stereochemistry...1 introduction, definitions and reminders 1.4 chirality an object or a system is...

by Dr. Dorian Didier

DidierResearchGroupDorian Didier Research Group

[email protected]: F 3.080Lab: F 2.064

Stereochemistry

1

0 Table of contents

1

2

3

4

Introduction, definitions and reminders

Preparation of optically active molecules

Diastereoselective reactions

Enantioselective reactions

by D. Didier (LMU)

2

0 Table of contents

1

2

3

4

Introduction, definitions and reminders

Preparation of optically active molecules

Diastereoselective reactions

Enantioselective reactions

by D. Didier (LMU)

3

1.1

1.2

1.3

1.4

Frontier Molecular Orbitals

Isomerism

Definitions and reminders

Chirality

1 Introduction, definitions and reminders

1.5 Absolute configurations

by D. Didier (LMU)

4


1.1 Frontier Molecular OrbitalsSteric vs. electronic effects

Steric effects

Electronic effects

Nonbonding interactions (Van der Waals repulsion) betweensubstituents within a molecule or between reacting molecules

The effect of bond and through-space polarization byheteroatom substituents on reaction rates and selectivities

Example: 1,4-addition

Electronic effect:coordination

Steric effect:repulsion

Tet. 2000, 7715 (Yakura)

by D. Didier (LMU)

5


1.1 Frontier Molecular OrbitalsStereoelectronic effects

Stereoelectroniceffects

Geometrical constraints placed upon ground and transition states by orbital overlap considerations

DG° = +0.6 kcal.mol-1

DG° = -0.6 kcal.mol-1

Anomeric effect

nO

s*(C-O)

(filled sp3)

by D. Didier (LMU)

6


1.1 Frontier Molecular Orbitals

sp3

1 x s + 3 x p

tetrahedral

sp3

sp3

sp3

sp3

s p p p

sp3 sp3 sp3sp3

sp2

1 x s + 2 x p

planar

p

sp2

sp2

sp2

s p p p

sp2 sp2 psp2

sp1

1 x s + 1 x p

linear

or sp

p

s p p p

sp sp pp

psp sp

Hybridization

by D. Didier (LMU)

7


1.1 Frontier Molecular Orbitals

sp3 sp2 sp

Resulting geometry

by D. Didier (LMU)

8


1.1 Frontier Molecular OrbitalsOrbital orientation

s bonds p bonds

s

s*

p

p*

bonding

antibonding

staggeredconformation

eclipsedconformation

sC-H s*C-H sC-H

s*C-H

HOMO LUMO HOMO

LUMO

Nat. 2001, 539 (Weinhold)

by D. Didier (LMU)

9


1.1 Frontier Molecular Orbitalsstudy case: N2F2

HOMOLUMO

HOMO

LUMO

nN nN

s*N-F

s*N-F

s*N-F

nN

s*N-F

nN

HOMO-LUMO delocalization is stronger

in the cis isomer dueto better orbital overlap

Lone pair delocalization appears to override

electron-electron anddipole-dipole repulsion in the stabilization of

the cis isomer

the cis isomer is favored by 3 kcal/ mol at 25 °C

by D. Didier (LMU)

10


1.1 Frontier Molecular OrbitalsSN2

The Nu–C–X bonding interaction is that of a 3-center, 4-electron bond (3c4e).The frontier orbitals which are involved are the nonbonding orbital from Nu as well as σC–X and σ∗C–X

3c4e model

E

s*C-X

nN

s C-X

Inversion Retention

nN

HOMO LUMO

s*C-XHOMO

LUMO

Constructive overlap between Nu & σ*C–X

Overlap from this geometry results in no

net bonding interaction

by D. Didier (LMU)

11


1.1 Frontier Molecular OrbitalsE2

The interaction between s C-H and s*C-X leads to a conformation with H and X being trans-antiperiplanar

synperiplanar antiperiplanar

s*C-Xs C-H

HOMO LUMO

s*C-Xs C-H

HOMO LUMO

by D. Didier (LMU)

12


1.1 Frontier Molecular Orbitalselectrophilic trapping

ACIE 2002, 717 (Basu)

ACIE 2018, 5516 (Knochel)

retentioninversion

by D. Didier (LMU)

13


1.2 Isomerism – reminder

Isomers are structures that possess the same chemical formula

Isomers

same connectivity?

