651.06

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Stereochemistry – The Chemistry of Shape a) Constitutional isomers: order of bond attachment is different

Br Br Br

vs. vs.

b) Stereoisomers: non-identical compound of identical connectivity

1) Configurational isomers: stereoisomers which are interconvertible by interchanging groups attached to the same (carbon) atom

vs.

2) Conformational isomers: isomers which are interconvertible by

rotation about single bonds

vs.

when such a rotation requires high energy (> 20 kcal/mol) the

isomers are known as atropisomers ex.

HO OH

3) Enantiomers: configurational or conformational isomers which

have a non-superimposable mirror-image relationship

CH3

H ClF

CH3

HClF

vs.

or vs.

651.06

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4) Diastereomers: any set of configurational or conformational

isomers which do not have a non-superimposable mirror-image relationship

5) Epimers: diastereomers that differ at one center Diastereomers behave as different chemical entities (different solubility, reactivity, spectra, etc.); Enantiomers behave identically except when exposed to a chiral reagent or polarized light. Optical activity (reported as ![ ]

D

20= x.xxx

o c = y.yy) ![ ]

D

20= specific rotation of Na D line (589.3nm)

= [observed rotation (degrees)] / [Length (dm) * g/cc] c = concentration in g / 100mL ORD: optical rotatory dispersion measurement of rotation as a function of wavelength enantiomers give mirror image curves Chiral: a stereoisomer non-superimposable on its mirror image

O

P

OF

S

O

R DH

Achiral: a stereoisomer superimposable on its mirror image due to a plane of symmetry

S

H

R HH

651.06

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Reevaluation of Stereochemistry: The Mislow Approach (JACS 1984, 3319) -Stereochemistry and chirality have nothing to do with one another. “Chirality and achirality are purely geometric attributes that are in no way dependent on models of bonding.” (Mislow & Siegel) stereogenicity: a property of tetrahedral atoms, in which all four ligands are different; exchange of any two ligands results in a different isomer. Such (stereogenic) atoms can be assigned an R or S designation using the Cahn-Ingold-Prelog system. chirotopicity: a term applied to any atom that exists in a chiral environment; in general, non-chirotopic atoms lie on a plane or point of symmetry Note: The term "stereogenic center" is now preferred to "chiral center" or "asymmetric center". Ex:

OH OH OH OH OH OHOH OH

Mislow also points out that the term "stereoisomer" is impossible to define in purely geometric terms and can be abandoned if one attaches no stereochemical significance to bonding. In addition, if we discard the term "stereoisomer," then "diastereomer" becomes a meaningless term.

molecules

symmetryequivalent?

YES NO

Symmetry equivalent Symmetry nonequivalent

equivalent?YES NO

homoisomers(the same thing)

enantiomers

same bondingconnectivity?

YES NO

diastereomers constitutionalisomers

sets of atoms

symmetryequivalent?

YES NO

Symmetry equivalent Symmetry nonequivalent

equivalent?YES NO

homotopic enantiotopic

same bondingconnectivity?

YES NO

diastereotopic constitutionallyheterotopic

Flow charts for the classification of symmetry relationships among molecules and topic relationships among sets of atoms

651.06

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Topicity Stereochemical relationships between individual atoms or groups within a single molecule can be defined in terms of topicity. Thus, two atoms equated by a mirror reflection of the molecule are enantiotopic and two atoms in equivalent environments (i.e., the methylene protons in n-propane) are homotopic. Two protons placed in diasteromeric positions by a mirror reflection are in diastereotopic environments.

HO

H H

! 2,1 (d)

HO

OH

H H

! 3.57 (dd) ! 3.59 (dd)

651.06

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Cahn-Ingold-Prelog Rules for Assignment of Stereogenicity 1) Assign each subsituent on the stereogenic atom a priority based on the following considerations: a) Atomic number (higher atomic numbers get higher priority) b) In the event of a tie, look at the substitutents attached to each substituent: c) The higher priority goes to the atom with the highest priority substituent d) In the event of a tie, give a higher priority to the atom with the greater number of higher priority substituents (count multiple bonds as multiple substitutents) e) In the event of a tie, repeat step b) until a difference is encountered 2) Once prioritites have been assigned, view the molecule from the perspective in which the lowest priority substitutent is directly behind the stereogenic atom. If the remaining three substituents are arranged such that traveling from highest to lowest priority occurs in a clockwise direction, the stereogenic atom is assigned the (R) designation; if traveling from highest to lowest occurs in a counterclockwise direction, the stereogenic atom is assigned the (S) designation.

