3-1 1. stereoisomerism 2. chirality 3. naming stereocenters - r/s configuration 4. acyclic molecules...
Post on 21-Dec-2015
242 views
TRANSCRIPT
3-3-11
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Stereochemistry- Chapter 3Stereochemistry- Chapter 3OH
CH
H3C F
HO
CH
H3CF
3-3-22
stereostereoisomersisomers - same connectivity
- different orientation in space
(recall cis/trans)
IsomersIsomers - same molecular formula - same molecular formula- different compounds- different compounds
constitutional constitutional isomersisomers - - different connectivity
3-3-33
Chirality Chirality handednesshandednessnot superposable on its mirror imagenot superposable on its mirror image
types:types:
planeplane imaginary plane through an object one half is the mirror image of the other
symmetry = superposablesymmetry = superposable
centercenter identical parts on an axisequidistant from a point
3-3-44
anti - point of symmetry
CH3
CHO H
H3C
OHHC
syn - plane of symmetry
CH3
CHO H
CH3
CHO H
Elements of SymmetryElements of SymmetryConformations of 2,3-butanediol*
.
If symmetry is present, the substance is achiral.
.
*meso or R,S (later)
3-3-55Elements of SymmetryElements of Symmetry
Plane of symmetry
HO OH
mirrorplane
H
H CH2
H
CH2HOH
H
H
OH
H
H
H
H
OH
HH
OH
HH
H H
achiral
3-3-66Chiral CenterChiral Centercommon source of chirality - tetrahedral (sp3)
carbon (atom) - bonded to 4 different groups
chiral centerchiral center - - carbon (atom) with 4 different groups
Enantiomers:Enantiomers: stereoisomers
nonsuperposable mirror images
All chiral centers are stereocenters Not all stereocenters are chiral centers
3-3-77EnantiomersEnantiomers
2-Butanol - 1 chiral center
different representations for this enantiomer
OH
CH3C CH2CH3
HH OH OH
(2) (3) (4)
OH
(4)
OH
representation of mirror imageor enantiomer
OHOR
OH
CH3C CH2CH3
H
(1)
3-3-1212R,SR,S Convention Convention - - Priority rules
Each atom bonded to the chiral center assigned a priority by atomic number
higher atomic number, higher the priority
Same atoms bonded to the chiral centerlook to the next set of atomspriority assigned to 1st point of difference
(53)(35)(17)(16)(8)(7)(6)(1)
-H -CH3 -NH2 -OH -SH -Cl -Br -I
increasing priority
(8)(7)(6)(1)
C HH
H
C CH
H HH
HC N
H
HH
HC O
H
H
Hincreasing priority
3-3-1313R,S ConventionR,S Convention
double (triple) bond atoms viewed as bonded to an equivalent number of atoms by single bonds
O
C
C C
C CH
HH
H
H
is treated as C CH
HH
C C
is treated asO
CH
C
O
is treated as C C HCC
C C
3-3-1414Naming Chiral CentersNaming Chiral Centers
1. Locate the chiral center, prioritize four substituents
1 (highest) to 4 (lowest)
ClH(1)
(2)(3)
(4)
2. Orient molecule so that lowest priority (4) group is directed away ( behind )
3. Read three groups toward you (in front) (1) to (3)
Clockwise RR configuration; counterclockwise S S
3-3-1515Naming Chiral CentersNaming Chiral Centers
( )-3-Chlorocyclohexene
ClH
(1)
(2)
(4)(3)
R
R
23
41
( )-mevalonic acid
HO OH
OHO CH3
R
3-3-1616
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Stereochemistry- Chapter 3Stereochemistry- Chapter 3OH
CH
H3C F
HO
CH
H3CF
3-3-1717IbuprofenCH3C
CH3
C
H3C H
C
O
OH
H
S isomer particularly active, but R slowly converted to S
C CH3
H3C
C
CH3H
C
O
OH
H
Naproxen
OCH3
CH3
HO2CH
S isomer
3-3-1818Assign R or S to carvone O
