

Chiral reagents: different reactivity

World of Molecules: Chirality

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Ph

N OH

Ph

N OH

O

Ph

N (-)-diisopropyl-tartarate OH

Ti(OiPr)₄, tBuOOH, -20°C

(+)-diisopropyl-tartarate Ti(OiPr)₄, tBuOOH

Me cHex

OH

Me 3 2

1 cHex OH O

Me cHex

OH O

Me cHex

OH

(R), ee > 98%

(1S), de = 98% (1R), de = 24%

(S), 63% ee (R), 95% ee (±)-1-phenyl-2-pyrrolidinoethanol

Geometric isomerism in alkenes and related compounds

Connecting two sp² centers results in achiral diastereoisomers their structural descriptors are E (entgegen) and Z (zusammen), and they are called as geometric isomers.

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World of Molecules: Chirality

An sp² centre in an alkene or a carbonyl group is planar and cannot be asymmetric, i.e. the mirror images are superimposable.

Superimposable mirror images (i.e. identical molecules)

Similarly, the bonds of an sp centre are linear with respect to each other and cannot give an asymmetric shape.

Superimposable mirror images (i.e. identical molecules) World of Molecules: Chirality

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C C C

H₃

C

H₃ CH₂CH₃ OCH₃

C C

CH₃

CH₃ H₃CH₂C

H₃CO

C C H C

H₃ H C C CH₃

World of Molecules: Chirality

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C C Cl

H CH₂ CH₃

CH₃ C C

17Cl

1H

C⁶ C⁶

C C

17Cl

1H

C

C H

C⁶ (E)-1-chloro 2-me- thylbuta-1-ene

trans buta-2-ene cis buta-2-ene

The p orbitals are in the same plane, result- ing in optimum geo- metry for the π bond

E-Z isomerisation requires high energy!

World of Molecules: Chirality

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C H₃

H

CH₃ H

C H₃

H CH₃

H

H

CH₃

CH₃ H

The p orbitals are prependicular to each other, the worst geometry for the π bond

The p orbitals are in the same plane, result- ing in optimum geo- metry for the π bond