Advances in molecular
chemistry
Anja Palmans
Ghislaine Vantomme
1
Stereochemistry
Chemistry in three dimensions: the study of the spatial
arrangement of atoms in molecules and the effect of spatial
arrangement on chemical properties
2
Background reading
1. Basic terminology in stereochemistry
R/S. Cahn, C. Ingold, V. Prelog. Angew. Chem. Int. Ed. 1966, 5, 385-415
G.P. Moss Pure & Appl Chem 1996, 68, 2193-2222
2. Advanced Organic Chemistry (March): chapter on stereochemistry
3. Stereochemistry of organic compounds (Eliel/Wilen) Wiley Interscience
• Van’t Hoff’s contributions to stereochemistry: E.W. Meijer, Angew. Chem. Int. Ed. 2001, 40,
3783-3789
• Information on symmetry and point groups:
http://csi.chemie.tu-darmstadt.de/ak/immel/script/redirect.cgi?filename=http://csi.chemie.tudarmstadt.de/ak/immel/tutorials/symmetry/
3
Previous knowledge in stereochemistry
Molecules can be chiral: i.e. their mirror image is non-superimposable
with the original, and therefore they are enantiomerically related
Enantiomers have identical properties unless when placed in a chiral
environment
The absolute configurations of an asymmetric atom is assigned using the
CIP (Cahn Ingold Prelog) system
Chiral, non-racemic molecules are capable of rotation the plane of
plane-polarized light, referred to as optical rotation
Determining absolute configuration
Relating absolute configuration to optical rotation
~100
years
Assigning absolute configuration (CIP)
History of Stereochemistry
Jean-Baptiste Biot (1774-1862)
Polarized light
In 1815, Biot demonstrated that polarized light, when passing through an organic substance, could be rotated clockwise or
counterclockwise, dependent upon the optical axis of the material. Later he found that the polarization direction of light
can also change when passing through (solutions of) organic compounds (turpentine, solutions of sucrose etc).
History of Stereochemistry
Louis Pasteur (1822-1895)
Enantiomorphous crystals
The first in physically separating the 2 enantiomeric forms of sodium ammonium tartrate crystals, which showed an
opposite optical rotation
History of Stereochemistry
Jacobus H. van ‘t Hoff (1852-1911)
1874: proposal of the tetrahedral carbon
Boerhaave museum, Leiden
When the 4 substituents of C are different
One can get 2 different tetrahedra that cannot be superimposed by each other
J. H. van 't Hoff, Archives neerlandaises des sciences exactes et naturelles, 1874, 9, 445 – 454.
History of Stereochemistry
1818-1884
H. Kolbe, “A Sign of the Times”
J. Prakt. Chem., 15, 474 (1877).
“ Not long ago, I expressed the view that the lack
of general education and of thorough training in
chemistry was one of the causes of the
deterioration of chemical research in
Germany…… Will anyone to whom my worries
seem exaggerated please read, if he can, a recent
memoir by a Herr van ‘t Hoff on “The
Arrangements of Atoms in Space”, a document
crammed to the hilt with the outpourings of a
childish fantasy…… This dr. J.H. van ‘t Hoff,
employed at the Veterinary College at Utrecht,
has, so it seems, no taste for accurate chemical
research. He finds it more convenient to mount his
Pegasus (evidently taken from the stables of the
Veterinary College) and to announced how, on his
bold flight to Mount Parnassus, he saw the atoms
arranged in space.”
Hermann Kolbe in 1877
History of Stereochemistry
William Thompson (Lord Kelvin, 1824-1907)
I call any geometrical figure, or group of
points, chiral, and say that it has chirality,
if its image in a plane mirror, ideally
realized, cannot be brought to coincide
with itself.
Baltimore lectures 1884
The word chiral was re-introduced into the
stereochemical language by Mislow (Introduction to
Stereochemistry) and Cahn/Ingold/Prelog (Angew
Chem Int Ed Engl, 1966, 5, 385)
1884: First introduction of the word chirality
9
History of Stereochemistry
Emil Fischer (1852-1919)
Martin A. Rosanoff (1874-1951)
1906: Fischer-Rosanoff convention
(+) rotation
Assigned stereochemical configuration of
all the known sugars and exactly foretold
the possible isomers.
(-) rotation
D-glyceraldehyde = R
L-glyceraldehyde = S
But is it??
History of Stereochemistry
Johannes Martin Bijvoet (1892-1980)
Determination of absolute configurations
(+)-tartaric acid corresponds to R,R-tartaric acid
D-glyceraldehyde (+ rotation) was correctly assigned to the
R-configuration
1951: Anomalous dispersion of X-ray radiation in
tartaric acid – Rb salt gives unequivocal proof of
absolute configuration
Bijvoet, J. M.; Peerdeman, A. F.; Van Bommel, A. J. Nature, 1951,
168 (4268): 271 "Determination of the Absolute Configuration of
Optically Active Compounds by Means of X-Rays”
doi:10.1038/168271a0
History of Stereochemistry
In the early sixties, R. S. Cahn (England), C. K. Ingold (England), and V. Prelog (Switzerland)
introduced the unequivocal and generally applicable (R,S) system.
Cahn, R.S.; Ingold, C.K.; Prelog, V. "Specification of Molecular Chirality".
