show a synthetic pathway. hint: alkenes may be formed from alkyl halides by reaction with a strong...

Show a synthetic pathwayNH2

Br

COOH

Cl

NH2

Br

Show a synthetic pathway

HO2C

Hint: Alkenes may be formed from alkyl halides by reaction with a strong base such as NaOCH3 resulting elimination of HX.

HO2C1)

Cl

AlCl3

2) Cl

O AlCl33) KMnO4, H2O4) H2, Pd/C5) NBS, h6) NaOCH3 in CH3OH, heat

(E2 elim of HBr)

1)

O

2)

O

HO2C3)

HO2C

HO2C

Br

4)

5)

6) workup w/ H3O+

Fill in the blanks.

NO2

A BH2, Pd/C

CSO3, H2SO4

StereochemistryStereochemistry refers to the

3-dimensional properties and reactions of molecules. It has its own language and terms that need to be learned in order to fully communicate and understand the concepts.

Definitions• Stereoisomers – compounds with the same

connectivity, different arrangement in space• Enantiomers – stereoisomers that are non-

superimposible mirror images; only properties that differ are direction (+ or -) of optical rotation

• Diastereomers – stereoisomers that are not mirror images; different compounds with different physical properties

More Definitions• Asymmetric center – sp3 carbon with 4

different groups attached• Optical activity – the ability to rotate the plane

of plane –polarized light• Chiral compound – a compound that is

optically active (an achiral compound will not rotate light)

• Polarimeter – device that measures the optical rotation of the chiral compound

Plane-Polarized Light

Plane-Polarized Light through an Achiral Compound

Plane-Polarized Light through a Chiral Compound

Polarimeter Measures Optical Rotation

Specific Rotation, [α]

[α] = α / cl = observed rotation

c = concentration in g/mLl = length of tube in dm

Dextrorotary designated as d or (+), clockwise rotation

Levorotary designated as l or (-), counter-clockwise rotation

Specific Rotations of some Common Organic Compounds

Compound [] # * centersPenicillin V +233.0 3Sucrose +66.5 10 Camphor +44.3 2MSG +25.5 1Cholesterol -31.3 8Morphine -132.0 5

Chirality CenterCarbon has four different groups attached

Enantiomers nonsuperimposible mirror images

OH

CH3HO2CH

OH

CO2HCH3

H

mirrorplane

(S)(+) lactic acid (R)(-) lactic acid

from muscle tissue from milk[] = +13.5 [] = -13.5

oo

Absolute Configuration

1

23

4

Use Cahn, Ingold, Prelog priorities

Place the lowest priority group back (focus down C - 4 bond)

(R)

clockwise

draw arrow from 1-2-31

2 34

(S)

counterclockwise

Assign Priority to each Group on Asymmetric Center

focus down C-4 bond

4

32

1I

ClHF

rotateI

FH

Cl

Lactic Acid

(S) (R)

4

3 2

1

4

32

1OH

CH3 CO2HH

OH

CH3HO2CH

C.I.P. Priorities

CH2CH2CH3 CH(CH3)2

CH2CH2OH CH2CH

O

CH2CH2CH3 CH=CH2

CO2H CH 2Cl

Low High

CH2CH2Br CH(CH3)2

Enantiomeric Excess(Optical Purity)

actually 94.3% (+)11.4% racemic88.6% (+)

= 88.6% e.e.

x 100 123.0109.0

e.e. =

oobserved rotation = +109

from oranges

o[] = +123.0

H

from lemons

o[=

(S)-(-) Limonene (R)(+) Limonene

H

x 100 = enantiomeric excess (e.e.)rotation of pure enantiomerobserved rotation

SSRI Efficacy depends on Stereochemistry

ON(CH3)2

F

NC

*

(+/-) Celexa(-) Lexapro

(+/-) Celexa (-) LexaproCost $17.10 per month $83.83 per month

Art in Chemistry

Lexapro is the S enantiomer. Draw the structure of Lexapro.

ON(CH3)2

F

NC

*

(+/-) Celexa(-) Lexapro

(R) O

F

N

NC

(S) O

F

N

NC

Art in Chemistry

Lexapro contains only the S enantiomer. Celexa is a racemic (50:50) mixture of both S and R forms.

Biological Activity

(R)(+) Thalidomide (S)(-) Thalidomide

NN

O

O

O

O

HH

a sedative and hypnotic a teratogen

N

NO

O

O

O

H

H

In the 50’s, thalidomide was sold as a racemic mixture!

Thalidomide was prescribed as a sedative and used against nausea and to alleviate morning sickness in pregnant women.