NO YES

Constitutional isomers

Stereoisomers

by D. Didier (LMU)

14


1.2 Isomerism

Form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space

Stereoisomerism

Stereoisomers

ConformersConfigurational

isomers

Throughbond rotation

Throughbond cleavage

by D. Didier (LMU)

15


1.2 IsomerismConformers

Nattaprojection

Sägebockprojection

Newmanprojection

staggeredconformation

eclipsedconformation

E (kcal.mol-1)

j ()00 60 120

3

by D. Didier (LMU)

16


1.2 Isomerismn-butane

180°

E(kcal.mol-1)

120° 60° 0°

3.6

0

0.9

4.5

anti-conformation

gauche-conformation

dihedral angle(H3C-C-C-CH3)

by D. Didier (LMU)

17


1.2 IsomerismConformers

boatconformation

chairconformation

E (kcal.mol-1)

0

5.5

7

11

twisted-boat

half-chair

by D. Didier (LMU)

18


1.2 IsomerismRelevance

chair 1

staggeredeclipsed

chair 2

Important to understand

Felkin-Anh models

Important to understand

Zimmermann-Traxlermodels

by D. Didier (LMU)

19


1.2 Isomerismhydrazine N2H4

anti-conformation

gauche-conformation

s*N-H

nN

s N-H

HOMO

LUMO

HOMO

Hydrazine can exist in either gauche or anti

conformations (relative to lone pairs)

The nonbonding lone pair orbitals in the gauche isomer should be destabilizing due to electron-electron repulsion.

s*N-H

nNs*N-H

s N-H

E

by D. Didier (LMU)

20


1.2 Isomerismhydrogen peroxide H2O2

H2O2 can exist in either gauche or anti

conformations (relative to H atoms)

anti-conformation

gauche-conformation

Major stabilizing interaction is the delocalization of O-lone pairs into the C–H antibonding orbitals. There are no such stabilizing interactions in the anti-conformation

while there are 2 in the gauche conformation.

s*O-H

nO

E

HOMO

LUMO

nO

s*O-H

by D. Didier (LMU)

21


1.2 IsomerismEsters – (E) or (Z)?

(E)-conformation (Z)-conformation?

by D. Didier (LMU)

22

?


1.2 IsomerismEsters – (E) or (Z)?

(E)-conformation (Z)-conformation

E (kcal.mol-1)

2-3

10-12

nO – s*C-O

overlapnO – s*C-R

1

overlap

σ*C–O is a better acceptor than σ*C-R1 (where R is a carbon substituent).

Therefore the (E) conformation is stabilized by this interaction.

s*C-O

nO

LUMO

HOMO

s*C-R1

LUMO

nO

HOMO

by D. Didier (LMU)

23


1.2 IsomerismDestabilizing effects

staggeredeclipsed

JACS 1985, 5035 (Wiberg)

JACS 1987, 6591 (Houk)

repulsive interaction betweenπC-C & σC-H

E (kcal.mol-1)

2

0

πC-CπC-C

σC-H

σC-H

σC-H

σC-H

σC-HσC-H

by D. Didier (LMU)

24


1.2 IsomerismAllylic systems

1-butene

E (kcal.mol-1)

0

0.49

1.32

j

by D. Didier (LMU)

25



2-propen-1-ol

E (kcal.mol-1)

0

1.18

2

j

0.37

by D. Didier (LMU)

26



2-methyl-1-butene

E (kcal.mol-1)

0

1.39

2.68

j0.06

by D. Didier (LMU)

27



2-methyl-2-propen-1-ol

E (kcal.mol-1)

0

1.16

2.01

j0.21

by D. Didier (LMU)

28



(Z)-2-pentene

E (kcal.mol-1)

3.88

0.560

by D. Didier (LMU)

29



(Z)-2-buten-1-ol

E (kcal.mol-1)

1.44

0.86

0

by D. Didier (LMU)

30


1.3 Definitions

Asymmetric synthesis

Stereocenteror stereogenic center

Chiral molecule

Preparation of chiral molecules

Point in a molecule bearing different substituents,such that interchanging any two of themleads to a stereoisomer

Molecule that possesses a non-superposablemirror image

by D. Didier (LMU)

31


1.3 Definitions

Configurationalisomers

are the molecules mirror images?