Angew. Chem. Int. Ed. Engl. 1966, 5 , 385–415.
doi:10.1002/anie.196603851
History of Stereochemistry
Determining absolute configuration
(anomalous XRD)
Relating absolute
configuration to a measurable
property (optical rotation)
Physical property
Assigning absolute
configuration (CIP)
Geometric property
Symmetry
and
Chirality
3D representation of molecules in 2D
Newman projection
Sawhorse projection
Haworth projection
Wedge and dash
Perspective formula
Fischer projection
OH
H 3C
F
3D representation of molecules in 2D
15
3D representation of molecules in 2D
Fischer projection formulas:
Vertical lines represent bonds that project behind the plane of the paper
Horizontal lines represent bonds that project out of the plane of the paper
16
Symmetry elements
symmetry operation:
symmetry elements:
an action that leaves an object looking the same after
the operation has been carried out
rotation / inversion / reflection
line / point / plane
ROTATION: axis of symmetry (symmetrie as) Cn
n = 360°/n
C1: 360° rotation / C3: 120° rotation
REFLECTION: mirror plane (spiegelvlak) σ
17
Symmetry elements
INVERSION: center of inversion (inversiepunt) i
n-FOLD IMPROPER ROTATION: (oneigenlijke rotatieas) Sn
Rotation around 360°/n followed by reflection through a plane
perpendicular to the axis of that rotation
HC
H
H
CH3
σh 3
18
Chirality
Chirality comes from the Greek word χειρ for hand
a molecule is called chiral when it cannot be superimposed
by its mirror image
• all molecules with a mirror plane are achiral
H H
Cl
Cl
H
H
achiral: σ
19
Chirality
Chirality comes from the Greek word χειρ for hand
a molecule is called chiral when it cannot be superimposed
by its mirror image
• all molecules with a mirror plane are achiral
• all molecules with a center of inversion are achiral
OH
HO2C
R
S
CO2H
OH
achiral: i
20
Chirality
Chirality comes from the Greek word χειρ for hand
a molecule is called chiral when it cannot be superimposed
by its mirror image
• all molecules with a mirror plane are achiral
• all molecules with a center of inversion are achiral
all molecules with an Sn axis are achiral (S1 = σ; S2 = i)
Cl
Cl
C C C
S4
Cl
Cl
achiral: S4
21
Definitions
Chirality is the phenomenon in which objects (or molecules) are mirror images
of each other, but they are not identical. They are also called incongruent
Chiral is an adjective that refers to the property of a molecule (or object) to
possess non-superimposable mirror images
Chiral molecules lack σ, i and S symmetry elements
Chiral molecules can have rotational symmetry elements
22
Which molecules are chiral?
O
OH
H3C
H H
O
CH3
OH
H
H
CH3
HO
OH
23
CH3
Which molecules are chiral?
Achiral
Chiral
Chiral
O
OH
H3C
Chiral
H H
O
CH3
chiral
achiral
Chiral
Achiral
OH
H
Chiral
H
CH3
HO
OH
24
CH3
Definitions
Asymmetric molecule: molecules with a complete absence of symmetry (C1)
F
Cl
H
asymmetric center (stereocenter, stereogenic center)
Br
WRONG: asymmetric carbon
Asymmetric center ≠ stereocenter or stereogenic center:
Asymmetric center: switching the position of 2 groups gives the other enantiomer
Stereogenic center: switching the position of 2 groups results in a different
stereoisomer
Cl
H
Cl
H
Cl
H
H
Cl
No asymmetric center
An atom having a spatial arrangement of ligands which is not superimposable on its
mirror image is an asymmetric center
=> All asymmetric centra are stereocentra but not all stereocentra are asymmetric 25
centra
Definitions
Dissymmetric molecule: molecule containing one or more proper rotation axis
C2
O
O
N
Ph
Fe
I I
N
Ph
All asymmetric molecules are chiral but not all chiral molecules are asymmetric
Note: Dissymetric is not equivalent to asymmetric since the molecule may posses Cn axis
The use of this word is discouraged but still frequently encountered in literature reporting on chiral ligands for transitionmetal-based catalysis
26
Definitions
Chirality is often associated with the presence of on (or more) stereogenic centra in molecules. But the presence of
a stereogenic / asymmetric center is not required. One can have other stereogenic elements
Stereogenic elements: stereogenic center, stereogenic axis, stereogenic plane
Interchange of two ligands attached to an atom in such a molecule leads to a different stereoisomer
H
H 3C
C
H
CH3
H 3C
H
C
H
CH3
Stereogenic axis
H
H3 C
C
CH3
H
Axial chirality: chirality in which a molecule posseses an axis around which a set
of ligands is held so that it results in a spatial arrangement which is not
superimposable on its mirror image.
Planar chirality: chirality in which a molecule possesses a chiral plane
A chiral plane is a plane passing through a molecule so located that placement of a substituent group in that plane destroys a
27
perpendicular plane of symmetry
Definitions
Some molecules that have a shape of helix, spiral, ship screw, trefoil knot, moebius ring, are chiral.