H
spearmint
S caraway/dill
R
N
H
H
Assign R/S to stereogenic carbon in coniine
Golden pitcher plant
R-(-)-coniine poison hemlock
3-3-1919Enantiomers & DiastereomersEnantiomers & Diastereomers
molecule with 1 chiral center:
21 = 2 stereoisomers are possible
molecule with 2 chiral centers:
a max of 22 = 4 stereoisomers “possible”
molecule with n chiral centers:
2n = maximum stereoisomers are possible
3-3-2121Enantiomers & DiastereomersEnantiomers & Diastereomers2,3,4-trihydroxybutanal 2 chiral centers
Diastereomers:Diastereomers: stereoisomers that are not mirror images
C
C
H OH
CHO
OH
CH2OH
H
22 = 4 stereoisomers “possible” & exist
2 pairs of enantiomer
C
C
HHO
CHO
HO
CH2OH
H
(Erythreose)
C
C
H OH
CHO
H
CH2OH
HO
C
C
HHO
CHO
H
CH2OH
OH
(Threose)(Erythrose)
3-3-2222Enantiomers & DiastereomersEnantiomers & Diastereomers
2,3-Dihydroxybutanedioic acid (tartaric acid)2n = 4 “possible”
C
C
H OH
COOH
H
COOH
HO
C
C
H OH
COOH
OH
COOH
H
enantiomers symmetry plane-superposable(same compound)
C
C
HHO
COOH
H
COOH
OH
but only three stereoisomers exist
C
C
HHO
COOH
HO
COOH
H
Meso compounMeso compoundd:: achiral but possessing 2 or more chiral centers
3-3-2323Enantiomers & DiastereomersEnantiomers & Diastereomers
2-Methylcyclopentanol
H H
CH3 OH
H H
HO H3C
H OH
CH3 H
HO H
H H3C
cis-2-Methylcyclopentanol
trans-2-Methylcyclopentanol
enantiomers left rightenantiomers left rightdiastereomers
topbottom
3-3-2424Enantiomers & DiastereomersEnantiomers & Diastereomers
1,2-cyclopentanediol
trans-1,2-cyclopentanediol(enantiomers)
diastereomers
H H
OH OH
H H
HO OH
H OH
OH H
HO H
H OH
cis-1,2-cyclopentanediol(a meso compound)
3-3-2525Enantiomers & DiastereomersEnantiomers & Diastereomers
cis-3-methylcyclohexanol
OHH3C HO CH3
HHHH
flip: axial-equatorial reverse but still cis
H
CH3
H
OH OH CH3
HH
3-3-2626Enantiomers & DiastereomersEnantiomers & Diastereomers
trans-3-methylcyclohexanol
HH3C H CH3
HOHOHH
flip: axial-equatorial reverse but still trans
OH
CH3
H
H
HO
H CH3
3-3-2828Properties of StereoisomersProperties of Stereoisomers
Enantiomers: identical physical and chemical properties in achiral environments
C
C
HHO
COOH
H
COOH
OH
C
C
HHO
COOH
HO
COOH
H
m. pt. 146o 174o
pK1 3.23 2.98
Diastereomers: different compounds different physical and chemical properties
C
C
H OH
COOH
H
COOH
HO
C
C
HHO
COOH
H
COOH
OH
m. pt. 174o 174o
pK1 2.98 2.98
3-3-2929Plane-Polarized LightPlane-Polarized Light
Light Light vibrating in all planes to direction of propagation
Plane-polarized light:Plane-polarized light: light vibrating only in parallel planes
optical activity
Plane-polarized lightPlane-polarized light the vector sum of the vector sum of left left and and right circularly polarized lightright circularly polarized light
3-3-3030Optically ActivityOptically Activity
Enantiomers (chiral) interact with Enantiomers (chiral) interact with circularly polarized light rotating the plane one way with R center
and opposite way with S
result: rotation of plane-polarized light clockwise (+)
or counterclockwise (-)
3-3-3131
Change in the polarized plane?
no change in the plane
achiral sample
Plane-Polarized Light (polarimeter)Plane-Polarized Light (polarimeter)
3-3-3232
rotates the plane
Plane-Polarized Light (polarimeter)Plane-Polarized Light (polarimeter)Change in the polarized plane?
