Are mirror images identical

(symmetric),

or different

(asymmetric)?

Left hand mirror Right hand the left and right hands are

nonsuperimposable

A molecular case: the amino acid alanine

Symmetric or asymmetric?

Molecules with the same constitution that differ only by the relative positions of their atoms in space:

1 stereoisomers!

Molecular stereoisomers that are nonsuperimposable mirror images are called

1 enantiomers

• An enantiomer possesses the property of molecular chirality.

Enantiomers

• Usually have 4 different functional groups bonded to an sp3-hybridized atom. That atom isreferred to as a

1 Stereogenic center1 Stereocenter1 Chiral center

• Have identical physical properites save for one: they cause exactly opposite rotations ofplane-polarized light and so are said to exhibit optical activity.

1 A clockwise rotation is

° (+) ° dextrorotatory ° d

1 A counterclockwise rotation is

° (-) ° levorotatory ° l

Light: electromagnetic radiation

Electric field

Electric wave

MagneticMagnetic wave field

Oscillating orthogonal electric and magnetic fields of a beam of light

Plane-polarized light and its consequences

1st polarizing 2nd polarizingfilter filter

observer sees maximum light

source plane- polarized light

observer sees no light

plane- polarized light

Polarimeter: An instrument to measure optical activity

[ α ]ECD = 100 α

cl

% e.e. = *[(+)-enantiomer] - [(-)-enantiomer]* x 100 [(+)-enantiomer] + [(-)-enantiomer]

% e.e. = α x 100 [ α ]EC

D

Defining a physical constant: Specific rotation

" = the observed rotation of plane-polarized light in degreesc = the concentration in g / 100mLl = the pathlength (always 1 dm)

Enantiomeric purity (% e.e.):

Note: a 50 : 50 mixture of enantiomers has no ". It appears to be achiral. Such mixtures are called racemates.

SO WHAT?

Is molecular chiralty important?

Consider:• Gloves• Smells• Drug-receptor interactions

Different stereoisomers like enantiomers interact with one another in different ways!

Stereochemical theory of odor

H

O

H

O

H H

(S)-(+)-CARVONE (R)-(-)-CARVONE

smells like caraway seeds smells like spearmint gum

(R)-(+)-LIMONENE (S)-(-)-LIMONENE

smells like citrus fruit smells like turpentine

Some drugs that exist as enantiomers and why this matters

(-)-ibuprofen (+)-ibuprofen [α]D

25 = - 20.6E (c 1.00, ethanol) [α]D25 = + 58.5E (c 2.00, ethanol)

Advil, Motrin

OTC for arthritis, fever; general anti-inflammatory analgesic

(+)-enantiomer is the active isomer

(-)-enantiomer is inactive

the enzyme 2-arylpropionyl-CoA epimerase converts (-)-enantiomerto the (+)-enantiomer

(Zhao, X.; Eur. J. Med. Chem. 2006, 41, 1352-1358; Piccolo, O.; J. Org. Chem. 1985, 50, 3945-3946.)

O

OH

O

OH

Some drugs that exist as enantiomers and why this matters

(-)-thalidomide (+)-thalidomide [α]D

25 = - 64.6E (DMF) [α]D25 = + 64E (DMF)

teratogen antiemetic

enantiomers are interconvertable (undergo racemization) in vivo

racemate is immunomodulator used to treat

erythema nodosum leprosum

(in combination with dexamethasone) newly diagnosed multiple myeloma

actinic prurigo

(Ellis, G.P.; West, G.B. Progress in Medicinal Chemistry, Elsevier: New York, 198, p 170)

N

O

H

O

N

O

O

N

O

H

O

N

O

O

Some drugs that exist as enantiomers and why this matters

(-)-ketamine (+)-ketamine [α]D

25 = - 91.88E (c 2.00, H2O) [α]D25 = + 92.48E (c 2.00, H2O)

analgesic racemate used to induce general anesthesia

(+)-enantiomer (Ketanest S) is more potent

(-)-enantiomer is more hallucinogenic: may cause nightmares

(Marrietta, M. P.; Way, W.L.; Castagnoli, N. Jr.; Trevor, A.J. J. Pharmacol. Exp. Ther. 1977, 202, 157-165.)

N

Cl

O

HN

Cl

O

H

N

H

N

H

(+)-methamphetamine(-)-methamphetamine

The Alan Baxter story

2002 Salt Lake City Winter Olympics bronze medalist in downhill skiing (slalom)

failed IOC routine drug test: + for methamphetamine

source of + : Vicks nasal spray

U.S. version contains the legal enantiomer of methamphetamine:

(decongestant) (crank)

IOC test did not differentiate between enantiomers

Baxter cleared, but lost his medal – now IOC explicitly bans both enantiomers

2006 Turin Winter Olympics Baxter finishes 16th

The R,S system of naming chiral centers:

• Use the Cahn-Ingold-Prelog “Priority Rules”

1. Rank the priorities of the 4 atoms attached to the chiral center, according toatomic number.

2. If 2 or more atoms attached are identical, rank the atoms attached to those atoms, two bonds away from the chiral center. Priority of the entire substituent isdetermined by the first point of difference. The highest priority substituent isassigned a 1, the next, 2, then 3, and the lowest, 4.