These lack symmetry elements σ, S, i
H 3C
CH3
CH3
28
Definitions & nomenclature
Constitution/configuration/conformation
Constitution: denotes number, kind and connectivity of atoms within a molecule (2D)
Configuration: same connectivity, spatial arrangement of atoms in a molecule differs
Conformation: same connectivity, spatial arrangement of atoms differs but only by rotations
constitution
(isomers)
a b c d e
b e
c
a
d
conformation
(stereoisomers)
a
b
b c d
configuration
(stereoisomers)
b
c d
a
e
29
Definitions & nomenclature
Constitutional isomers: same molecular formula but not the same connectivity
between the atoms
OH
Br
H
H
Br
OH
C3H7BrO
HC
H3C
3
Stereoisomers: connectivity between the atoms is the same, but they are arranged
CN
differently in space
F
F
Br
H
Cl
Br
Cl
H
C8H17
C8H17
CN
Configurational isomers: relative position or order of the arrangement of atoms in
space which characterises a particular isomer
enantiomers (mirror image)
diastereomers
Conformational isomers: interconvertible via rotations around single bonds
30
30
Definitions & nomenclature
Atropisomers: optical activity due to an axis of chirality. The conformers can be interconverted by rotation but
the barrier is too high and thus can be isolated as separate chemical species
(conformational isomers with high energy barriers for rotation)
NO2
O2N
From Greek:
a – not
tropos – to turn
31
Definitions & nomenclature
enantiomers
HO
H
O
diastereomers
CH3
H3C
NH2
H 2N
CO2H
OH
OH
HO2C
HO2C
CO2H
OH
OH
CO2H
HO2C
OH
O
OH
OH
HO2C
OH
H
CO2H
OH
OH
OH
HO2C
CO2H
OH
HO2C
CO2H
OH
identical: i
achiral
meso compound
32
Definitions & nomenclature
Cis-trans isomers: cannot be interconverted by rotation (configurational isomers)
conf ormation
H3C
CH3
trans-1,4-dimethylcycohexane
CH3
CH3
conf iguration
CH3
CH3
cis-1,4-dimethylcycohexane
H3C
CH3
H
H
H
H
H3C
CH3
H3C
H
H
H
H
CH3
33
Definitions & nomenclature
https://en.wikipedia.org/wiki/Isomer
34
Definitions & nomenclature
Bruice: Organic Chemistry
Relationships between molecules
what is the relationship between the following pairs of molecules?
NHMe
NHMe
OH
OH
NO2
NO2
HOOC
O2N
O2N
OH
HO2C
CO2H
OH
D
OH
HO2C
H3C
O
O
CH3
CH3
H
COOH
H
HOOC
COOH
D
CH3
CO2H
OH
36
Relationships between molecules
what is the relationship between the following pairs of molecules?
Configurational
isomers
enantiomers
NHMe
Structural or
constitutional
isomers
NHMe
OH
OH
NO2
NO2
HOOC
O2N
O2N
OH
Configurational
isomers
diastereomers
No relation
HO2C
CO2H
OH
D
OH
HO2C
CO2H
OH
H3C
O
O
CH3
CH3
H
COOH
H
HOOC
COOH
D
CH3
Configurational
isomers
enantiomers
Configurational
isomers
diastereomers
37
What’s in a name??
D/L
+/-
R/S
cis/trans
d/l
E/Z
syn/anti
Re/Si
Exo/endo
Λ/∆
P/M
38
Nomenclature
R/S:
describes the absolute configuration of a stereocenter (Cahn-IngoldPrelog)
2 O
1
NH2
HO
H
3
S
C O
=
C O (C)
(O)
C C
=
C C (C)
(C)
C C
=
(C) (C)
C C
(C) (C)
S-carvone
•
•
•
•
Atoms with higher atom number get highest priority, also for isotopes (T>D>H)
If atoms are the same, consider the atoms at distance 2 from the stereocenter and make a list. Each list is
arranged in order of decreasing atomic number. Then the lists are compared atom by atom; at the
earliest difference, the group containing the atom of higher atomic number receives higher priority.
If atoms are still the same, make sub-list of the other atoms bonded to it at distance 3 from the
stereocenter
This process is repeated, each time with atoms one bond farther from the stereocenter
39
Nomenclature
Assigning R/S in Fischer projections
Cl
H 3C
H
=
C 2H 5
Cl
H3C
H
H
H 3C
C 2H 5
1
Cl
1
Cl
3 H 3C
H
=
C 2H 5
Cl
C 2H 5 2
3 H 3C
H
C 2H 5
2
R if lowest priority
group is on a vertical
axis
S!!!