3-3-3333
1. Stereoisomerism
2. Chirality
3. Naming stereocenters - R/S configuration
4. Acyclic Molecules with 2 or more stereocenters
5. Cyclic Molecules with 2 or more stereocenters
6. Properties of Stereocenters
7. Optical activity
8. Separation of Enantiomers, Resolution
9. Significance of Chirality in the biological world
Stereochemistry- Chapter 3Stereochemistry- Chapter 3OH
CH
H3C F
HO
CH
H3CF
3-3-3434
observed rotation:observed rotation: , degrees a compound rotates polarized light - dextrorotatorydextrorotatory (+) (+) right
- levorotatory- levorotatory (-) (-) left
Optical ActivityOptical Activity
( )-(+)-lactic acid ( )-(-)-lactic acid S R
Tspecific rotation [specific rotation []]D D ==
(observed, deg.)
l(dm) [g/ mL]
(obs deg)x100
l(dm) [g/ 100mL]
*book also uses []t
=
H3CC
OHH
COOH
CH3
C
HOH
COOH
DD[]
21 = -2.6°= +2.6°21[]
3-3-3535Example: 0.5g (-)-epinephrine-HCl in 10mL H2O measured in 20 cm cell (25o/D) obs = -5.0o, []D =?
25o
(obs)
l(dm) [g/ mL]
[]D =25o
obs)
(2dm) [0.05g/ mL]
[]D =25o
[]D =25o
-50o
OHOH
C OHC
HN
HH
HH
CH3
Cl
R-enantiomer is (-); R or S above?
[] = deg (cm2g-1 )
3-3-3636Optical ActivityOptical Activity
Racemic mixture: Racemic mixture: equal amounts of (+) and (-) enantiomers - rotation is 0o
H3CC
OHH
COOH
CH3
C
HOH
COOH
DD[]
21 = -2.6°= +2.6°21[]
For a 50/50 mixture of S and R, = ? 0o
3-3-3737
Mix is between 100% S and 50/50 (S/R)
CBrH
CH3
CH2CH3
(S)-(+)-2-bromobutane, []D=+23.1o21o
But from the obs, []D= +9.2? 21o
It’s not pure; possibly some R present! If some R, what percent?
+23.1o > +9.2o < 0o
percent of rotation = +9.2+23.1
x100% = 40%optical purity
40% excess = 40%S
the sample has 70%S and 30%R
+ (60%S/R mixture)
40% excess = 40%S + (30%S + 30%R)
3-3-3838Optical Purity:Optical Purity: composition of a mixture of composition of a mixture of
enantiomerenantiomerss
enantiomeric excess (ee):enantiomeric excess (ee): difference between the percent of 2 enantiomers in a mixture
x 100[]sample
optical purity % = []pure enantiomer
ee = optical purity
x 100[R] + [S][R] - [S]
ee = = (R - S)%
3-3-3939e.g. 6g of (+)-2-butanol plus 4g of (-)-2-butanol, ee = ?
= 20%ee = x100% 6 - 46 + 4
[]D of (+)-2-butanol = +13.5o; obs sample = ?rt
20% = obs
+13.5pure
obs = (.20)(+13.5%) = +2.7o
opt pure = = eeobs
pure
3-3-4040Enantiomeric ExcessEnantiomeric Excess
Example:Example: A commercial synthesis of naproxen (Aleve) gives the S enantiomer in 97% ee.
What are the percentages of the R & S in this mixture?