Fischer Projections

Vertical bonds move away (dashed bonds)Horizontal bonds approach you (wedge bonds)

OH

CO2H

CH3

HOH

CH3HO2CH

OH

CO2H

CH3

H

Assigning Absolute Configuration to Fischer

Projections

OH

CO2H

CH3

HOH

CO2H

CH3

HOH

CH3HO2CH

(S) (S) (S)rotate

Rotation of the Projection 90o

Reverses Absolute Configuration

90o

90oo90

(S) (R) (S) (R)

CH3

H

OH

HO2C

CO2H

CH3

H

HO

H

OH

CO2H

CH3

OH

CO2H

CH3

H

Translation: If you rotate the Fisher projection 90o you are drawing the opposite enantiomer!

Determine the stereochemistry at all chiral centers.

COOH

HHO

OH

NH2

O

HO

O

O-

(S)(S)

(R) (S)

(Z)

(R)

COOH

HHO

OH

NH2

(S)

O

HO

O

O-

H3C H

(S)

OH

(1)

(R)

(R)(2)

(R)

(Z)(3)

(R) (S)

OH

(4)

(5)

Br

Br

O

(S) (R)HH3C

CH3CF3

HH3CH2C

(6)

(7)

(R) (S)

(8)

(R) (S)

(9)

(10)

O

CH3

HCl

CHO(R)

OHH(S)

HHO

OH

O

(R)

(S)

HOHO

OHOH

(S)

(S)

OH

Front C: RBack C: R

(7) Should be R, R, S, R from C-1;5th chiral center not included.

1

DiastereomersStereoisomers That Are Not Mirror Images

3 3 22

opposite stereochemistry at C3

same stereochemistry at C2 (S)

CO2H

OHH

Br HCO2H

OHH

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

Fischer Projections with 2 Chiral Centers

CO2H

CH3

H OH

Br H H Br

H OH

CO2H

CH3

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

2

3

2

3

2 Chiral Centers4 Stereoisomers

Identical, Enantiomers or Diastereomers?

H

H

CH3

CH3

&CH3

CH3

H

H CC

a)

CH2CH3

CH3

H

H

Br

Br

CH2CH3

CH3&

b)

OH

HO

NH2

NH2

Identical, Enantiomers or Diastereomers?

H

H

CH3

CH3

&CH3

CH3

H

H CC

a)

CH2CH3

CH3

H

H

Br

Br

CH2CH3

CH3&

b)

OH

HO

NH2

NH2

S-2-Bromobutane S-2-Bromobutane

(2R,3S)-3-aminobutan-2-ol(2R,3S)-3-aminobutan-2-ol

Tartaric AcidsCO2H

CO2H

H OH

HO H H OH

HO H

CO2H

CO2H

CO2H

CO2H

H OH

H OH HO H

HO H

CO2H

CO2H

R,R S,S

R,S S,R

Solve one structure first.Make sure you do itcorrectly!

Use it as reference for others.

Racemic Mixture

o

(g/mL) 1.7598 1.7598 1.7723

m.p. C 168-170 168-170 210-212

[] (degrees) - 12 + 12 0

(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid

Racemic Mixture (Racemate): 50/50 mixture of enantiomers

CO2H

CO2H

H OH

HO H H OH

HO H

CO2H

CO2H

R,R S,S

Meso CompoundInternal Plane of Symmetry

Optically Inactive

orotate 180

superimposible

CO2H

CO2H

H OH

H OH HO H

HO H

CO2H

CO2H

R,S S,R

mirror plane

2,3,4-trichlorohexaneHow many stereoisomers?

Cl

Cl

Cl3 asymmetric centers

8 stereoisomers

* **

2n, n= # asymmetric centers (3)

n = 3; 2n = 8

CH3

CH2CH3

H Cl

Cl HH Cl Cl H

H Cl

Cl HCH3

CH2CH3

CH3

CH2CH3

Cl H

H Cl

H Cl Cl H

Cl H

H Cl

CH3

CH2CH3

H Cl

H Cl

H Cl

CH3

CH2CH3

Cl H

Cl H

Cl H

CH3

CH2CH3

Cl H

H Cl

H Cl

CH3

CH2CH3

H Cl

Cl H

Cl H

CH3

CH2CH3

S

S

R

RR

S

A CarbohydrateCHO

CH2OH

H OH

HO H

H OH

H OH

(+) D-Glucose

R

S

R

R

Internal Planes of Symmetry

CH3CH3

CH3CH3

CH3CH3

CH3 CH3

Both are Meso

Asymmetric Centers on Rings

Br

Br

Br

Br

1(R),2(S) cis 1,2-dibromocyclohexane

nonsuperimposible but A flips into B

A B

BrBr

Meso

Reactions that Generate Chirality Centers

Hydrogenation, syn

CH3CH3

CH2CH3CH2CH3

H2, Pt/C

CH2CH3 CH2CH3CH3CH3

HH

CH2CH3

CH2CH3

H CH3

H CH3

product is meso

BrominationTrans is formed exclusively

No Meso is formed (cis)