40
Nomenclature
D / L:
derived from the assignment of (+)-glyceraldeyde tentatively assigned
as D-glyceraldehyde by Rosanoff
now only used for L-amino acids and D-sugars
CHO
H
OH
D-glyceraldehyde: R-configuration, (+) rotation
CH2OH
41
Nomenclature
+/-:
rotation of plane polarised light: positive (+) or negative
(-) rotation
in old literature d and l are still used
P/M: helical descriptors
(P from plus, right handed; M from minus, left handed)
∆/ Λ: In organometallic complexes: ∆ (dextrus) and Λ (levus)
are used
Relation between R/S, P/M or ∆/ Λ and +/- must be
determined experimentally
42
Nomenclature
M
P
go down the stairs
check which hand holds the inside handrail
right hand = P helix
α-helix in proteins
M-hexahelicene
P
43
Nomenclature
Distinguishing enantiomers in axially chiral systems
44
Nomenclature
OH
OH
OH
OH
Ra
Sa
OH
OH
P
R
S
S
R
P
Sa and Ra can are sometimes changed
to M and P when helical shapes are
present
45
Nomenclature
∆ versus Λ:
No exam material
Nomenclature
cis/trans
OH
OH
OH
OH
cis-1,4-cyclohexanediol
trans-1,4-cyclohexanediol
OH
HO
H
H
H
OH
OH
H
OH
H
H
both OH occupy positions
at the upper side of the ring
H
H
H
cis-decaline
trans-decaline
H
H
OH
H
H
H
H
OH
HO
H
47
Nomenclature
E/Z
H3C
H
CH3
H3C
H
H
H
CH3
cis
trans
H3C
COOH
H3C
CH3
H
CH3
H
COOH
Z
N
H
N
O
H
E
N
N
O
Z
E
HO
CH3
N
H3C
N N
Ph
CH2CH3
E
E
48
Nomenclature
Re/Si
Prochiral carbonyl
center
A face is labeled re if, when looking at that face, the substituents at the
trigonal atom are arranged in decreasing priority order in a clockwise
order, and si if the priorities decrease in counter-clockwise order.
49
Nomenclature
syn-adducts
Syn/anti addition/adducts
O
O
+
Y
anti = on opposite sides of a reference plane
syn = on the same side of a reference plane
O
OH
O
OH
O
OH
O
OH
base
H
X
anti-adducts
R1
R2
X-Y
R1
syn
R2
X-Y
anti
X
Y
R1
R2
50
Nomenclature
Exo/Endo
endo = isomer with the substituent located closest, or "syn", to the longest bridge.
exo = isomer with the substituent located farthest, or "anti", to the longest bridge.
"longest" and "shortest" refer to the number of atoms that comprise the bridge.
Nomenclature
52
Assigning configurations
OH
OH
(-)-(S)-citronellol
(+)-(R)-citronellol
H 3C
H 2N
H
H
O
L-alanine
S-configuration
HS
H2N
H
L-citronellol
OH
O
L-cysteine
R-configuration
R,R
P,P
trans or E
53
Nomenclature
Stereoselective vs stereospecific synthesis
stereoselective synthesis: the preferential formation of one stereoisomer over
another in a chemical reaction
stereospecific synthesis: Starting materials differing only in their configuration
are converted to stereoisomerically distinct products
-
“Selective” implies that there are factors which favor
one product over the other, while “specific” is usually
a sign that there’s something inherent to the
mechanism that leads to only one product.
54
Nomenclature
Examples of stereospecific reactions:
Et
Nu
Me
TsO
H
SN2
H OTs
Nu
Nu-
S
Br2 addition
H
S
Br
Br2
meso
Br2
+
anti
Br
syn
Br-
Br
Br
racemate
Br
Stereoisomers: connectivity between the atoms is the same, but they are arranged differently in space
Nomenclature
Examples of stereoselective reactions: one product is formed preferentially!!
-
NaBH4
O
+
HO
H
HO
H
80
20
H
H
H
O
OH
O
O
O
R
O
CH3
+
S
OH
Lipase
106
1
56
Optical activity
and
chirality
Optical activity and chirality
Optical activity:
ability to refract and absorb right en left circularly polarised light
to different extents
ORD = optical rotatory dispersion (rotation of plane polarised light)
CD = circular dichroism (preferential absorption of one handedness
in circularly polarised light)
History:
Biot (1774-1862) observed that the polarisation
direction of light could change when passing through
certain solutions
Pasteur (1822-1895) first physically separated the 2
enantiomeric forms of sodium ammonium tartrate
crystals, which showed an opposite optical rotation
58
Optical activity and chirality
B
direction of
propagation
=
+
right CPL
left CPL
E
E = electric field
B = magnetic field
=
+
faster
slower
plane is rotated
Chiral molecules exhibit circular birefringence, which means that a solution of a
chiral substance presents an anisotropic medium through which left circularly
polarised (L-CPL) and right circularly polarised (R-CPL) propagate at different
speeds. Measuring optical rotation as a function of wavelength is termed optical
rotatory dispersion (ORD) spectroscopy
59
Optical activity and chirality
LCPL
RCPL
https://www.jasco-global.com/wp-content/uploads/2019/04/cd1.gif
ORD (optical rotatory dispersion)
specific rotation:
[c] = g/mL, [l] = dm, α = optical rotation
[α]λΤ= α / (cxl)
T = temperature, λ = wavelength
Pure:
[α]λΤ= α / (dxl)
[d] = g/mL
Typically: λ = 589 nm (sodium D line) so: [α]DΤ
• achiral compounds do not show optical activity
• chiral compounds do (when non-racemic) although the optical activity may not be
expressed (cryptochirality)
• sign of rotation depends on λ, temperature, concentration and solvent
COOH
D-malic acid:
(+) in pyridine
(D-appelzuur)
(-) in alcohol
CH2
H
OH
COOH
• optical purity = [α]DΤ (mixture)/ [α]DΤ (pure) = enantiomeric excess (usually)
• % major isomer = (ee+100%)/2
61
ORD (optical rotatory dispersion)
ORD (optical rotatory dispersion)
HO
HO
S
R
D-citronellol
L-citronellol
Compounds
Source
[α]D20
ee
(S)-citronellol
Takasago
-5.3° (neat)
98.4
(R)-citronellol
Aldrich
+5.2° (neat)
100
S-enantiomer
R-enantiomer
63
CD (Circular Dichroism) spectroscopy
preferential absorption of circularly polarised light
∆ε = εL-εR
= difference in molar extinction coefficient for L and R
circularly polarised light
= CD-effect/(32980xcxl) where [c] = mol/L, [l] = cm
CD effect is given by the measurement in millidegrees!!