NO YES

Diasteoisomers Enantiomers

by D. Didier (LMU)

32


1.3 Definitions

Racemic mixture

Enantioenriched mixture

Enantiopure compound

Mixture containing equal quantities of both enantiomers

Mixture containing only one enantiomer

Mixture containing different quantities of two enantiomers

by D. Didier (LMU)

33


1.3 Definitions

Enantiomeric excess(ee)

Value representing the excess of one enantiomer over the second one

ee =n[(R)-A] – n[(S)-A]

n[(R)-A] + n[(S)-A]

100 ·

er =n[(R)-A]

n[(S)-A]

Diastereomeric ratio(dr)

enantiomeric ratio

62% ee

er = 81:19

dr = 93:7 dr = 95:3:1:1

by D. Didier (LMU)

34


1.3 Definitions

Stereoselectivite reactionA reaction that selectively leads to one or a series of stereoisomers, disfavoring the other ones. This can be a result of competitive interactions.

Stereospecific reaction

A reaction in which the stereochemical outcome is guided by the mechanism. It requires a particular (specific) arrangement of the atoms (or functional groups) for the reaction to proceed.

!

Stereospecific does not mean that only one stereoisomer is obtained. If a reaction gives only one diastereoisomer, it is fully diastereoselective. However, the ratio of stereoisomer in the product after a stereospecific transformation is identical to the ratio of stereoisomer in the substrate.

by D. Didier (LMU)

35


1.4 Chirality

An object or a system is chiral if it is distinguishable from its mirror image,and cannot be superposed onto it.

Two mirror images of a chiral molecule are called enantiomers or optical isomers. Pairs of enantiomers are often designated as "right-", "left-handed“.

If mirror image molecules are superimposable, they are "achiral".

As polarized light passes through a chiral molecule, the plane of polarization, when viewed along the axis toward the source, will be rotated clockwise (to the right) or anticlockwise (to the

left). A right handed rotation is dextrorotary (d); that to the left is levorotary (l).

by D. Didier (LMU)

36


1.4 Chirality

Central chirality

C-centered chirality S-centered chirality

P-centered chiralityM-centered chirality

by D. Didier (LMU)

37


1.4 Chirality

Axial chirality

allene chirality

biaryl chirality helical chirality

spirocyclic chirality

by D. Didier (LMU)

38


1.4 Chirality

Planar chirality

metallocene chirality papacyclophane chirality

constraint chirality (E)-cyclooctene chirality

by D. Didier (LMU)

39


1.5 Absolute configurationsCIP rules

Cahn-Ingold-Prelog rules are used to determine the priorities of substituents in order to assign R, S, E and Z configurations

1. The groups directly attached to the stereocenter (first sphere) are sorted following their atomic numbers. The group having the atom of higher atomic number receives higher priority.

2. If one or more atoms identical in the first sphere, look at the second sphere.

3. If one or more atoms identical in the sphere x, look at the sphere x+1.

4. Double bonds (C=X) count as two single C-X bonds. Triple bonds (C X) count as three single C-X bonds.

by D. Didier (LMU)

40


1.5 Absolute configurationsCIP rules

1. Atomic number

2. Second sphere

3. x+1 sphere

4. Multiple bonds

> > > > > > > > >

> >

> > > > >

> > > > > > >

> >

by D. Didier (LMU)

41



12

3

1 2

3

1

2 3

1

3 2

2

3 1

2

1 3

(R)

(S)

(S)

(R)

(S)

(R)

Central chirality

by D. Didier (LMU)

42


1.5 Absolute configurationsFischer representation

1.

The longest chain isplaced vertically

2.

The most oxidized group is placed

on top

3.

Side chains point toward the viewer

D-Glucose

L-Fructose

Fisher projectionsD

L

by D. Didier (LMU)

43



(R) 1

2

3

1

2

3

(S)

(R) 1

2

3

(R)1

2

3absolute configuration

(2R,3S,4R,5R)

Fischer representation

D-Glucose

by D. Didier (LMU)

44


1.5 Absolute configurationsFischer representation

let the chain fall on the right

Fischer projection

rotate C4-C5 to align OH

Haworth projection

D-Glucose

a-D-Glucose b-D-Glucose

Chair model

a-D-Glucose b-D-Glucose

cyclization

by D. Didier (LMU)

45


1.5 Absolute configurationsDisubstituted c-hexane

(1R,2R)-2-aminocyclohexan-1-ol

(1R,3R)-3-aminocyclohexan-1-ol

mirror images aresuperimposable

Achiral

stereoisomersnot enantiomers

=diastereoisomers

trans-4-aminocyclohexan-1-ol

cis-4-aminocyclohexan-1-ol

! No stereocenter

by D. Didier (LMU)

46


1.5 Absolute configurationsDiast. without C*

trans-cyclohexaneseries

cis-cyclohexaneseries

trans-cyclobutaneseries

cis-cyclobutaneseries

trans-alkeneseries

cis-alkeneseries

by D. Didier (LMU)