racemic mixture

S SR RBr BrBr Br

Br2

Bromonium Ion is Opened Equally from Both Sides

Br2

Br Br Br BrR R S S

racemic mixture

Br

Br

Br

Br

Br Br + -

trans alkene + anti addition = MESO

CH2CH3

CH2CH3 H

H

Br2

CH2CH3

CH2CH3

HH

Br

Br

Br Br

CH2CH3CH2CH3HH

meso

cis Alkene + anti addition = racemic mixture

H

CH2CH3 CH2CH3

H

Br2

Br Br

CH2CH3CH2CH3 H

HR R

CH2CH3

CH2CH3

H

H

Br

Br

CH2CH3CH2CH3 H

H

Br BrS S

Br

H HCH2CH3CH2CH3

Br

Br

BrH

H

CH2CH3

CH2CH3

a b

a b

Brominations Often Generate Asymmetric Centers

Br2

R RS S

racemic mixture

CH3CH3

H H

CH3CH3

Br BrH H

CH3CH3

Br BrH H

CH3

CH3 H

H CH3

CH3 HH

Br

Br

CH3CH3

Br BrH H

S Rmeso

Br2

Asymmetric Center is Generated Racemic Mixture Formed

H-Br

HH

Br

Br

a)

b)

Br

H

a) Br

H

b)(R) (S)

Asymmetric Induction

PPh2

PPh2

RuCl2

CH3

OHH2

Ru(BINAP)Cl2

CH3H

OH

96% e.e.

Noyori and Knowles shared Nobel Prize in Chemistry, 2001

Preparation of (L)-Dopafor Treatment of Parkinson’s

HO

HO

CH2CCO2H

NH2

H

l-(-) Dopa

HO

HO

CH2CH2NH2

Dopaminecannot cross blood-brain

barrier

C=CNH2

CO2HH

HO

HO

H2Rh(DIOP)Cl2

enz.

Relevance of Stereochemistry

(S,S)(R,S)useful decongenstants

d-pseudoephedrine and l-ephedrine

4 stereoisomers

**

2 asymmetric centers

EPHEDRA from Ma Huong

NHCH3

CH3

OH

One-step synthesisPseudophed

*

d-(S)- "Meth"l-(R) - Vicks

(methamphetamine)"desoxyephedrine"NHCH3

CH3

-(p-isobutylphenyl)propionic acid

CH3 CO2HH

(S)(+) ibuprofen (R)(-) ibuprofen

CH3HO2C

H

anti-inflammatory 80-90% metabolized to (S)(+)

How Sweet it is!

Sucrose

O

HOOH

O

CH2OH

OCH2OH

CH2OH

HO

HO

OH

Sucralose or Splenda

O

Cl

HOOH

O

CH2OH

OCH2Cl

CH2Cl

HO

HO

Sucralose is 600 times sweeter and does not get metabolized.

Sildenafil (Viagra) and Caffeine

NN

NN

CH3

H

O

CH3CH2O

SN

NCH3

O

O

NN

N

N

CH3

O

O

CH3

CH3

Radiosensitizer of Choice Until 2004

Okadaic acid17 asymmetric centers

O

OH

HOOC

OH

OH

O

OH

HO

OH

HOH

OO

How is each Cpd related to X?

H3C

CH3CH2CH3

H

HHO

HO H

CH3

CH3

CH2CH3H

OH OH OH

H3C

OHCH2CH3

H

HH3C

H3C

CH2CH3OH

H

HH3C

CH2CH3

CH3

HH3C

OHH

CH2CH3

CH3

CH3H

OHH

H

CH2CH3

OHH3C

HH3C

Cpd X

B C

E F

G H I

A

D

(R)

(R)

H3C

CH3CH2CH3

H

HHO

HO H

CH3

CH3

CH2CH3H

(S) (S)

OH

(S) (R)

OH

(S) (S)

OH

(S)

(R)

H3C

OHCH2CH3

H

HH3C

(R)

(S)

H3C

CH2CH3OH

H

HH3C

CH2CH3(R)

(R)

CH3

HH3C

OHH

CH2CH3(S)

(R)

CH3

CH3H

OHH

H(R)

(S)

CH2CH3

OHH3C

HH3C

Cpd X

B C

E F

G H I

A

D

Front: RBack: R

Enantiomers:A, C

Diastereomers:B, E, F, H, I

Identical:D, G