100% sample = 97%S + (3%S and R)
97%S + (1.5%S+1.5%R)
98.5%S + 1.5%R
H3CO
C
(S)-naproxen sodium
CH3
O
O Na
H
3-3-4141Resolution - separation of enantiomersResolution - separation of enantiomersOne strategy: convert enantiomeric pair into 2 diastereomers
Common - reaction forming salt
diastereomers - different compoundsdifferent physical properties
separate diastereomers
remove :B
leaves pure enantiomers4
2( :B )HB+
(R,R)-Salt
(R)-Base(R,S)
+R CO
O H
R CO
O
HB+
R CO
O
(S,R)-Salt)
2
3-3-4242ResolutionResolution
racemic acids - resolved w/ available chiral bases, e.g. (S)- and (R)-1-phenylethanamine
N NH HH H
3-3-4343
Resolution by acid-base reactions
Pure-Sb
racemic mix
+
NH
C
H
H3CPh
H
CH3
CH
CF3
CO O
H
CH3C
CF3
CO O
NH
C
H
H3CPh
H
H
H
CH3C
H
CO O
NH
C
H
H3CPh
H
H
F3C
+
CH3C
F3C
CO
ON
H
CH
CH3
Ph
HHH
C
H3C
H
C
O
ON
H
CH
CH3
Ph
HHF3C
CH3 C
H
CF3
CO
O
CH3C
H
CF3C
O
O
3-3-4444
Examples of enantiomerically pure bases
ResolutionResolution
= -165D25
[]= +228
D23
[]
(+)-Cinchonine
H
N
HCH2=CH
N
HHO
CH2=CH
(-)-Quinine
HHO
N
N
CH3O
H H
H
H
3-3-4545
[]D = -127o HCCl3 from Strycnos seeds (S nux-vomica)
brucine
Strychnine no methoxy groups
N
N
O
H
H
O
H
H3CO
H3COH
H
racemic bases with chiral acids like:
OHHO
O
OOH
OH(2R,3R)-(+)-tartaric acid
[ or (2S,3S) }
OHHO
O
O
OH(S)-(-)-malic acid
3-3-4646enantiomeric mixture
OHH
[] = 0
OHH
OHH
R
S
pure enantiomer
O
HF
ClS
O
HF
HOS
OHH
S
OHH
R
R
S
S
S
+
O
O
HFH
O
HFO
H
O
O
HFH
R
O
HFO
H
S
3-3-4747enantiomeric mixture
[] = 0
OHH
OHH
R
S
pure enantiomer
O
HF
ClS
[]25 = -8.2DOHH
R
O
HF
HO
+
OHH
S
O
HF
HO+
[]25 = +8.2D
3-3-4848
H3C
CH2
H2C
CH2
H2C
C
C
OO
CH2
FH
CH3
OHH O
H
O
H
lipase
R-Enzyme
H3C
CH2
H2C
CH2
H2C
C
CO
OH
FH
>69%ee
CH3
H2C
CH2
H2C
CH2
C
CO
OH2C
FH
H3C
50/50 mix
H3C
CH2
H2C
CH2
H2C
C
CO
OCH2
FH
CH3
3-3-4949
OHH O
H
O
H
lipase
R-Enzyme
H3C
CH2
H2C
CH2
H2C
C
CO
OH
FH
>69%ee
CH3
H2C
CH2
H2C
CH2
C
CO
OH2C
FH
H3C
CH3
H2C
CH2
H2C
CH2
C
CO
OH2C
FH
H3C
CH3
H2C
CH2
H2C
CH2
C
CO
OH2C
FH
H3C
CH3
H2C
CH2
H2C
CH2
C
CO
OH2C
FH
H3C A 50/50 enantiomeric mixture of esters
forms R-acid and recover S-ester.
3-3-5050Enzymes as resolving agents
racemic mix ethyl ester of (S)- and (R)-naproxin
+H3CO OCH3
CH3
O OEt
H3C
EtO O
NaOH, H2O1. esterase2. HCl, H2O
(S)-naproxen
H3CO
CH3
O OH (R)-ester - no effect
(S)-now aciddifferent functional gp.
3-3-5151CHEMICAL & ENGINEERING NEWS Oct 23, 2000, pg 55
Chiral Drugs Sales top $100 Billion
O
HOH
H
HO
H
H
HO
HOH2C
H
OHcarbohydrates
O
OH3N
R
side chain ionized or zwitterion
amino acids
N
NN
N
NH2
O
HOH
HH
HH
OPHOOH
O
deoxynucleic acid