bioorganic compounds. amino acids – proteins lipids carbohydrates nucleic acids miscellaneous...

Bioorganic Compounds

Bioorganic CompoundsBioorganic Compounds

• Amino Acids – Proteins• Lipids• Carbohydrates• Nucleic Acids• Miscellaneous

• Alkaloids • Vitamins• Drugs

In most cases biological activity depends on stereochemistry

Stereochemistry

StereochemistryStereochemistry

• Sterical structure:• Constitution• Configuration• Conformation

• Deals with:• Determination of the relative positions in space

of atoms, groups of atoms• Effects of positions of atoms on the properties

IsomersIsomersIsomersIsomers

stereoisomersstereoisomersconstitutionalconstitutionalisomersisomers

IsomersIsomersIsomersIsomers

stereoisomersstereoisomersconstitutionalconstitutionalisomersisomers

diastereomersdiastereomersenantiomersenantiomers

A molecule is A molecule is chiralchiral if its two mirror image if its two mirror image forms forms are notare not superposable upon one another. superposable upon one another. ASYMMETRICASYMMETRIC!!

A molecule is A molecule is achiralachiral if its two mirror image if its two mirror image forms forms areare superposable. superposable. SYMMETRICSYMMETRIC!!

ChiralityChiralityChiralityChirality

BrBrClCl

HH

FF

Bromochlorofluoromethane is chiralBromochlorofluoromethane is chiralBromochlorofluoromethane is chiralBromochlorofluoromethane is chiral

It cannot be It cannot be superposed point superposed point for point on its for point on its mirror image.mirror image.

BrBrClCl

HH

FF

Bromochlorofluoromethane is chiralBromochlorofluoromethane is chiralBromochlorofluoromethane is chiralBromochlorofluoromethane is chiral

HH

ClClBrBr

FFTo show To show nonsuperposability, rotate nonsuperposability, rotate this model 180° around a this model 180° around a vertical axis.vertical axis.

Another lookAnother lookAnother lookAnother look

ChlorodifluoromethaneChlorodifluoromethane

is is achiralachiral

ChlorodifluoromethaneChlorodifluoromethane

is is achiralachiral

The two The two structures are structures are mirror images, mirror images, but are not but are not enantiomers, enantiomers, because they because they can be can be superposed on superposed on each other.each other.

The Chirality CenterThe Chirality Center

a carbon atom with foura carbon atom with fourdifferent groups attached to itdifferent groups attached to it

also called:also called:chiral centerchiral centerasymmetric centerasymmetric centerstereocenterstereocenterstereogenic centerstereogenic center

The Chirality CenterThe Chirality CenterThe Chirality CenterThe Chirality Center

ww

xx yy

zz

CC

A molecule with a single chirality center A molecule with a single chirality center is chiral.is chiral.

BromoBromochlorochlorofluorofluoromethanemethane is an example. is an example.

Chirality and chirality centersChirality and chirality centersChirality and chirality centersChirality and chirality centers

ClCl FF

BrBr

HH

CC

Chirality CentersChirality CentersOther Than CarbonOther Than Carbon

SiliconSiliconSiliconSilicon

Silicon, like carbon, forms four bonds in its stable Silicon, like carbon, forms four bonds in its stable compounds and many chiral silicon compounds compounds and many chiral silicon compounds have been resolvedhave been resolved

SiSi SiSidd dd

aabb

cc

aabb

cc

Nitrogen in aminesNitrogen in aminesNitrogen in aminesNitrogen in amines

Pyramidal geometry at nitrogen can produce a Pyramidal geometry at nitrogen can produce a chiral structure, but enantiomers equilibrate too chiral structure, but enantiomers equilibrate too rapidly to be resolvedrapidly to be resolved

NN NN:: ::

aabb

cc

aabb

cc

very fastvery fast

Sulfur in sulfoxidesSulfur in sulfoxidesSulfur in sulfoxidesSulfur in sulfoxides

Pyramidal geometry at sulfur can produce a chiral Pyramidal geometry at sulfur can produce a chiral structure; pyramidal inversion is slow and structure; pyramidal inversion is slow and compounds of the type shown have been resolvedcompounds of the type shown have been resolved

SS SS:: ::

aabb

O_O_

aabb

O_O_

slowslow++ ++

A molecule with a single chirality centerA molecule with a single chirality centermust bemust be chiral. chiral.