OH

O > C(H)(CH[CCC])2 > C(H)(CH3)2 > C(H)2(C) Note: If two substituents differ only in their stereogenicity, we give a higher priority to the (R) configuration and assign r and s designations to the stereogenic center. Prochirality (Stereotopicity) of sp2 Atoms Any sp2 atom attached to three different ligands is considered prochiral and the faces of the multiple bond are either enantiotopic or diastereotopic. The two faces can be designated as si or re using a variation of the Cahn-Ingold-Prelog convention: the face in which the travel is clockwise is designated re; the face in which the travel is counterclockwise is given the si designation.

O

R H

si

O

RH

si

vs.

H3C CO2H

O

pyruvate

reductase

H3C CO2H

OH

(S)(si facial selectivity)

651.06

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Symmetry Operations: operations which convert an object into itself a) Rotation (Cn) rotation of 360o/n about an axis gives the original species b) Reflection (σ) reflection in a plane gives the original species c) Rotation-reflection (Sn) rotation of 360o/n about an axis followed by

reflection in a plane perpendicular to the axis of rotation gives the original species Relationship Between Chirality and Symmetry Groups Chiral without stereogenic carbons

I Chiral with stereogenic carbons II

III Achiral without stereogenic carbons

IV Achiral with stereogenic carbons

Class I

H

Cl

C

Cl

H

H

Cl

C

Cl

H

O OOO

optically active no stereogenic carbons but chiral

651.06

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Class II

CH3ClH2C

OH

H3C CH2Cl

HOHO OH

H2N CO2H HO2C NH2 non-superimposable mirror images, no plane of symmetry (lots of molecules in this class) Class III

H3C

CH3H3C

OH CH3

H3C CH3

HO1

423

12

34

superimposable mirror images plane of symmetry - C1, C2, C3, C4, OH plane (lots of molecules in this class) Class IV

OH

OH

HO

O

OH

O

meso compound, 2 stereogenic centers but a plane of symmetry running through

the molecule

651.06

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Cycloalkanes: Draw the possible stereoisomers of 1,2-dimethylcyclobutane

CH3

H

CH3

H

H

CH3

CH3

H

CH3

H

H

CH3 meso enantiomers Draw the possible stereoisomers of 1,3-dimethylcyclobutane

CH3

H

H

CH3

CH3

H

CH3

H achiral achiral one plane of symmetry two planes of symmetry Diastereomers:

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

H

H

O

O

HO

HOH

O

H

O

D-erythrose L-erythrose

D-threose L-threose

enantiomers

enantiomers

DiastereomersDiastereomers Diastereomers

651.06

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Stereochemistry of Transition States

Like ground state molecules, transition states also have stereochemical properties:

‡ ‡

O

LiO

Ph

H

vs.

enantiomers

O

LiO

Ph

H

-same energies, so equally populated

‡ ‡

O

LiO

Ph

H

vs.

diastereomers

O

LiO

Ph

H

-different energies, so differentially populated

651.06

47

Conformation a) Ethane

H

H

H

H

H

H

H

H H

H

H

H

EN

ER

GY

Eclipsed Ethane Conformation

Staggered Ethane Conformation

Newmanprojection

Newmanprojection

SS

EEEE

S

HCCH

dihedral

angle = 60o

HCCH

dihedral

angle = 0o

Angle of rotation, degrees

3 Kcal/mol

360 = 0o300o240o180o

120o60o0o

eclipsed form = (E)

(rear H's behind front H's)

staggered form = (S)

(rear H's bisect front H's)

H

H H H

HH

HH

HH HH

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b) Butane

H

CH3

H

H

CH3

H

H3C

H H

CH3

H

H

H

H

CH3

H

CH3

H

H

H CH3

CH3

H

H

fullyeclipsed

(one eclipsed CH3-CH3;and two eclipsed H-H )

0o60o 120o 180o 240o 300o

360 = 0o

Angle of rotation, degrees.

gauche

(offset CH3-CH3 and offset H-H)

partlyeclipsed

(two eclipsed CH3-H; and one eclipsed H-H)

anti

(CH3 's 180o apart

and H-H offset)

0.9Kcal/mole

0.9Kcal/mole

6 Kcal/mole

6 Kcal/mole

4 Kcal/mole

1

4 Kcal/mole

4

3 3

2 2

1 1

4

3

2

EN

ER

GY

CH3H3C

H HHH

CH3

HH

CH3H

HH3CHH

CH3

H3C H

H

H

H

H

HCH3

651.06

49

Alkane Steric Interactions

Gauche butane = 0.9 Kcal/mol

Eclipsed H...H = 1 Kcal/mol

Eclipsed H...CH 3 = 1.5 Kcal/mol

Eclipsed CH3...CH3 = 4 Kcal/mol

Substituted Butane

YX

X,Y = OR, Cl, F (electronegative groups)

