ISOMERS two distinct molecules Constitutional isomers...

ISOMERS two distinct molecules with the same molecular formula

Constitutional isomers(Structural isomers)isomers that differ in their bonding sequence

Stereoisomers

differ only in how their atoms are oriented in space

Diastereomersstereoisomers that arenot mirror-images

Enantiomersa pair of nonsuperimposable mirror-image molecules

Geometric isomers(Cis-trans isomers)

they differ in the geomerty of the groups on a double bond or ring

Other diastereomers(usually molecules with 2 or more chiral centers)

! epimers: diastereomers that differ in configuration at only one of the stereogenic centers! meso compounds: achiral molecules with chiral centers

Confirmational isomers: are interconvertible by rotations about single bondsConfiguration: the relative position of the arrangement of atoms in space

Constitutional isomers

pent-1-ene pent-2-ene cyclopentene methylcyclobutane

diethyl ether methyl propyl ether

butan-1-ol1° alcohol butan-2-ol

2° alcohol2-methylpropan-2-ol

3° alcohol 2

Conformations - Butane

Conformations – Cyclohexane

Geometric isomers

H3CH2C CH2CH3

CH2CH2CH3

cis (Z) trans (E) no geometric isomers

(Z)-2-bromo-1-fluoro-1-chloroethene

(E)-4-ethyl-3-methylhept-3-ene

Difference in reactivity

maleic acidmp 138 °Ctoxic, irritant

fumaric acidmp 287 °C

essential metabolite6

CIP ruleinversion

enantiomers absoluteconfiguration

Fischerprojection

2racemisation

R, Sresolution

achiral

plane of symmetry

Chiral molecules / central chirality

[α]D20 = +12 (c = 2, H2O)

αmeasured x 100 = [α] x c x l [α] =lc

[α]: specific rotationl: 1 dmc: concentration (g/100 ml)

(2R,3R)-tartaric acid

Specific rotation

polarizer sample analyzer

Measurement of optical activity

Polarimeter

CHO CH3

(R)-lactic acid

COOCH3

CHO CH3

(R)-methyl lactate[α]D20 = -3,3 [α]D20 = +8,2

"esterification"

tBuH tBuH

(S)-4-tert-butyl-cyclohexene

Specific rotation and absolute configuration

CH=CH2

CCH3CH2CH2 CH3

HCH2-CH3

CCH3CH2CH2 CH3

HH2-Pd/C

(S)-3-methylhex-1-ene (R)-3-methylhexane

(R)-3-bromo-5-tert-butyl-cyclohexene

Enantiomeric excess (ee)

ee =[R] - [S][R] + [S]

x 100 = %R -%S

Optical purity (OP) OP% =[α]measured

[α]maxx 100

if R = 70%, S = 30%, then ee = 40%

The mixture contains: 40% R enantiomer, and 60% racemic mixture

Example

Determination of enantiomeric excesschromatographic methods (chiral stationary phase)NMR spectroscopy (chiral shift reagents)

HOOC COOH

atropisomerism

Optically active molecules without chiral center

Cl ClCH3H3C

spiranes

C C CCH3

ClC C C

allenes

C C CH3C

ClC C C

BUT! odd number of cumulated bonds cis-trans isomerism

Molecules with different symmetry elements

H3C CH CH CH CH3

a) cis-trans isomerism and stereogenic center

b) hindered rotation and stereogenic center

1,1cis-1,3

cis-1,4trans-1,4

Stereoisomerism of 1,2-disubstituted cyclohexanes (conformational chirality)

achiral derivatives (have inner mirror plane)

trans-1,2

trans-1,3

chiral derivatives (no plane of symmetry)

acis-1,2

chiral molecules, but optilally inactive beacuse of the conformational equilibrium

not only conformers but also enantiomers

Stereogenic centers (not carbon atoms)

ΔH+ = 30 kJ/mol

amines (not resolvable)

ammonium cation

a + SOb

sulfonium cation sulfoxide

cfast inversion

phosphonic acid ester

resolvable molecules

HContergane- drug molecule- teratogenic

Carvone- spearmint smell- caraway smell

CH2CHCH3

Amphetamine-stimulatory effect-side effects

Limonene- lemon smell- orange smell

Different biological activity of the enantiomers

2' 2'3'

enantiomers enantiomers

diastereomers

Two stereogenic centers with different ligands

Erythrose, threose:

4 stereoisomers

CHOHCHC

CH2OHOHOH

* * ***

11 stereogenic carbon atoms(2048 stereoisomers)

cholic acid

CH3H3C

CH2CH2COOH

n stereogenic center 2n stereoisomer

H3CCH2CH2COOH

enantiomers

meso formoptically inactive

diastereomers

Two stereogenic centers with the same ligands / meso compounds

tartaric acid3 stereoisomers

Concepts in stereochemistry (topism)

Homotopic = same H H

Enantiotopic: different; replacement of one or the other of them generates enantiomers

OHHpro S pro R

prochiral C

enantiomers20

Diastereotopic: different; replacement of one or the other generates diastereomers

H HCOOH

D HCOOH

diatereomers

Prochiral C

Nu: CH3

si face (counterclockwise)

re face (clockwise) 21

Example

O 1. LDA2.

3. H3O+

4 stereoisomers

syn diastereomers

anti diastereomers

enantiomers

diastereomersdiastereomers

Synthesis of enantiomers

1) Isolation of chiral compounds and/or transform e.g. morphine, and morphine derivatives

2) Stereoselective synthesis

a) Utilization of chiral reagent

O AlOR

Ph CH3

b) Utilization of chiral catalyst

Ph2P RhPPh2

CPh CH3

H NHR + H2

enantiomers

enantiomeres(not separable)

diastereomers(separable)

C C C C

achiral reagent

chiral reagent

3) Optical resolution of racemic mixtures

enantiomeric mixture formation of diastereomers

separationneutralization

(±)-R COOH (+)-Q NH2

(+)-R COO- (+)-Q NH3+

(-)-R COO- (+)-Q NH3+

(+)-R COO- (+)-Q NH3+ (-)-R COO- (+)-Q NH3

(+)-R COOH (-)-R COOH

Formation of diastereomers with salt formation

separation (e.g. crystallization)

neutralization

a) using one equivalent of resolving agent

diastereomeric salt pair

neutralization

racemic mixture resolving agent

(R)-phenylethylamine

CH COOH

racemic mandelic acidC

(R)-mandelic acid

(S)-mandelic acid

Example

b) Using half equivalent resolving agent

COOH (+)-Q NH2+ + NaOH

(+)-R COO- (+)-Q NH3+ (-)-R COONa

aqueous solution

insoluble solution

(+)-R COOH

(-)-R COOH

2 (±)-R

COOH (+)-Q NH2+ + NaOH

(+)-R COOH

(-)-R COOH

CHCl3, H2O

aqueous phase organic phase

(-)-R COONa (+)-R COO- (+)-Q NH3+

Optical resolution by extraction

neutralization

2 (±)-R

Resolving agents

(S)-(-)-phenylethylaminequinine

(S)-(+)-mandelic acid

(S)-(+)-camphene-10-sulfonic acid

(R,R)-tartaric acid derivativespl. R = H, benzoyl, acethyl

Optical resolution with derivatization

(+)-R COOH

separation

(+)-Q O CO (+)-R

(-)-Q O CO (+)-R

esterification+

(+)-Q O CO (+)-R (-)-Q O CO (+)-R

hydrolysis

(+)-Q OH (-)-Q OH

(±)-Q

chiral stationaryphase

Optical resolution using chromatography

(±)-A + R

Kinetic resolution

(+)-AR

(-)-AR

if k1 > k2, then end the reaction at a certain conversion gives [(+)-AR] > [(-)-AR]

Example

enzyme (cat.)

46% conversion

Dynamic kinetic resolution

Me COOH

H Meenzym

(R)-ibuprofen

krac > kR > kS

SELECTIVITYChemoselectivity

LiAlH4

RegioselectivityH2O / H+

Markovonikov ruleOH

+ HBr BrBr

40 °C

80 °C

thermodynamic control

kinetic control

StereoselectivityDescribes reactions that have two mechanistically acceptable but stereochemically different pathways, so that the molecule may select the more favorable (e.g. the faster pathway - kinetic control; or the more stable product - thermodynamic control).

H COOH

fumaric acid

H2O / enzyme COOH

HOOCH2C OHH

(S)-malic acid

Stereospecific reactionsGives specific and predictable stereochemical outcomes because the mechanism of thereaction demands this.

H COOH

fumaric acid

COOHBr

Stereospecific reactions

Substitution SN2R1

Nu:inversion

Elimination E2H

base anti-periplanar X and H

Hydrogenation of alkenes and alkynes

H2, Pd/C R1

cis addition

Electrophilic additionto alkenes

cis additionOsO4

Electrophilic additionto alkenes

trans additionBr2

ISOMERS two distinct molecules Constitutional isomers...

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