gvalue = ∆ε/ε (between +2 and -2) (=(AL-AR)/0.5*(AL+AR)
∆ε = molar circular dichroism
ε = extinction coefficient
Circular dichroism only occurs at wavelengths of light that can be absorbed by a
chiral molecule. A chiral chromophore may absorb 90% of R-CPL and 88% of LCPL. This effect is called circular dichroism and is the difference in absorption of
L-CPL and R-CPL.
https://chem.libretexts.org/@api/deki/files/295223/Circular_dichroism_angle.gif?revision=1&size=bestfit&width=440&height
=291
http://chemwiki.ucdavis.edu/Physical_Chemistry/Spectroscopy/Electronic_Spectroscopy/Circular_Dichroism
64
CD spectroscopy
• enantiomers have by definition mirror image CD effects
• absorption bands in de CD spectrum are called Cotton effects
• sign of the CD effect of a chromophore depends on the chirality
of the chromophore
• optically inactive chromophores (eg C=O) may show a CD effect
because they are dissymmetrically perturbed by a chiral
environment
65
CD spectroscopy
Cotton effect
Named after the French physicist Aimé Cotton (1859–1951).
Cotton effect = the wavelength dependence of the optical rotary dispersion curve or the
circular dichroism curve in the neighbourhood of an absorption band
If the wavelength is decreased, the rotation angle increases until it reaches a maximum and
then decreases, passing through zero at the wavelength at which the maximum of
absorption occurs. As the wavelength is decreased further the angle becomes negative, until
it reaches a minimum after which it rises again. This pattern is called the positive Cotton
effect.
CD spectroscopy
https://www.youtube.com/watch?feature=player_detailpage&v=Fu-aYnRkUgg
CD spectroscopy
CD of proteins
• important in determining protein
secondary structure
• very sensitive to small changes in
α-helix and β-sheet content
68
Applications of CD at SMO
R
N
H
H
N
O
C8H17
O
H
N
O
H
C8 17
N
H
H
O
N
C8H17
O
H
N
O
C8H17
CD-effect / mdeg
S
Temperature / oC
Properties
of
stereoisomers
Properties of stereoisomers
enantiomers have identical physical properties
diastereomers have different physical properties
(1R,2S)-(-)ephedrine
(1S,2R)-(+)ephedrine
NHMe
NHMe
OH
OH
(1S,2S)-(+) pseudoephedrine
(1R,2R)-(-) pseudoephedrine
NHMe
NHMe
OH
OH
m.p
.
40-40.5°C
40-40.5°C
117-118°C
117-118°C
[α]D
-6.3
+6.3
+52
-52
! melting behavior of racemates may deviate from
the pure enantiomer
71
Crystallisation of a racemate
If an equimolar mixture (a
racemate) of 2 enantiomers
crystallises:
S S
R
R
S R SS S R
R
R
R S SS
S
R S
S
R
R
SR
RS RS
S RS R
SR RS RS
RS SR
RS
SR
racemic compound
SR
RS RR
SS
SS
SS
SR
SR
RS S R
SS
RS
RS
solid solution
S
RR S
S
SS
RR S
SS SS
R
R RS S R
R
R
RR
conglomerate
72
More definitions
Enantiomeric excess (ee)
% major = (ee+100)/2
73
More definitions
Diastereomeric excess (de)
identical to definition of ee except that now diastereomers are
used
de = [(RS-SS)/(RS+SS)]x100%
enantiomeric and diastereomeric ratio (er and dr)
ratio of the percentage of one enantiomer (or
diastereomer) to that of the other(s)
eg: er = 70:30
74
More definitions
• a collection containing only one form of a chiral object is called: enantiomerically
pure, enantiopure or optically pure
• a collection containing equal amount of both enantiomers is called a racemate
• if the of 2 enantiomers are present in unequal proportions, the term scalemic mixture
is used
75
Methods to determine ee
optical rotation/CD: compare with known molecules
problematic when you are the first to make a
specific molecule
chiral GC/HPLC:
applicable for unknown substances too, but
racemate must be available
NMR:
make diastereomers showing different NMR
shifts
76
Methods to determine ee
The optical rotation of a sample of 2-butanol is +6.76°. Enantiopure (S)-2-butanol
shows an optical rotation of +13.52°
Of 100 molecules, how many are R and how many S? (fR= (ee+1)/2)
What is the optical purity?