But, a molecule with two or more But, a molecule with two or more chirality centers chirality centers may bemay be chiral chiral

or it or it may notmay not..

Allenes of the type shown are chiralAllenes of the type shown are chiral

AA

BB

XX

YY

A A BB;; X X YY

Have a stereogenic axisHave a stereogenic axis

Chiral AllenesChiral AllenesChiral AllenesChiral Allenes

CCCC CC

analogous to difference between: analogous to difference between:

a screw with a right-hand thread and one a screw with a right-hand thread and one with a left-hand threadwith a left-hand thread

a right-handed helix and a left-handed helix a right-handed helix and a left-handed helix

Stereogenic AxisStereogenic AxisStereogenic AxisStereogenic Axis

Absoluteand

Relative Configuration

Relative configurationRelative configuration compares the compares the arrangement of atoms in space of one compound arrangement of atoms in space of one compound with those of another.with those of another.

UUntil the 1950s, all configurations were relativentil the 1950s, all configurations were relative

Absolute configurationAbsolute configuration is the precise is the precise arrangement of atoms in space.arrangement of atoms in space.

WWe can now determine the absolute configuration e can now determine the absolute configuration of almost any compoundof almost any compound

ConfigurationConfigurationConfigurationConfiguration

Fisher ProjectionsFisher ProjectionsFisher ProjectionsFisher Projections

Purpose of Fischer projections is to showPurpose of Fischer projections is to show configuration at chirality center without necessity configuration at chirality center without necessity of drawing wedges and dashes or using models. of drawing wedges and dashes or using models.

Rules for Fischer projectionsRules for Fischer projectionsRules for Fischer projectionsRules for Fischer projections

Arrange the molecule so that horizontal bonds at Arrange the molecule so that horizontal bonds at chirality center point toward you and vertical chirality center point toward you and vertical bonds point away from you.bonds point away from you.

Br Cl

F

H

Rules for Fischer projectionsRules for Fischer projectionsRules for Fischer projectionsRules for Fischer projections

Projection of molecule on page is a cross. When Projection of molecule on page is a cross. When represented this way it is understood that represented this way it is understood that horizontal bonds project outward, vertical bonds horizontal bonds project outward, vertical bonds are back.are back.

Br Cl

H

F

Absolute configuration:

1.) D/L system

2.) R/S system

D = dexter = right = R = rectus

L = levus = left = S = sinister

H H

H

C C

CC

C C

H X X

C

CC

CHOOH

CH2OHCH2OH

O O

H H

D(+)-glyceraldehyde L (-)-glyceraldehyde

D-configuration L-configuration

(ox) (ox)

(red)(red)

Configuration of Amino AcidsConfiguration of Amino Acids

The Cahn-Ingold-Prelog The Cahn-Ingold-Prelog R-SR-S

Notational SystemNotational System

1. 1. Rank the substituents at the stereogenic Rank the substituents at the stereogenic center according to center according to decreasing atomic number.decreasing atomic number.

2. 2. Orient the molecule so that lowest-ranked Orient the molecule so that lowest-ranked substituent points away from you. substituent points away from you.

The Cahn-Ingold-Prelog RulesThe Cahn-Ingold-Prelog RulesThe Cahn-Ingold-Prelog RulesThe Cahn-Ingold-Prelog Rules

(2) When two atoms are identical, compare the (2) When two atoms are identical, compare the atoms attached to them on the basis of their atoms attached to them on the basis of their atomic numbers. Precedence is established atomic numbers. Precedence is established at the first point of difference. at the first point of difference.