Egauche < Eanti

“gauche effect” ascribed to a dipole / dipole interaction

c) Pentane

H

HH

H

HH

1,7 interaction

very bad steric interaction ( > 5 kcal/mol )

d) Butadiene

HH

s-trans s-cis

e) acrolein

OO

H

H

H

HHH

HH

s-trans s-cis (less stable ≈ 0.5 - 1.0 kcal/mol)

651.06

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f) alkenes

YR1

R3

R2

lobes of !*

R1 eclipses C=Y to allow R2 & R3 to hyperconjugate

(allows overlap with π*)

-contributes electron density to electron deficient π*

(esp. when Y = N, O and R2 & 3 = H > C > N > O > X)

- C-H hyperconjugates better than C-C > C-O (C-N)

YR1

R3R2

Y

R2

R1

R3 ∴ the more electropositive R2 & R3 the better Topics in Stereochem, 1971, 5, 167

ex

OH3C

HH H

OH

H3CH H

>

by ≈ 1 kcal/mol

OF O

H HF

dipole / dipolerepulsion

Exception!

-true for carbonyls

-not true for olefins (due to sterics)

H

H

H

H

H

H

H H3C

HH

H

H

H

HH

CH3H

1,6 interactionapprox. 1 kcal/mol

bisectedapprox. 2 kcal/mol

lowest E0 kcal/mol

2 kcal/mol energy difference is typical for not eclipsing a bond (Ebisected - Eeclipsed ≅ 2 kcal/mol)

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H H3C

H

H

H

H

H3C

HH

H3C

H

H3C

HH

CH3H

eclipsed+0.6 kcal/mol

bisected+0.5 kcal/mol

eclipsed+4 kcal/mol

H3C

H

H3C

H

H

perpendicular+0 kcal/mol

H3C

HH

H

H3CH

bisected+5 kcal/mol

substituted sp2 - sp2

OO

H

H

CH3

CH3HH

H3CCH3

α - CH3 destabilized s-cis

≈ 4 : 1 ΔG ≈ 0.5 kcal/mol

OO

H3C

H3C

CH3

HCH3H3C

HCH3

β - CH3 destabilized s-trans

≈ 1 : 2

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R1 O

R2

O

R1 O

R2

O

ΔG ≈ 10 kcal/mol

s-trans (favored by 3-4 kcal/mol)

R1 N

H

R2

O

R1 NH

R2

O

ΔG ≈ 15 kcal/mol

s-trans s-cis

R1 N

R2

O

R1 N

R2

O

R3

R3

ΔG ≈ 12 kcal/mol

for R2 larger than R3

Dale, Stereochemistry & Conformational Analysis (Verlag Chemie)

H N

O

CH3

CH3

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53

g) Cyclohexane 3 representations

HH

H

H

H

H

H

H

H

H

HH

HaxHax

Hax

Hax

HaxHax

Heq

HeqHeq

Heq Heq

Heq

Hax Hax

Heq Heq

HaxHax

Heq Heq

Hax

Hax

a dot denotates a non-visible

bond (Heq on C-1) toward the observer.

an open circle denotates an invisible

bond (Heq on C-4) away from the observer.

1

3

4

612

4

5

1

2

2

3

4

5

6

6

651.06

54

interconversion of cyclohexane conformers

HaxHaxHax

HaxHax

Hax

Heq

HeqHeq

HeqHeq

Heq

H"eq"

H"eq"H"eq"

H"ax"

H"ax"

H"ax"

H"eq"

H"eq"H"eq"

H"ax"

H"ax"

H"ax"

C CC CH

H

H

H

H

H

H

H

H HH

HH

H

H

H HHH

H

HH

H

HH

H H

H

H

H

HH

H

HH

H H

H

H

H

H H

1

Twist-boat (two views)

Boat (three views)

"Flagpole Hydrogens"

32 6

54

1

Half-Chair 2

Chair 2

Half-Chair 1

The eight hydrogensshown are all eclipised

12

34

6

52

1

3

4

5

6Note that the ring flipinterchanges axial and equatorial protons

32

6 5

4

1

Bring C2,1,6,5 all into same planewhile keeping C3,4 unchanged

Chair 1

1

4

In the twist-boat form, the two flagpolehydrogens are "offset" so they do notdirectly run into each other as in theboat form.

