PETER PAZMANY CATHOLIC UNIVERSITY · 2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 . 1. Development of Complex Curricula for Molecular Bionics and Infobionics Programs within

2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 1

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

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITYConsortium 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 UNIVERSITYSEMMELWEIS

UNIVERSITY

2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 2

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 Mátyuswith contribution by dr. Gábor Krajsovszky

Formatted by dr. Balázs Balogh

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Table of Contents

World of Molecules: Chirality

1. Constitutional isomerism 3 – 32. Tautomerism 4 – 43. Stereochemistry 5 – 54. Configurational and onformational stereoisomers 6 – 65. 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

CH3 CH2 CH2 CH3 CH3 CH CH3

CH3

n-butane i-butane

CH2

CH

CH2

CH3

CH2

CH2

CH2

CH2

H

CH3CH3

H CH3

CH3



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Tautomerism

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

Keto-enol



CH2 C

H

O

R CH2 C

H

O

R

N O

H

OH

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History1874 – van’t Hoff (Dutch), Le Bel (French): tetrahedral carbon atom1901 – 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)


CH3

HCH3

CH2

CH3

HCH3

CH2

N

O

O

NH

HO N

O

O

NH

HO

R-enantiomer(sedative, hypnotic)

S-enantiomer(teratogenic)


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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 otherwithout breaking and making a covalent bond.

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

Stereoisomers: configurational and conformationalstereoisomers



H COOH

H COOH

HOOC H

H COOH

Z E

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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.



L

COOH

CH3H2NH

R

D

COOH

CH3 NH2H

S

COOH

CH3

H NH2

COOH

CH3

H2N H

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Symmetry elements- Plane of symmetry (δ)

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

- Symmetry axis (Cn)Rotation around the symmetry axis makes the object superimposable upon itself.

Molecules possessing plane of symmetry are achiral.



HOOC

COOHHOOC COOH

plane axis

Two grip mirror axis of symmetry One grip mirror axis of symmetryCentre of symmetry Plane of symmetry

Mirror Axis of SymmetryAn object may be defined with Sn, an n-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.

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C C

CH3

H CH3

H

axis

plane

180° C C

CH3

H H

CH3

axis

plane

360°

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C

C

H

H H

C

H

HH

O

H

H

C

H

H

O

Cl

C

Cl

HH

C

HH

The plane of symmetry in2-propanol is defined bythe three atomsH–(C–2)–O

Planes of symmetry indichloromethane: oneplane is defined by the three atoms H–C–Hthe other by Cl–C–Cl

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R S

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



C e

a

db

C e

a

bd

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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

of the stereoisomers in higher ratio


C CH3

O

CH2CH3 H HNi

+ CH*

CH3

OH

CH2CH3

butan-2-one (±)-butan-2-olracemic mixture


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Enantiotopic groupSubstitution with a new achiral group gives a pair of enantiomers.

enantiomers

OH

MeHZ

OH

MeHH

OH

MeZH

MeHH

Me HCl

diastereomers

MeZH

Me HCl

MeHZ

Me HCl

ProciralityProciral molecule contains enantiotropic and/or diastereotopic group.

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



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Enantiotopic facesAttack of achiral reagents from different sides produces enantiomers.

same

O-

A HH

O-

AHH

AA

HC

H

O

HC

CH3

OA AO-

ACH3H

O-

A CH3H

enantiomers

Et

Me H CN

H OHEt

Me H CN

HO H

HCN

Et

Me H

H

OHCN

diastereomers

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

Diastereotopic facesAttack of achiral reagents from different sides produces diastereomers.



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EnantiomersThey are isometric (distances between constitutionally same atomsare 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)

%100(S)(R)(S)-(R) ee ⋅

+= (optical purity)



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polarimetertube

Unpolarizedlight fromsource

Polarizer;fixed Nicolprism

Plane-polarizedlight

Solution of opticallyactive material

Plane ofpolarizationhas undergonea rotation

Analyizer;movable Nicolprism

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 radiation.

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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

2n

Diastereomers:Stereoisomers with non-enantiomeric relationship to each other.



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H

ClCl

H

H

H

H

ClH

Cl

H

H

Cl

HCl

H

H

H

meso SS RR

cis trans


Different isomers of 1,2-dichloro-cyclopropane

Achiral form Chiral forms

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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:

axial chirality 1,3-disubstituted alleneatropisomerism

planar chirality rare



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mirror


C C CCH3

H

H

CH3

CCCCH3

H

H

CH3

NH

NH

NH

NH


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Resolution

Separation of the enantiomers of the racemic mixturee.g. with a chiral reagent,e.g., through formation of diastereomeric pairs of a salt (crystallization)

(+)B (-)BS*

S*(+)B S*(-)B separation



A common way of separation of enantiomersuses the conversion into diastereomers, that are not mirror imagesof each other.

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


1. Mechanical separation (Pasteur, 1848)

H

HOOC

H

COOH

OH

OH OH

HOOC

OH

COOH

H

H

(2R,3R)-tartaric acid[α]D = +12

(2S,3S)-tartaric acid[α]D = -12


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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 saltssemmelweis-egyetem.hu

(R)-acid + (S)-acid2 (S)-base

(R)-acid-(S)-base + (R)-acid-(S)-base


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Synthesis of rac-amphetamine


CH3

O

H2N-OH CH3

NOH

* CH3

NH2

NaBH4

Phenylacetone Phenylacetone-oxime 1-Phenylpropane-2-amineβ-PhenylpropylamineAmphetamine


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Formation of diastereomeric salt (resolution of racemic amphetamine)


CH3

NH2

H

+

CH3

NH2

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


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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



CH2 H

HCH2

(CH2)4 NH2 C

Ph

Me

HPt

Cl

Cl

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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



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



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Chiral HPLCSingle 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



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5. Chiral recognition



Chiral crown

C NH3+

Me

H

Ph PF6-

O

O

O

O

O

O

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6. Kinetic resolution

Chiral reagents: different reactivity



PhN

OH

PhN

OH

OPh

N

OH(-)-diisopropyl-tartarate

Ti(OiPr)4, tBuOOH, -20°C

(+)-diisopropyl-tartarate

Ti(OiPr)4, tBuOOH

Me cHex

OH

Me 32

1 cHex

OHO

Me cHex

OHO

Me cHex

OH

(R), ee > 98%

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

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

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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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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)



C C

CH3

CH3 CH2CH3

OCH3

CC

CH3

CH3H3CH2C

H3CO

C C HCH3 CCH CH3

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C C

Cl

H CH2

CH3

CH3C C

Cl17

H1

C6

C6

C C

Cl17

H1

C

C H

C6

(E)-1-chloro 2-me-thylbuta-1-ene

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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!



CH3

H

CH3

H

CH3

H CH3

H

H

CH3

CH3

H

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

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

Documents

PETER PAZMANY CATHOLIC UNIVERSITY · 2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 . 1. Development of Complex Curricula for Molecular Bionics and Infobionics Programs within