——CCHH22CCHH33 outranks — outranks —CCHH33

——CC((CC,H,H),H,H)

CIP RulesCIP RulesCIP RulesCIP Rules

——CC(H,H,H)(H,H,H)

(3) Work outward from the point of attachment, (3) Work outward from the point of attachment, comparing all the atoms attached to a comparing all the atoms attached to a particular atom before proceeding furtherparticular atom before proceeding furtheralong the chain. along the chain.

——CCH(H(CCHH33))22 outranks outranks —C—CHH22CCHH22OHOH

——CC((CC,,CC,H),H) ——CC((CC,H,H),H,H)

CIP RulesCIP RulesCIP RulesCIP Rules

(4) (4) Evaluate substituents one by one. Evaluate substituents one by one. Don't add atomic numbers within groups.Don't add atomic numbers within groups.

——CCHH22OOH outranks H outranks —C—C(CH(CH33))33

——CC((OO,H,H),H,H) ——CC(C,C,C)(C,C,C)

CIP RulesCIP RulesCIP RulesCIP Rules

(5)(5) An atom that is multiply bonded to another An atom that is multiply bonded to another atom is considered to be replicated as a atom is considered to be replicated as a

substituent on that atom.substituent on that atom.

——CCH=H=OO outranks outranks —C—CHH22OOHH

——CC((OO,,OO,H),H) ——CC((OO,H,H),H,H)

CIP RulesCIP RulesCIP RulesCIP Rules

(A table of commonly encountered substituents ranked according to (A table of commonly encountered substituents ranked according to

precedence is given on the inside back cover of the text.)precedence is given on the inside back cover of the text.)

43

2

1

ExampleExampleExampleExample

4 3

2

1

Order of decreasing rankOrder of decreasing rank44 of of 33 2 2

clockwiseclockwiseRR

anticlockwiseanticlockwiseSS

1

35 17 17

1

9

35

H=1 F=9 Cl=17 Br=35

9

Application of C. I. P. rules for Geometric Isomers

Application of C. I. P. rules for Geometric Isomers

CH3

CH3

C

C H

H CH3

C

C

CH3H

H

CCl

C

Br

CH2CH3 CH3 CH3CH3 CH2

Cl

C

Br C

E/Z system

cis trans

(Z)-1-Bromo-1-chloro-2-methyl-1-butene (E)-1-Bromo-1-chloro-2-methyl-1-butene

Zusammen = together Entgegen = opposit

1

2

2

1

1 2

12

(1)(1) Higher atomic number outranks lower Higher atomic number outranks lower atomic numberatomic number

Br > FBr > F Cl > HCl > H

((Z Z )-1-Bromo-2-chloro-1-fluoroethene)-1-Bromo-2-chloro-1-fluoroethene

higherhigher

lowerlower

BrBr

FF

ClCl

HH

higherhigher

lowerlower

CC CC

CIP RulesCIP RulesCIP RulesCIP Rules

CC CCCC CC

The E-Z Notational SystemThe E-Z Notational SystemThe E-Z Notational SystemThe E-Z Notational System

EE : : higher ranked substituents on higher ranked substituents on oppositeopposite sides sides

ZZ : : higher ranked substituents on higher ranked substituents on samesame side side

EntgegenEntgegen ZusammenZusammen

higherhigher

higherhigherlowerlower

lowerlower

lowerlower

higherhigher

lowerlower

higherhigher

Same:Same: melting point, boiling point, density, etcmelting point, boiling point, density, etc

Different: Different: properties that depend on shape of molecule properties that depend on shape of molecule

(biological-physiological properties) can be(biological-physiological properties) can bedifferent different

Physical properties of enantiomersPhysical properties of enantiomersPhysical properties of enantiomersPhysical properties of enantiomers

Properties of Chiral Properties of Chiral Molecules:Molecules:

Optical ActivityOptical Activity

A substance is optically active if it rotates A substance is optically active if it rotates the plane of polarized light.the plane of polarized light.

In order for a substance to exhibit opticalIn order for a substance to exhibit opticalactivity, it must be chiral and one enantiomer activity, it must be chiral and one enantiomer must be present in excess of the other.must be present in excess of the other.

