Stereochemistry...1 Introduction, definitions and reminders 1.4 Chirality An object or a system is...
Transcript of 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
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0 Table of contents
1
2
3
4
Introduction, definitions and reminders
Preparation of optically active molecules
Diastereoselective reactions
Enantioselective reactions
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0 Table of contents
1
2
3
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Introduction, definitions and reminders
Preparation of optically active molecules
Diastereoselective reactions
Enantioselective reactions
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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
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.1 Frontier Molecular Orbitals
sp3 sp2 sp
Resulting geometry
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.1 Frontier Molecular Orbitalselectrophilic trapping
ACIE 2002, 717 (Basu)
ACIE 2018, 5516 (Knochel)
retentioninversion
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1 Introduction, definitions and reminders
1.2 Isomerism – reminder
Isomers are structures that possess the same chemical formula
Isomers
same connectivity?
NO YES
Constitutional isomers
Stereoisomers
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.2 IsomerismConformers
Nattaprojection
Sägebockprojection
Newmanprojection
staggeredconformation
eclipsedconformation
E (kcal.mol-1)
j ()00 60 120
3
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
1.2 IsomerismConformers
boatconformation
chairconformation
E (kcal.mol-1)
0
5.5
7
11
twisted-boat
half-chair
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1 Introduction, definitions and reminders
1.2 IsomerismRelevance
chair 1
staggeredeclipsed
chair 2
Important to understand
Felkin-Anh models
Important to understand
Zimmermann-Traxlermodels
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.2 IsomerismEsters – (E) or (Z)?
(E)-conformation (Z)-conformation?
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?
1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
1-butene
E (kcal.mol-1)
0
0.49
1.32
j
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
2-propen-1-ol
E (kcal.mol-1)
0
1.18
2
j
0.37
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
2-methyl-1-butene
E (kcal.mol-1)
0
1.39
2.68
j0.06
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
2-methyl-2-propen-1-ol
E (kcal.mol-1)
0
1.16
2.01
j0.21
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
(Z)-2-pentene
E (kcal.mol-1)
3.88
0.560
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1 Introduction, definitions and reminders
1.2 IsomerismAllylic systems
(Z)-2-buten-1-ol
E (kcal.mol-1)
1.44
0.86
0
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.3 Definitions
Configurationalisomers
are the molecules mirror images?
NO YES
Diasteoisomers Enantiomers
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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.
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1 Introduction, definitions and reminders
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).
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1 Introduction, definitions and reminders
1.4 Chirality
Central chirality
C-centered chirality S-centered chirality
P-centered chiralityM-centered chirality
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1 Introduction, definitions and reminders
1.4 Chirality
Axial chirality
allene chirality
biaryl chirality helical chirality
spirocyclic chirality
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1 Introduction, definitions and reminders
1.4 Chirality
Planar chirality
metallocene chirality papacyclophane chirality
constraint chirality (E)-cyclooctene chirality
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1 Introduction, definitions and reminders
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.
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1 Introduction, definitions and reminders
1.5 Absolute configurationsCIP rules
1. Atomic number
2. Second sphere
3. x+1 sphere
4. Multiple bonds
> > > > > > > > >
> >
> > > > >
> > > > > > >
> >
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1 Introduction, definitions and reminders
1.5 Absolute configurations
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3
1 2
3
1
2 3
1
3 2
2
3 1
2
1 3
(R)
(S)
(S)
(R)
(S)
(R)
Central chirality
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.5 Absolute configurations
(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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.5 Absolute configurationsDiast. without C*
trans-cyclohexaneseries
cis-cyclohexaneseries
trans-cyclobutaneseries
cis-cyclobutaneseries
trans-alkeneseries
cis-alkeneseries
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1 Introduction, definitions and reminders
1.5 Absolute configurationsL and D
D L
! The metal is the stereocenter
achiral D Loptically active
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1 Introduction, definitions and reminders
1.5 Absolute configurationsL and D
D L L
used in asymmetric catalysisused as photocatalyst
Chem. Rev. 2013, 5322 (MacMillan)
Nat. 2014, 100 (Meggers)
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
1.5 Absolute configurationsSpiranes
4 cases
achiral central chirality axial chirality axial chirality
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1 Introduction, definitions and reminders
1.5 Absolute configurationsSpiranes
mirror imagesare identical
achiral
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1 Introduction, definitions and reminders
1.5 Absolute configurationsSpiranes
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)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsSpiranes
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)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsSpiranes
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
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1 Introduction, definitions and reminders
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
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsHelical chirality
ACIE 2015, 5470 (Marinetti)
JOC 2020, 3981 (Mastalerz)
(P) (M)
(P)
(M)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsMetallocene chirality
TL 2015, 1751 (Ogasawara)
(R)(S)
the “old way”
(R) (R)
>R1 R2
(R)
(R)
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
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)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsParacyclophane chirality
achiral
plane of symmetry(meso)
achiral
plane of symmetry(meso)
achiral
plane of symmetry(meso)
achiral
center of symmetry(meso)
homochiral homochiral homochiral
define the pilot atom (S)
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1 Introduction, definitions and reminders
1.5 Absolute configurationsParacyclophane chirality
Dynamic Stereochemistry of Chiral Compounds (C. Wolf) 2008, RSC Publishing
(R)
(S)
(R)
priority pilot atom
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1 Introduction, definitions and reminders
1.5 Absolute configurationsPlanar chirality
(R)
pilot atom
(R)pilot atom
priority(R)
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