3-1 1. stereoisomerism 2. chirality 3. naming stereocenters - r/s configuration 4. acyclic molecules...

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 compoundsdifferent 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-Chlorocyclohexene

Cl Cl


A nitrogen chiral center

N

CH2CH3H3C

+N

CH3H3CH2C

enantiomers

+


2-Chlorobutane

CH3CHCH2CH3

Cl

ClH Cl H

How is handedness designated?

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





7. Optical activity




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

3-3-2020

O

O

OH

H

H

H

(sugar-O)3

256 (ignore sugar)

2n

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)


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


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


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)


cis-3-methylcyclohexanol

OHH3C HO CH3

HHHH

flip: axial-equatorial reverse but still cis

H

CH3

H

OH OH CH3

HH


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





7. Optical activity




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

3-3-5252ProteinsProteins

• proteinsproteins are long chains of amino acids covalently bonded by amide bonds formed between the carboxyl group of one amino acid and the amino group of another amino acid

O

HN

NH

O R

HN

O-

OO

H3N

R R

Rn

for most proteins, n= 10-750

Chapter 5

3-1 1. stereoisomerism 2. chirality 3. naming stereocenters - r/s configuration 4. acyclic molecules...

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