Optical ActivityOptical ActivityOptical ActivityOptical Activity

LightLightLightLight

has wave propertieshas wave properties

periodic increase and decrease in amplitude of periodic increase and decrease in amplitude of wavewave

LightLightLightLight

optical activity is usually measured using light optical activity is usually measured using light having a wavelength of 589 nmhaving a wavelength of 589 nmthis is the wavelength of the yellow light from a this is the wavelength of the yellow light from a sodium lamp and is called the sodium lamp and is called the D line of sodiumD line of sodium

Polarized lightPolarized lightPolarized lightPolarized light

ordinary ordinary (nonpolarized) (nonpolarized) light consists of light consists of many beams many beams vibrating in vibrating in different planesdifferent planes

plane-polarized plane-polarized light consists of light consists of only those beams only those beams that vibrate in the that vibrate in the same planesame plane

Nicol prismNicol prism

Polarization of lightPolarization of lightPolarization of lightPolarization of light

Rotation of plane-polarized lightRotation of plane-polarized lightRotation of plane-polarized lightRotation of plane-polarized light

observed rotation (observed rotation () depends on the number ) depends on the number of molecules encountered and is proportional to:of molecules encountered and is proportional to:

path length (path length (ll), ), andand concentration ( concentration (cc))

therefore, define specific rotation [therefore, define specific rotation [] as:] as:

Specific rotationSpecific rotationSpecific rotationSpecific rotation

100 100

clcl

concentration = g/100 mLconcentration = g/100 mLlength in decimeterslength in decimeters

[[] =] =

a mixture containing equal quantities a mixture containing equal quantities of enantiomers is called a of enantiomers is called a racemic mixtureracemic mixture

a racemic mixture is a racemic mixture is optically inactiveoptically inactive(( = 0) = 0)

a sample that is optically inactive can bea sample that is optically inactive can beeither an achiral substance or a racemiceither an achiral substance or a racemicmixturemixture

Racemic mixtureRacemic mixtureRacemic mixtureRacemic mixture

an an optically pure optically pure substance consists exclusively substance consists exclusively of a single enantiomerof a single enantiomer

enantiomeric excess enantiomeric excess = = % one enantiomer – % other enantiomer% one enantiomer – % other enantiomer

% optical purity % optical purity = = enantiomeric excess enantiomeric excess

e.g. 75% (-) – 25% (+) = 50% opt. pure (-)e.g. 75% (-) – 25% (+) = 50% opt. pure (-)

Optical purityOptical purityOptical purityOptical purity

Resolution of EnantiomersResolution of Enantiomers

Separation of a racemic mixture into its two Separation of a racemic mixture into its two enantiomeric formsenantiomeric forms

Resolution of a racemic modificationResolution of a racemic modification

1. Physical methods:- Spontaneous resolution

- Inclusion compounds

- Chromatography

2. Chemical methods:

- Diastereomeric salt formation

3. Biochemical methods:

- Enzymatic decomposition

enantiomersenantiomers

C(+)C(+)C(+)C(+) C(-)C(-)C(-)C(-)

StrategyStrategyStrategyStrategy

enantiomersenantiomers

C(+)C(+)C(+)C(+) C(-)C(-)C(-)C(-)

2P(+)2P(+)

C(+)C(+)P(+)C(+)C(+)P(+) C(-)C(-)P(+)C(-)C(-)P(+)

diastereomersdiastereomers

StrategyStrategyStrategyStrategy

enantiomersenantiomers

C(+)C(+)C(+)C(+) C(-)C(-)C(-)C(-)

2P(+)2P(+)

C(+)C(+)P(+)C(+)C(+)P(+) C(-)C(-)P(+)C(-)C(-)P(+)

diastereomersdiastereomers

C(+)C(+)P(+)C(+)C(+)P(+)

C(-)C(-)P(+)C(-)C(-)P(+)

StrategyStrategyStrategyStrategy

enantiomersenantiomers

C(+)C(+)C(+)C(+) C(-)C(-)C(-)C(-)

2P(+)2P(+)