77
Methods to determine ee
CD spectroscopy
C8H17
H
H
60
C8H17
40
O
N
O
20
CD (mdeg)
N
O
H
N
R
CD-effect@223 nm = 50 mdeg
c = 3x10-5 M
l = 1 cm
∆ε = (+/-) 40 L/mol.cm
(molar circular dichroism)
gvalue = (+/-) 0.0038 = ∆ε/ ε
0
-20
-40
-60
200 220 240 260 280 300 320 340
C8H17
O
λ (nm)
N
H
H
C8H17
O
N
O
H
N S
78
Methods to determine ee
Chiral gas chromatography (GC)
• compound must be volatile
• many columns commercially available
• columns are rather specific
HO
ee = 98.7 %
HO
ee = 99.9 %
L = 15-30 m; i.d. = 0.25 mm
Df = 0.25 µm
OH
O
HO
OH
O
O
HO
OH
34
36
O
HO
O
HO
OH
time (min)
OH
O
O
HO
OH
OH
O
OH
O
OH
OH
O
HO
O
OH
OH
O
79
Methods to determine ee
Chiral high pressure liquid chromatography (HPLC)
• also possible for non-volatile compounds
• solvents and column material can be varied
• endless amount of combinations possible
• detection can be a problem (typically with UV or fluorescence)
80
Methods to determine ee
Nuclear magnetic resonance (NMR)
• need to make diastereomers since enantiomers have identical NMR spectra
• Mosher’s acid chloride for alcohols and amines
• chiral lanthanide shift reagents which form Lewis acid-base complexes
• chiral alcohol TFAE which forms either H-bonds or p-stacking complexes
• phosphate complexes (Feringa)
O
O
F 3C
CF3
H
OH
Cl
Mosher’ acid chloride
1H or 19F-NMR, 31P possible
(S)-(+)-TFAE
81
An example to determine ee with NMR
An example to determine ee with NMR
CF3
D
OMe
Cl
(R)
O
CF3
OMe
(R)
OH
pyridine, CHCl3
O
O
D H
(S)-ester
(R)-ester
racemic ester
5.00
4.80
4.60
4.40
4.20
4.00
83
An example to determine ee with NMR
An example to determine ee with NMR
ee = 90%
O
O
F 3C
ee = 90%
Cl
Importance
of
chirality
Importance of chirality
• enantiomeric smells
O
R-(-)-carvone
caraway seeds
O
S-(+)-carvone
spearmint
R-(+)-limonene
oranges
S-(-)-limonene
lemons
87
Importance of chirality
• enantiomeric effects on metabolism
C8H17
O
O
C8H17
R-enantiomer:
Japanese beetle pheromone
O
O
S-enantiomer
inhibitor for R-enantiomer
1% of S-enantiomer is enough to destroy all activity of R-enantiomer
Implications for pest control!
http://www.sciencedaily.com/releases/2008/06/080625153342.htm
88
Importance of chirality
• enantiomeric effects on metabolism
HO
HO
NH2
COOH
L-DOPA
S-enantiomer
treatment of Parkinson’s disease
NH2
OH
OH
HOOC
D-DOPA
R-enantiomer
toxic
89
Importance of chirality
• enantiomeric effects on metabolism
O
H
N
O
O
N
O
S
Treatment of morning
sickness for pregnant women
H
H
O
N
O
N
H
O
R
O
teratogenic
chiral pharmaceuticals must be made available in enantiopure form
Synthesis of enantiopure compounds!!
90
Importance of chirality
Rotate counter-clockwise
Axl lasts longer (no splintering of
the wood)
Rotate clockwise
91
Importance of chirality
92
Chirality in the pharmaceutical industry
diastereomers
single enantiomers
racemates
80
new drugs launched
70
60
50
40
30
20
10
0
1985-88
1989-92
1993-96
1997-00
H. Murakami Top. Curr. Chem. 2007, 269, 273-299
• 1984: the non-active isomer in a
racemate should be regarded as an
impurity
• in 2004 all approved chiral synthetic
drugs were single enantiomers
• total amount of approved drugs has
decreased steadily during this time
• 31% of approved chiral drugs during
1985-2004 are cardiovascular agents!!
2001-2004
93
Chirality in the pharmaceutical industry
achiral
single enantiomer
racemic (white)
O’Boyle, J. Med. Chem. 2024, 67, 2305−2320
Racemates versus enantiopure compounds
R-ibuprofen
S-ibuprofen
S is the active form but in vivo an isomerase (2-arylpropionyl-CoA
epimerase) converts the R-enantiomer into the active S-enantiomer
95
Chirality in the pharmaceutical industry
Of the 55 chiral drugs with one chiral center introduced during 1985-2004:
number of chiral drugs
with 1 stereocentre
25
20
15
10
5
0
chiral pool
resolution
1. Chiral pool: 26 drugs (half from
natural amino acids)
2. Optical resolution: 27 drugs
(most via diastereomer
crystallisation)
3. Asymmetric synthesis: 5 drugs
(despite huge efforts of
asymmetric
academic and industrial
synthesis
research in this topic)
H. Murakami Top. Curr. Chem. 2007, 269, 273-299
96
What you should know…
• recognise, based on symmetry arguments, if a molecule is chiral
• know and assign nomenclature (R/S/E/Z/cis/trans/P/M/re/si) to a
molecule
• differentiate between asymmetric and dissymmetric molecules
• know the definition of ee and how to measure ee with a selection
of analytical techniques
97
Conclusions
• chirality is a geometric property
• symmetry rules allow you to establish if a molecule is chiral
• optical activity is a measured property
• there are many definitions and names in stereochemistry
• determination of the absolute configuration and the ee is crucial
98
The origin of homochirality in Nature
1.
2.
3.
4.
Ehrenfreund&Charnley 2002
Molecules?
Macromolecules?