47


1.5 Absolute configurationsL and D

D L

! The metal is the stereocenter

achiral D Loptically active

by D. Didier (LMU)

48


1.5 Absolute configurationsL and D

D L L

used in asymmetric catalysisused as photocatalyst

Chem. Rev. 2013, 5322 (MacMillan)

Nat. 2014, 100 (Meggers)

by D. Didier (LMU)

49


1.5 Absolute configurationsAllenes

Nat. 2018, 240 (Bach)

Org. Chem. Front. 2014, 1210 (Ma)

The assignment of absolute configurationfollows the CIP rules

The front substituents have the priorityover the substituents in the back

1

2

43 12

3

(R)

12

4

3

1

2

43

(R)

(S)

4

by D. Didier (LMU)

50


1.5 Absolute configurationsSpiranes

4 cases

achiral central chirality axial chirality axial chirality

by D. Didier (LMU)

51



mirror imagesare identical

achiral

by D. Didier (LMU)

52



The central carbon atom possesses 4 different substituents.It is therefore treated as a classical stereocenter.

has the lowest priorityhere,

1

2

3

(S)

1

2

3

(R)

1

2

3

(R)

by D. Didier (LMU)

53



The central carbon atom possesses 2 different substituents.It is not a stereocenter. The molecule is axially chiral.

In this case, the priority should be given according to CIP rules.The substituent with the highest priority

should not be placed in the back (behind the plane).

The substituent in the back is given the lowest priority ( ).

3

1

2

(S) (R)

1

3

2

1

3

2

(R)

by D. Didier (LMU)

54



The substituents on both rings are pointing in different directions. The central carbon is not a stereocenter.

The molecule is axially chiral.

The absolute configuration should be assigned as for an allene, where both rings are assimilated to double bonds.

12

4

3

1 2

4

3

1 2

4

3

(R) (S) (S)

simplifiedmodel

by D. Didier (LMU)

55


1.5 Absolute configurationsAlkylydenecycloalkanes

1 2

4

3 1

2

43

(R)(S)

The molecule is axially chiral. The configuration should be determined as for allenes and spiranes.

axially chiral

achiral

assignment of R and S

configurations

assignment of cis and trans

or E and Z

by D. Didier (LMU)

56


1.5 Absolute configurationsBiaryls

The molecule is axially chiral.

CIP rules apply, considering that the substituents in front (on the model) have the priority over the ones in the back.

CEJ 2019, 15694 (Corti)JACS 1993, 3814 (Wulff)

1

2

4

3

(S)-BINAP

1

2

4

3

(R)-VAPOL

1

2

4

3

(S)

by D. Didier (LMU)


1.5 Absolute configurationsHelical chirality

ACIE 2015, 5470 (Marinetti)

JOC 2020, 3981 (Mastalerz)

(P) (M)

(P)

(M)

by D. Didier (LMU)

58


1.5 Absolute configurationsMetallocene chirality

TL 2015, 1751 (Ogasawara)

(R)(S)

the “old way”

(R) (R)

>R1 R2

(R)

(R)

by D. Didier (LMU)

59


1.5 Absolute configurationsMetallocene chirality

current way (IUPAC)1. define the atom of highest precedence

2. assign the priorities following CIP rules

Dynamic Stereochemistry of Chiral Compounds (C. Wolf) 2008, RSC Publishing

2

1

3

1

23

45

2

1

3 3

1

2

(1S) (2R) (4S)

(S)

1

(1S,2R,3R,4S,5S)

by D. Didier (LMU)

60


1.5 Absolute configurationsChirality in p-complexes

(S) (Sp) (Sc)

TL 2015, 1751 (Ogasawara)

2

1

3 2

1

3

2

1

3 3

1

2

(S) (Rp)(Sc)

by D. Didier (LMU)

61


1.5 Absolute configurationsParacyclophane chirality

achiral

plane of symmetry(meso)

achiral


achiral


achiral

center of symmetry(meso)

homochiral homochiral homochiral

define the pilot atom (S)

by D. Didier (LMU)

62


1.5 Absolute configurationsParacyclophane chirality

Dynamic Stereochemistry of Chiral Compounds (C. Wolf) 2008, RSC Publishing

(R)

(S)

(R)

priority pilot atom

by D. Didier (LMU)

63


1.5 Absolute configurationsPlanar chirality

(R)

pilot atom

(R)pilot atom

priority(R)

by D. Didier (LMU)

64

stereochemistry...1 introduction, definitions and reminders 1.4 chirality an object or a system is...

Documents