C(+)C(+)P(+)C(+)C(+)P(+) C(-)C(-)P(+)C(-)C(-)P(+)

diastereomersdiastereomers

C(+)C(+)P(+)C(+)C(+)P(+)

C(-)C(-)P(+)C(-)C(-)P(+)

P(+)P(+)

P(+)P(+)

C(+)C(+)C(+)C(+)

C(-)C(-)C(-)C(-)

StrategyStrategyStrategyStrategy

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

enantiomers(R,S)-salt (S,S)-salt

diastereomers

(R,S)-salt (S,S)-salt

HCl HCl

(S)-baseH+

+(R)-acid

(S)-baseH+

+(S)-acid

Resolution of a Racemic MixtureResolution of a Racemic MixtureResolution of a Racemic MixtureResolution of a Racemic Mixture

Lock and Key ModelLock and Key Model

CH2OH

C

CHO

H

H

OH

OH

CHO

CH2OH

C

CHO

H

H OH

OH

CHO

Discrimination of Enantiomers byDiscrimination of Enantiomers byBiological MoleculesBiological Molecules

Discrimination of Enantiomers byDiscrimination of Enantiomers byBiological MoleculesBiological Molecules

Chiral MoleculesChiral Moleculeswithwith

Two Chirality CentersTwo Chirality Centers

How many stereoisomers when a particular How many stereoisomers when a particular molecule contains two chiral centers?molecule contains two chiral centers?

2,3-Dihydroxybutanoic2,3-Dihydroxybutanoic acidacid2,3-Dihydroxybutanoic2,3-Dihydroxybutanoic acidacid

4 Combinations = 4 Stereoisomers4 Combinations = 4 Stereoisomers

OO

CHCH33CHCHCOHCHCHCOH

HOHO OHOH

2233

Carbon-2Carbon-2 RR RR SS SSCarbon-3Carbon-3 RR SS RR SS

HOHO

COCO22HH

CHCH33

HH

OHOHHHRR

RR

COCO22HH

CHCH33

HH

HHHOHO

OHOH

SS

SS

enantiomersenantiomersenantiomersenantiomers

COCO22HH

HH

CHCH33

HOHO

HHHOHO

RR

SS

diastereomersdiastereomersdiastereomersdiastereomers

COCO22HH

CHCH33

HH OHOH

OHOHHHRR

SS

enantiomersenantiomersenantiomersenantiomers

[[] = -9.5°] = -9.5° [[] = +9.5°] = +9.5°

[[] = -17.8°] = -17.8°[[] = +17.8°] = +17.8°

Three stereoisomers of 2,3-butanediolThree stereoisomers of 2,3-butanediolThree stereoisomers of 2,3-butanediolThree stereoisomers of 2,3-butanediol

22RR,3,3RR 22SS,3,3SS 22RR,3,3SS

chiralchiral chiralchiral achiralachiral

CHCH33

CHCH33

OHOHHH

HHHOHOHH OHOH

CHCH33

CHCH33

HHHOHO HH

CHCH33

CHCH33

OHOH

OHOHHH

maximummaximum number of stereoisomers = 2 number of stereoisomers = 2nn

where where nn = number of structural units capable of = number of structural units capable of stereochemical variationstereochemical variation

structural units include chirality centers and cis structural units include chirality centers and cis and/or trans double bondsand/or trans double bonds

number is reduced to less than 2number is reduced to less than 2nn if meso forms if meso forms are possibleare possible

How many stereoisomersHow many stereoisomers??How many stereoisomersHow many stereoisomers??

HOHO OHOH

HH

HH

HOHO

HH33CC

HH

HHCHCH22CHCH22COCOOOHH

CHCH33

HH

CHCH33

11 chirality centers11 chirality centers

221111 = 2048 stereoisomers = 2048 stereoisomers

one is "natural" cholic acidone is "natural" cholic acid

a second is the enantiomer of a second is the enantiomer of natural cholic acidnatural cholic acid

2046 are diastereomers of cholic 2046 are diastereomers of cholic acidacid

Cholic acidCholic acid Cholic acidCholic acid