Symmetry breaking?
Amplification of asymmetry?
99
DNA
terpenes
vitamins
L-amino acids
D-sugars
triacylglycerides
100
X
SYNTHETIC ORGANIC CHEMISTRY
?
EVOLUTIONARY BIOLOGY
Dissipative out-of-equilibrium
Thermodynamic equilibrium
102
Life is based on C
All living things we know today is based on C and organic
molecules, and the presence of water
Life is we know it on other planets has not been found (yet)
Many scientific groups try to understand orgin of life and
homochirality. Both are linked.
George Whitesides (Eindhoven, July
2018):
How might life have originated and not
did originate
Rock eating Horta in Star trek
The origin of Life
some key dates
Earth
4.5x109 years ago
Life
3.5x109 years ago
First organic
molecule
Woehler (1828)
Amino acids
in prebiotic conditions
Miller (1953)
The origin of live cannot be discovered, as other things in
science, it can only be re-invented
A. Eschenmoser, 2008
104
The origin of Life on Earth
• origin of life requires organic compounds
• potential sources:
synthesis in prebiotic atmosphere
synthesis in hydrothermal vents
extraterrestrial synthesis
105
Formation of the earth
• hot formation process, carbon material combusted
• organic compounds must have formed after the surface cooled
• or, organic compounds were seeded via impact of small bodies
http://infinity-imagined.tumblr.com/post/13506249743/the-formation-of-planet-earth
http://www.universetoday.com/58177/earth-formation/
http://www.livescience.com/15084-radioactive-decay-increases-earths-heat.html
106
Formation of organic molecules in space
Carbonaceous chondrite meteorites
p = 10-18 bar
T = -230°C (Pluto)
Everywhere!
Dense Clouds
Disk Plane
Shocked regions (HH objects)
Collapsing Dense Clouds
Turbulent disks
Photon Dominated Regions
Surface regions of dusty disks
Cometary Ices
Molecules freeze-out onto cold dust
high number of organic molecules are found in the interstellar medium, comets, asteroids,
meteorites and interplanetary dust particle
Fraser, Collings & McCoustra Rev. Sci. Inst. 73, no.5, 2161 (2002)
107
Space as a source of organic compounds
Methyl cyanide
Methyl formate
Dimethyl ether
Acetic acid
Benzene
Ethanol
Ethyl cyanide
‘Sugar’
108
Formation of organic molecules on asteroids
De Sanctis et al., Science 355 ,719 – 722 (2017)
Meteorites introduced organic compounds
105 – 106 kg material / day
60-80% insoluble aromatic C material
in soluble C-material:
amino acids
fullerenes
acids
volatile hydrocarbons
N-heterocycles
amines
alcohols
110
Origin of organic compounds on earth
Oparin (1924)/Haldane (1928) theory:
• life was formed from a “primordial soup” that containing simple organic
molecules, forming biomolecules of increasing complexity
• early atmosphere of earth was reducing (ie: H2, NH3, CH4)
• oxygen in atmosphere came from photodissociation of water by UV light
• no experimental evidence
A. Oparin
1894-1980
J.B.C. Haldane
1892-1964
111
Origin of amino acids on earth
Water
Methane
Hydrogen
Ammonia
Electric discharge
After 1 week|:
• 10-15% of C was isolated in the form of organic compounds
• 2% of C was isolated in the form of amino acids
• several of the 20 amino acids present in life were isolated
• all amino acids were racemic
S.L. Miller
1930-2007
Miller (1953)
simple gases can be converted into
amino acids in a reducing atmosphere
Miller: Science 1953, 117, 528; JACS 1955, 77, 2351; Biochim Biophys Acta, 1957, 23, 480
112
Origin of amino acids on earth
In the spark:
HCN (ammonia and methane)
Formaldehyde (CO and hydrogen)
Strecker synthesis and hydrolysis
RCHO + NH3 + HCN → RCH(NH2)CN + H2O
RCH(NH2)CN + 2 H2O → RCH(NH2)COOH + NH3
Glycine
Alanine
Aspartic acid
Glutamic acid
113
Origin of amino acids on earth
50 years later, and better analytical tools
Bada, Science, 2008, 322, 404
The Miller experiment in Eindhoven
Does it still work in the 21st century??
• electrodes are important (Ni no, Tu yes)
• reaction time is important (after 1 week: glass dissolves)
• spark source is very important
• no amino acids in U-tube
• glycine and alanine found in concentrations of about 0.2 mg/mL
• concentrations of Gly and Ala comparable to Miller’s experiment
115
The Miller experiment in Nemo (Amsterdam)
116
The Miller experiment in Nemo (Amsterdam)
117
The Miller experiment in Nemo (Amsterdam)
https://www.youtube.com/watch?v=BRlfrxVYCg8
Origin of other organic biomolecules on earth
Adenine from HCN
Sugars from formaldehyde
“formoso reaction”
ambient T: strong base required
High T: weak base suffices
J. Oro, Biochem Biophys Res Commun 1960, 2, 407
Breslow, Tetrahedron Lett, 1959, 1, 22
Anonietti, NewJ.Chem.,2011,35, 1787
Sutherland, Angew. Chem. 2016, 55, 104
Criticism on the Miller experiment
1. Atmosphere was reducing: highly debated
Ponnamperuma (Quarterly Rev. Biophys. 1971, 4, 77):
2. Concentrations are too low to be significant
Concentration may have occurred locally
3. Racemic mixture was formed
All biomolecules are chiral
120
Organic molecule synthesis in hydrothermal vents
• many organic compounds are formed in black smokers
• structures consist of microscale caverns that are coated by
thin membraneous metal sulfide walls
The reactions are thermodynamically sound and feasible in
relatively normal conditions
Wächtershäuser Phil. Trans. R. Soc. B 2006 361, 1787-1808
121
122
What about chirality??