HH4

651.06

55

energetics of the cyclohexane interconversion process

1.5 kcal/mol

boat

Chair 1

Half-chair 1

Twist boat 1

Energy

10.1Kcal/mol

3.8 Kcal/mol

Chair 2

Half-chair 2

Reaction co-ordinate

10.1Kcal/molTwist boat 2

Substituted Cyclohexanes a) Methylcyclohexane

H

H

H

H

H

H

H

H

HH

H

H

H

H

HaxHax

Hax

HaxHax

Hax

Heq

HeqHeq

HeqCH3

HeqHax Hax

Heq Heq

HaxHax

Heq CH3

Hax

Hax

4

2 1 64

2

1

2

3

4

6

5

5

1

3

6

651.06

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interconversion of equatorial and axial methylcyclohexane

HaxHax

Hax

HaxHax

Hax

Heq

HeqHeq

HeqCH3

Heq

HHH

HH

HH

CH3

H

H

H

Hax Hax

Heq Heq

HaxHax

Heq CH3

Hax

HaxCH3

H

H

H

H

HH

H H

H

CH3

CH2

H

H

HH

H

62 1

The axial methyl group is in a gauchebutane conformation with the two axialprotons on C-1 and C-3; a total of (1.8 Kcal/mol) destabilization.

The equatorial methyl group is inan anti-butane conformation;no destabilizing interactions.

4

2 1 6

Chair 1

6

5

4

3

1

25

6

43

21

Chair 2

Newmanprojection of gauche butane;(0.9 Kcal/mol)destabilization.

H

The amount of energy necessary to convert from an equatorial form to an axial form is called the A-value for a given substituent. review: Topics in Stereochem., 1, 199?

Typical “A” Values For Monosubstituted Cyclohexanes

(Kcal / mol) (Kcal / mol)

CH3 1.80C2H5 1.90

n-C3H7 2.10i-C3H7 2.10

t-C4H9 5.60

C6H5 3.10

F 0.25Cl, Br, I 0.50

OH 0.70OCH3 0.70

NH2 1.80NR2 2.10

CO2H 1.20CN 0.20

651.06

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b) trans-1,2-dimethylcyclohexane

HH

H

HHH

H

HH

HCH3

CH3

CH3

HH

HH

HH

CH3

H

H

H

H H

H CH3

HH

H CH3

H

H CH3

H

H

CH3

H

HH

H H

H

Chair 2

12

34

6

5 2

1

3

4

5

6

Chair 1

612

4

The diequatorial dimethyl cyclohexanehas one gauche butane type interaction...this results in a destabilization of thediequatorial isomer by 0.9 Kcal/mol.

The two axial methyl groups(on C5,6) are each in a gauchebutane conformationwith two axial protonson C-1 and C-3, and C-2 and C-4respectively; this results in a total of four destabilizations,each worth 0.9 Kcal/mol...Total = 3.6 Kcal/mol.

12 6

The difference in energy between the two forms favors the diequatorial conformer by 2.7 Kcal/mol, this meansthat this form will represent 99% of the equlibrium mixture.

>99%<1%

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c) cis-1,2-dimethylcyclohexane

HH

H

HCH3

H

H

HH

H CH3

H

HH

H

HH

HH

CH3

H

H

H

H CH3

H H

HH

H CH3

H

H CH3

H

H

H

CH3

HH

H H

H

CH3

Each of these isomers will be present in equlibrium in equal amounts, (50% : 50%) since they are of equal energy.

62 1

The monoaxial, monoequatorialdimethylcyclohexane has threegauche butane type interactions;this results in a destabilization of this isomer by a total of 2.7 Kcal/mole.

4

2 1 6

Chair 1

6

5

43

1

25

6

43

21

Chair 2

Same for this form.

d) cis-1,3-dimethylcyclohexane

HH

H

HHH

H

HCH3

H CH3

H

HHH

HH

CH3H

CH3

H

H

H

CH3

H

H

H

H

HH

H CH3

H

Chair 2 has two gauche butane interactions (0.9 kcal/mole each; dotted arrows), in addition to the 3.7 Kcal/mol (solid arrows) for a total of 5.5 Kcal/mole!

Chair 2Chair 1

12 6

1,3-diaxial CH3-CH3 interaction(3.7 Kcal/mol destabilization)

Chair 1 has no destabilizingsteric interactions; the two equatorial methyl groups areboth anti-butane type.