3. Position the molecule so that your line of sight is from the chiral center, directlyback to the priority 4 substituent.

4. If priority groups 1, 2, and 3 are arranged clockwise in descending rank, the chiralcenter is assigned the stereodesignator

R

4. If priority groups 1, 2, and 3 are arranged counterclockwise in descending rank,the chiral center is assigned the stereodesignator

S

C X

Y

Z

C X

X C

Y

Z

For comparison purposes, identical atoms must be compared in the same hybridization state:

• The “Phantom atom” Rules

1. For naming purposes, a π bonded atom is considered to replicated by a phantomσ bond to a phantom atom.

2. Rule 1 is applied to both atoms of the π bond.

3. Rules 1 and 2 apply to each π bond of multiply bonded atoms.

4. All other things being equal, phantom atoms rank below real atoms of the sameatomic number.

Cl

H

An example:

Is this an R or an S molecule?

So, it is R.

Cl

HC

CCl

H

H

H H

CC

CCl

H

H H

C HH

C

Cl

H

1

4

1

4

3

2

What ways are there to draw enantiomers?

1. Hatched and wedged line projections (most popular)

are these these enantiomers, or just different hatched and wedged line projections of the same molecule?

2. Sawhorse projections could be used, too:

CH3H

H

CH3

H

H H

H

O

H

O

H H

Remember carvone and limonene?

Do these have R or S configurations?

What ways are there to draw enantiomers?

3. Newman projections

Are these anti-staggered and gauche staggered conformations of the same molecule?

CH3

CH2CH3

H

H H

CH2CH3

H

CH2CH3

CH3

CH3CH2 H

H

CH3

CCH2

H3CBr

H

1

2

3

4

CH3

C

CH2

CH3

Br H

What ways are there to draw enantiomers?

4. Fisher projections

\

a. Orient your point of view so that your body lines up with the parent chain of the molecule andyour line of sight bisects the bond angle formed by the remaining two substituents of the chiralcenter.

b. Draw the molecule as it appears to youusing wedged and hatched lines:

c. The Fisher convention replaces wedged and hatched lines with regular ones.

• The vertical lines of a chiral center are always pointing away from you

• The horizontal lines of a chiral center are always pointing towards you

Two of these Fisher projections of different conformations of the same configuration. Which two?

CH3

CH2CH3

Br H

CH2CH3

CH2CH2CH2CH3

HOHCH2CH3

H

OHCH3CH2CH2CH2

CH2CH3

CH2CH2CH2CH3

OHH

Draw (R)-2,3-dimethylheptane as a wedged and hatched line structure and as a Fisher projection:

A molecule with 2 chiral centers and 4 stereoisomers

2,3-dihydroxybutanoic acid, also called tartaric acid:

• Draw all four R,S isomers of this molecule

O

OH

OH

OH

* *

CH3

O

OH

OHH

OHH

H3C

O

OH

OHH

OHH

CH3

O

OH

HOH

OHH

H3C

O

OH

HOH

OHH

CH3

H OH

H OH

CO2H

CH3

HOH

HOH

CO2H

CH3

H OH

OH H

CO2H

CH3

HOH

OHH

CO2H

(2R,3R) (2S,3S)

(2R,3S) (2S,3R)

enantiomers

enantiomers

diastereomers

A molecule with 2 chiral centers and 4 stereoisomers

OH

OH

CH3

CH3OHH

OHH

H3C

H3C OHH

OHH

CH3

CH3HOH

OHH

H3C

H3C HOH

OHH

CH3

H OH

H OH

CH3

CH3

HOH

HOH

CH3

CH3

H OH

OH H

CH3

CH3

HOH

OHH

CH3

(2S,3R) = meso (2R,3S) = meso

(2S,3S) (2R,3R)

the same

enantiomers

diastereomersdiastereomers

A molecule with 2 chiral centers and 3 stereisomers: one isomer is a meso isomer

Consider with 2 chiral centers and (not counting conformational isomers)

22 = 4 possible stereoisomers, but there are only 3!

O

O

OH

OH

Cl

O

Cl

OHHO

OH

Cl

O

O

OH

OH

OH

O

OHHO

OH

OH

OH

sucralose (Splenda™)400-800 times as sweet as sugar

sucrose

How many chiral centers does Splenda have? nine

What is the theoretical maximum number of stereoisomers can this sugar substitute have?

2n , where n = number of stereogenic groups: 29 = 512

O

O

OH

OH

Cl

O

Cl

OHHO

OH

Cl

Are the configurations of Splenda’s indicated chiral centers R or S?

O

O

OH

OH

Cl

O

Cl

OHHO

OH

Cl

Cl

HC

CO

C

H

OH

CC

OC

O

C

CO

OCl

R

1

2

3

4

3

2

4

1

R