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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
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 3
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
semmelweis-egyetem.hu
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 4
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
World of Molecules: Chirality
semmelweis-egyetem.hu
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 5
Tautomerism
particular case of constitutional isomerisation, it is a ‘spontaneous’,reversible process
Keto-enol
World of Molecules: Chirality
semmelweis-egyetem.hu
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)
semmelweis-egyetem.hu
CH3
HCH3
CH2
CH3
HCH3
CH2
N
O
O
NH
HO N
O
O
NH
HO
R-enantiomer(sedative, hypnotic)
S-enantiomer(teratogenic)
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 7
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
World of Molecules: Chirality
semmelweis-egyetem.hu
H COOH
H COOH
HOOC H
H COOH
Z E
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 8
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
semmelweis-egyetem.hu
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.
World of Molecules: Chirality
semmelweis-egyetem.hu
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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World of Molecules: Chirality
semmelweis-egyetem.hu
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
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 12
R S
Absolute configuration can be determined according to thepriority order of the substituents (a > b > d > e)
World of Molecules: Chirality
semmelweis-egyetem.hu
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
semmelweis-egyetem.hu
C CH3
O
CH2CH3 H HNi
+ CH*
CH3
OH
CH2CH3
butan-2-one (±)-butan-2-olracemic mixture
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 14
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.
semmelweis-egyetem.hu
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 15
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.
semmelweis-egyetem.hu
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 16
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)
World of Molecules: Chirality
semmelweis-egyetem.hu
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 17
World of Molecules: Chirality
semmelweis-egyetem.hu
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.
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 18
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.
semmelweis-egyetem.hu
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 19
semmelweis-egyetem.hu
H
ClCl
H
H
H
H
ClH
Cl
H
H
Cl
HCl
H
H
H
meso SS RR
cis trans
World of Molecules: Chirality
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
semmelweis-egyetem.hu
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 21
mirror
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C C CCH3
H
H
CH3
CCCCH3
H
H
CH3
NH
NH
NH
NH
World of Molecules: Chirality
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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
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World of Molecules: Chirality
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.
semmelweis-egyetem.hu
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
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 24
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
World of Molecules: Chirality
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Synthesis of rac-amphetamine
semmelweis-egyetem.hu
CH3
O
H2N-OH CH3
NOH
* CH3
NH2
NaBH4
Phenylacetone Phenylacetone-oxime 1-Phenylpropane-2-amineβ-PhenylpropylamineAmphetamine
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 26
Formation of diastereomeric salt (resolution of racemic amphetamine)
semmelweis-egyetem.hu
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
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 27
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
semmelweis-egyetem.hu
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
World of Molecules: Chirality
semmelweis-egyetem.hu
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
semmelweis-egyetem.hu
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 30
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
World of Molecules: Chirality
semmelweis-egyetem.hu
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5. Chiral recognition
World of Molecules: Chirality
semmelweis-egyetem.hu
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
World of Molecules: Chirality
semmelweis-egyetem.hu
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.
semmelweis-egyetem.hu
World of Molecules: Chirality
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 34
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
semmelweis-egyetem.hu
C C
CH3
CH3 CH2CH3
OCH3
CC
CH3
CH3H3CH2C
H3CO
C C HCH3 CCH CH3
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World of Molecules: Chirality
semmelweis-egyetem.hu
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!
World of Molecules: Chirality
semmelweis-egyetem.hu
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