651.06

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e) Various mono-substituted cyclohexanes

R1

R2 R3Ha

H

H

H

H

Hc

H

H

H

Hb

CR1R2R3

CR1R2R3

Ha

Hb Hc

R1

R2 R3

Ha(eq)

HH

H H

H

Ha(eq)

HdHe

equatorial

= H coming out of page

= H going into page

axial

dot ! Hd dot ! He

Destabilizing Interactions

R1 R2 R3 Equatorial Axial Energy Diff. (kcal/mol)

H H H none (2) g.b. 1.8 Me H H (2) g.b. (2) 1,3-diax. 5.6 H Me H (1) g.b. (3) g.b. 1.8 H H Me (1) g.b. (3) g.b. 1.8

Me Me H (3) g.b. (1) g.b. plus (2) 1,3-diax.

5.6

H Me Me (2) g.b. (4) g.b. 1.8 Me H Me (3) g.b. (1) g.b. plus

(2) 1,3-diax. 5.6

Me Me Me (4) g.b. (2) g.b. plus (2) 1,3-diax.

5.6

f) 6-member ring heterocycles

H

OO O

O

CH3

CH3CH3

CH3 H

H3C

H

H

H3C CH3

CH3

favored ΔGo ≈ -2 kcal/mol Why?

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g) Other rings 5:

HH

H

HH

H

H

H

H

H

H

H

“envelope” “half-chair” (2 of them) 8:

HH

H

H

“boat-chair” “chair-chair” or “crown” 10:

HH

HH

“boat-chair-boat”

cyclohexene:H

H

H

H

H

HH

H

H

H

H

H

H

HH

H

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h) Bicyclics decalin:

H

Htrans

H

H

H

H

cis

Ha

Hb

Hb

Ha

ring-flip

H

H H

H

(3) 1,6-interactions = 3 ( 0.87 kcal/mol ) = 2.61 kcal/mol methyldecalin:

CH3 CH3

HH

vs

CH3 HH

HH

H

CH3H

H

VS

4 gauche 5 gauche ΔE = 0.9 kcal/mol

651.06

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Stereochemistry and Chemical Reactions

Increasingly important topic: the FDA has mandated that all new drugs be sold as single

enantiomers! Much effort is now put in to the development of enantioselective reactions

and asymmetric catalysis.

A) Achiral compounds.

Achiral compounds react with achiral reagents to produce achiral products.

1) Addition of an achiral reagent to an achiral substrate

a) bromination of an achiral olefin

Formation of bromonium ion intermediate from either face of the

olefin generates the same symmetrical (achiral) species

b) osmylation of an achiral olefin

C

CCH3

CH3

CH3 CH3

CH3

CH3

C

C

CH3 CH3

CH3

OHOH

CH3CH3

HOOH

Syn addn OsO4below olefin.

Syn addn OsO4above olefin.

1) OsO4

2) NaHSO3

CH3

Achiral and identical

achiral

achiral

CH3

C CH2

CH3

CH3

C CH2

CH3

CH3

C

CH3

CH2Br

Br

CH3

C

CH3

Br

CH2Br

Br+

CH3

C CH2

CH3

Br+

Br-

Br2

Br-

achiral

achiral

Identical Achiral and identical

Br-

Br-

651.06

63

B) Prochiral compounds.

Prochiral compounds are an important subclass of achiral compounds (those

containing no preexisting chiral centers). Prochiral materials bear at least one sp2

atom which becomes a stereogenic center in the course of a chemical reaction.

Prochiral compounds react with achiral reagents to produce racemic products

(enantiomers have exactly equal free energy and therefore will be formed in equal

amounts when produced from achiral reagents). Optical activity never arises

spontaneously in the reactions of prochiral compounds.

c) bromination of a prochiral olefin

d) osmylation of a symmetrical trans-olefin

C

CH

CH3

CH3 H

H

CH3

C

C

H CH3

CH3

OHOHH CH3

CH3H

OH

OH

CH3H

HOOH

Anti addition (to give the meso compound from a symmetrical trans-olefin) is not observed since OsO4 adds via a concerted syn addition mechanism!

Syn addn OsO4below olefin.

Syn addn OsO4above olefin.

50% S,S

50% R,R

These enantiomers will be produced in equal amounts since OsO4 is an achiral reagent and access to either face of the olefin is equally likely.

1) OsO4

2) NaHSO3

Anti addn

meso

H

CH3

C CH2

H Br2

CH3

C CH2

HBr+

CH3

C CH2

H

Br+

Br-

Br-

Br-

Br-

H

CCH3

CH2Br

Br

HC

CH3

Br

CH2Br

S

R

or

50%

50%

Formation of bromonium ion intermediate is equally likely from either face of the olefin.

The two enantiomers are produced in exactly a 50:50 ratio

prochiral

Prochiral center(becomes a chiral center in the product)

651.06

64

C) Chiral compounds.

