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