Chirality = principal criterion for life
Chiral compounds cannot be made from achiral or racemic compounds in an achiral
environment: enantiomers have the same free energy
Biotic theory:
Life originated initially from achiral molecules & racemates
Use of specific enantiomers is a result of evolution
Argument: D-amino acids (albeit rare) do exist in nature
(see Green, Two equal runners, one tripped: Org. Life Evol. Biosphere, 2009, DOI
10.1007/s11084-009-9180-7)
L-amino acids
α-helix
Abiotic theory:
Chirality preceded life
Homochirality is a prerequisite for folded structures (α-helix) and replication (DNA)
DNA
123
How was the symmetry broken?
Extraterrestrial origin
Murchison meteorite (Murchison, Australia, 1969)
6 natural amino acids isolated (glycine, alanine,
valine, proline, glutamic acid, aspartic acid)
ee = 9% for L-isomer (isovaline)
Where does ee come from??
In interstellar molecular clouds: flux of CPL of
specific handedness may result in asymmetric
photosynthesis or degradation
(JACS 1974, 96, 5152; ibid 1977, 99, 3622)
Pizzarello: Science, 1997, 275, 9511
124
How was the symmetry broken?
Terrestrial origin
Stochastic (random) events:
by chance one enantiomer is present in a higher amount but there is an
equal probability for affording either enantiomer
Deterministic events:
Forces (internal or external) exist that lead to the preferential
formation/breakdown/… of one enantiomer over the other
In either case, a mechanism is required in which the random or
deterministic enantiomeric imbalance is amplified to a homochiral state
we know today
Bonner: Origin Life Evol. Biosphere, 1991, 21, 59
125
How was the symmetry broken?
Stochastic events
• spontaneous symmetry breaking by statistical fluctuations
N flips of coin: expected number of heads = 0.5xN
In 100 flips: 46 H and 54 T: difference with the expected 50H and 50T is
statistical fluctuation
If 107 chiral molecules are formed in a random conditions: ee = 0.021%
-> practically impossible to make a true racemic mixture
When autocatalysis is operative, statistical fluctuation can lead to a homochiral
state
126
How was the symmetry broken?
• spontaneous symmetry breaking upon crystallisation
formation of a conglomerate (in 10% of the cases)
crystallisation of NaClO3
.
preferred formation
of 1 enantiomorph
Time / h
Viedma, PRL, 2005, 94, 065504
127
How was the symmetry broken?
• stereoselective adsorption or reaction of one of the enantiomers on
chiral crystals (e.g. quartz)
Quartz
Threonine
128
How was the symmetry broken?
Deterministic mechanisms
• Electric/magnetic/gravitational fields
Tried but all failed or irreproducible
• Circularly polarised light
Emitted by interstellar stars and is presumably the cause of the ee’s > 0 found for
amino acids in meteorites
Amount of CPL on earth is very small and only a tiny bias can be observed
depending on time an place for rCPL and lCPL
Asymmetric degradation of enantiomers with CPL was observed experimentally
(rac-leucine degraded by UV-rCPL@213 nm: L-Leu with ee up to 2%)
Bonner: Origin Life Evol. Biosphere, 1991, 21, 59
Science 1998, 281, 672
129
How was the symmetry broken?
• Weak force
4 forces in nature
gravitational force
electromagnetic force
parity conservation
strong nuclear force
weak force : parity violation
Radioactive decay (β-particle) of a
neutron in the nucleus of an atom into a
proton by emitting an electron and an
electron antineutrino
If Co-60 is aligned in a magnetic field, β
rays should be equally distributed
between the two poles
β-rays were note equally distributed : Lelectrons are formed preferentially to Relectrons
Wu et al Physical Review, 1957, 105, 1413–1415
130
How was the symmetry broken?
• Weak force: parity violation
The weak force has a handedness and chirality exists at the
level of elementary particles!
parity-violating energy difference = 10-14 J/mol -> 10-15% ee
Experiments on the degradation of rac-leucine using the weak
force showed preferential degradation of D-Leu (1.4%)
With the weak force, calculations showed that there is a 98%
chance that all molecules are left-handed within 50000100000 years
The theoretical physicists (Tsung-Dao Lee and Chen-Ning
Yang) that predicted this got the Nobel price
The experimentalist (Chien-Shiung Wu) who verified it did not
131
How was the symmetry broken?
Theoretical fluctuations in racemic mixtures
Stochastic
Deterministic
Fluctuations of 1012 molecules/mole
chiral bias of 106 molecules/mole
1 mole = 6.02x1023 molecules
Both processes must be coupled with
an amplification process to reach single handedness
And this is the big question
Lahav Top. Curr. Chem. 2005 259,123
132
Amplification of asymmetry
Process in which the ee is amplified from a low value to a high value
133
Importance
of
chirality
135