1) Pure enantiomers

a) bromination of a single enantiomer of a prochiral olefin

When reactions can produce a mixture of diastereomers, the products will always be

formed at different rates; thereby producing unequal amounts of the diastereomers. The

ratio of the diastereomers can be either almost 50/50 or may range up to >99.9999 to

.0001 but, in principle, one expects that diastereomers should be formed in differing

amounts since they have different free energies.

C CH2

H

CH3

Cl

HBr2

(S)

C CH2

HBr+

C

Cl

CH3

H

C

C CH2

H

Br+

Cl

CH3

H

Br-

Br-

Br-

Br-

(S)

(S)

(R)

(S)

H

C

Br

CH2BrC

Cl

CH3

H

HC

CH2Br

BrC

Cl

CH3H

Formation of bromonium ion intermediate is preferred from the top face (steric effect).

prochiral center

This stereogenic center remains the same in starting material and product.

optically active(S,R) diastereomerMajor product

optically active(S,S) diastereomerMinor product

Major

Minor

Symchiralsingle enantiomer(optically active)

The two transition states have different energies; therefore the two diastereomeric products will be formed in unequal amounts.

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Stereospecificity: The product (or mixture of products) from the reaction of two (or

more) isomeric starting materials under the same reaction conditions are different.

Br2

Br

Br-

Br

Br

Br

Br

Br

+ ++ erythro

Br2

Br

Br-

Br

BrBr

BrBr

+ ++ threo

Stereoselectivity: given a particular starting material and a particular set of reaction

conditions, one of the possible diastereomers / enantiomers is formed in excess.

H

O

MeMgBr

OH

OH

tBuOOH

Ti(OiPr)4

CO2Et

CO2Et

HO

HO

OH

O

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2) Racemic mixtures

When the starting material of a chemical reaction is a racemic mixture (a 50:50

mixture of one enantiomer and its mirror image) the creation of a new chiral center again

results in the formation of diastereomers. However in this case, each of the diastereomers

is accompanied by equal amounts of its mirror image so a racemic mixture of

diastereomeric products is formed.

a) bromination of a racemic prochiral olefin

HC

CH2Br

BrC

CH3

ClH

HC

Br

CH2BrC

Cl

CH3

H

H

C

Br

CH2BrC

CH3

ClH

H

C

CH2Br

BrC

Cl

CH3H

(S)

(S)

(R)

(R)

(R)

(S)

(S)

(R)

Br-

Br-

Br-

Br-

C CH2

HBr+

C

Cl

CH3H

C CH2

HBr+

C

CH3

ClH

C

C CH2

H

Br+

CH3

ClH

C

C CH2

H

Br+

Cl

CH3

H

Br2

Br2

C CH2

H

CH3

Cl

H

C CH2

H

Cl

CH3

H

(S)

(R)

(S,R) stereisomerMajor product

(S,S) stereisomerMinor product

Major

Minor

(R,R) stereisomerMinor product

(R,S) stereisomerMajor product

Major

Minor

50:50 R:S Enantiomeric mixture

en

an

tiom

ers

ena

ntio

me

rs

The (S,R/R,S) racemic stereoisomers are diastereomeric to the (R,R/S,S) racemic stereoisomers.

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3) Resolutions of racemic mixtures.

An analogous situation occurs when we consider the reaction of enantiomers with

a chiral reagent. This also results in the formation of a pair of diastereomers; once again,

since diastereomers have different energies, they should be formed in unequal amounts.

This allows us to perform resolutions (chemical separations of enantiomers).

a racemic dl pair

(1:1 mixture

of enantiomers)

Single enantiomer(0.5 equivalent)

Classical resolution:

Single enantiomer(1.0 equivalent)

Kinetic resolution:

R,SR*

R,R*

S,R*

slow

fast

Diastereomers

Consider the limiting case where the slow reaction is about 100 times slower than the fastreaction, and we use only 1/2 the stoichiometric quantity of our optically active reagent R*;this will provide the following mixture:

(almost none formed ...ca. 0.5% yield)

fast

slow

S,R*

R,R*

R*R,S

(50% formed) + 50% recovered R enantiomer

If this reaction is run until the total amount of the

slow-reacting component has been completely consumed,

it will produce a 50:50 mixture of two diastereomers which

can be separated. If we then perform chemistry on the

diastereomers to regenerate the two component parts, we

would have achieved a classical resolution by forming

(and then cleaving) the diastereomeric derivatives.

Easily separated; each in essentially opticallypure form.

a racemic dl pair

(1:1 mixture

of enantiomers)

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D) Asymmetric induction.

Reaction of achiral compounds with optically active chiral reagents allows the

stereogenic center of the reagent to take an active part in the creation of a new

stereogenic center on the substrate (a diastereomeric process). To the extent that these

two reaction pathways differ in energy, absolute stereochemistry will be induced in the

product; a process referred to as asymmetric induction. We measure the effectiveness

of such a process in terms of enantiomeric excess (ee).

t-BuC

O

CH3

Prochiral ketone

B

Cl

H

MeH

O

t-Bu

R

Me

B

Cl

Me

H O

t-Bu

R

MeH

(R) Center created at *'d stereogenic atom

B

Cl

H

MeH

O

Me

R

t-Bu

+

*

B

Cl

Me

H O

Me

R

t-BuH+

*

Pro-R transition state

Pro-S transition state

Severeinteraction

Moderateinteraction

prochiral center

(S) Center created at *'d stereogenic atomMe

Me

B

Me

Me

Me Me

Me

Cl

The optically active borane is unsymmetrical. There are two different orientations (transition states) from which the hydrogen from the borane can be delivered to the carbonyl group of the ketone. The (Pro-S) transition state has smaller through-space interactions between the methyl group on the borane and the methyl group of the ketone and is therefore preferred.

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Stereochemistry of Reactions (cont.'d)) 1) Cram’s Rule

To explain the selectivity seen in nucleophilic addition to carbonyls

O

NaBH4 +

OH OH

Minor MAJOR

Cram proposed the following rule (where S, M, L denote the size of the

substituent)

JACS 1952, 74, 5828

JACS 1959, 81, 2748

L

R

O

L

R

L

R

S SSHO Nu

M M M

OHNu

L

M S

S

L

MOH

RNu

O

R

Nu NuS

L

MOH

NuR

minor major

1 : 1.5 - 4

According to Cram, the nucleophile should attack from the side of the

smallest substituent.

-assumes a reactive conformer when L eclipses R

-problem: when M = Cl the wrong product is predicted

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2) Karabatsos model

O

R

Nu

LS

M

-assumes a reactant-like transition state

-Nucleophile approaches from side of S.

-model breaks down when S ≠ H

JACS 1965, 87, 1367

JACS 1969, 91, 1124, 3572 & 3577

3) Felkin-Ahn model

M

S

L

R

O Nuc

S

M

L

R

O

vs

A B

TL 1968, 2199

-observation

previous models suffer from torsional strain

-assumptions:

a) reactant-like transition state

b) incoming nucleophile avoids L

c) incoming nucleophile will approach anti to most electroneg. atom

Which to use?

a) as M or R increase in size, B is favored over A

b) if an electronegative atom (-O, -N, -X) is present, make it L and

make the larger of the two remaining substituents M.

c) does not work well for cyclic systems

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OLi

tBu

+

O

H

tBu

OOH

tBu

OOH

tBu

O

tBu

OOH OH

A (syn / Cram) C (anti / Cram)

B (syn / anti-Cram) D (anti / anti-Cram)

+

+

86% 0%

14% 0%

syn / anti > 98 : 2

Cram / anti-Cram 6 : 1

4) Cieplak Hypothesis

O CH3

OH

OH

CH3+MeLi

MAJOR minor

Cieplak proposed “that the carbonyl group has undergone extensive pyramidalization in

the transition state, and the outcome is primarily a consequence of interactions between

the vicinal occupied σ orbital and σ∗ orbital of the incipient bond between the nucleophile

and the carbonyl group.”

Eliel & Wilen, Stereochemistry of Organic Compounds, Wiley & Sons: NY, 1994.

O

Nu

FilledVacant !"

vsO

Nu

Filled

Vacant !"

axial approach equatorial approach

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O

XX X

+NaBH4

i-PrOH

HO OH

E Z

X E / Z

Cl 59:41

p-Cl-C6H5 60:40

C6H5 58:42

p-HO-C6H5 44:56

p-H2N-C6H5 34:66

FF F

+

O O

RCO3H

H H

66 : 34

see: JACS 1981, 103, 4540

JACS 1989, 111, 8447

JACS 1986, 108, 1598

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5) Bürgi - Dunitz Angle

Angle of nucleophilic attack to an sp2 hybridized carbon should be ~110o!

O

Nuc ~110o

This was proved by the following crystallographic data

N

O

O

O

O

O

N(CH3)2

O

PhPh

CH3

N

O

O

OO O

O

O

N

OH

O

O

O

OO

O

O

O

O

N

Methadone

Cryptopine

ProtopineRetusamine

Clivorine

C O

N

CH3

Compound C=O Length (Å) N…C Distance (Å) N-C-O Angle

methadone 1.214 2.910 105.0

cryptopine 1.209 2.581 102.2

protopine 1.218 2.555 101.6

clivorine 1.258 1.993 110.2

retusamine 1.38 1.64 110.9

N-brosylmitomycin A 1.37 1.49 113.7

JACS 1973, 95, 5065 JACS 1974, 96, 1956

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NH

O

O

Ph

Ph NaBH4 NH

O

Ph

Ph

OH

Why?

6) Baldwin’s Rules (J. Chem. Soc. Chem. Comm. 1976, 734)

X Y

Exo

XY

X Y

Endo

X Y

a) Tetrahedral systems

1) 3 to 7-Exo-Tet are all favored processes with many literature precedents

2) 5 to 6-Endo-Tet are disfavored

YX

!! = 180"

X Y

!

X Y X YX

YX Y

X

Y

X

Y

X

Y

3-Exo-Tet 4-Exo-Tet

5-Exo-Tet

6-Exo-Tet

7-Exo-Tet

5-Endo-Tet 6-Endo-Tet

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b) Trigonal systems

1) 3 to 7-Exo-Trig are all favored processes with many literature precedents

2) 3 to 5-Endo-Trig are disfavored, 6 to 7-Endo-Trig are favored

Y

X

!X

Y

!! = 109"

X YX Y

X

Y X Y

X

Y

X

Y

XY3-Exo-Trig 4-Exo-Trig

5-Exo-Trig6-Exo-Trig

7-Exo-Trig

5-Endo-Trig 6-Endo-Trig

XY X Y

XY

3-Endo-Trig 4-Endo-Trig7-Endo-Trig

c) Digonal Systems

1) 3 to 4-Exo-Dig are disfavored processes, 5 to 7-Exo-Dig are favored

2) 3 to 7-Endo-Dig are favored processes

! " 120#X

Y

!

!

!

!

X

Y

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XY

XY

X

YXY

X

Y

XY

X

Y

X

Y

X YX

Y

3-Exo-Dig 4-Exo-Dig5-Exo-Dig 6-Exo-Dig

7-Exo-Dig

5-Endo-Dig 6-Endo-Dig3-Endo-Dig4-Endo-Dig 7-Endo-Dig

ex.

MeO

OHO

O

O

O

CO2Me

5-Exo-Trig

5-Endo-Trig

7) Anomeric Effect

A polar group on a carbon α to a heteroatom prefers the axial position. One set of lone pair electrons on the polar atom connected to the carbon atom can be stabilized by overlapping with an antibonding orbital of the bond between the carbon and the other polar atom.

Y Y

X

vs X

!"

!" X= electronegative atom

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OHOHO OH

OHOH O

HOHO

OHOH

OH

• Kinetic anomeric effect:

O ClAg+

OMeOH

O OMeO

OMe

8) Stereoelectronic Control

O

LDA

OLi

EE

OO

E

+

cis trans

45 : 55

look at the transition state:

OLi

E

E

(cis)

(trans)

cis

trans

E

O

O

E

cis

trans

boat-like

chair-like

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78

O

R

O

R

O O

R

CH3CH3

R

+base CH3I

trans cis

R

H 2 1

CD3 2 1

CO2R 4 1

CO2R

baseH

HOM

OR

E (ax.)

E (eq.)

axial

equatorial

E

CO2R

CO2R

E

minor

MAJOR

(5-7:1)

see: JACS 1956, 78, 6629

9) Macrocyclic Stereocontrol

O

O

1) LDA

2) MeI

O

O

O

O

+

50 : 1

Tetrahedron 1981, 37, 3981

works for rings ≥ 9 members

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O

OH E approaches from exterior of the ring

See, for ex. JACS 1984, 106, 1148

10) Acyclic Stereocontrol

The stereochemistry of the molecule near the reaction site determines /

influences the stereochemistry of the reaction product.

R1 CO2R

2

OHLDA Li

OO

R1

H

HOR

2

N

O OLi

R1

OR2

Li

E

R1 CO2R

2

OH

E

OH

tBuOOH, VO(acac)2

CH2Cl2, 0oC

OH OHOO

+

95 : 5

for a general review: Tetrahedron 1980, 36, 3

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80

Example – Diastereoselective reduction of β-hydroxyketones:

OH O

NaBH4

OH OH

OH OZn(BH4)2

OH

OH ONH4

+ -BH(OAc)3

OH OH

OH OZn

O

H-BH4

O

B

O

H

OAc

OAc

OHOH

HOH

OH

H