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1
Advanced Organic Chemistry III Contents
1. Stereochemistry of Organic Compounds 2. Stereocontrol in
Organic Reactions 3. Stereocontrol in Catalytic Reactions
References General Eliel, E. L.; Wilen, S. H. Stereochemistry of
Organic Compounds, Wiley, 1993. Robinson, M. J. T. Organic
Stereochemistry, Oxford University Press, 2000.
( , , 2002.) Kagan, H. B. La Stereochimie Organique, Press
Universitaires de France, 1975.
( , , 1981.) , , NMR , , 2012. Abbreviations of substituents
http://pubs.acs.org/paragonplus/submission/joceah/joceah_abbreviations.pdf
1. Stereochemistry of Organic Compounds (1) Structure and size
of organic compounds
(a) Bond length bond length () bond length () bond length ()
bond length () CH 1.09 CF 1.38 CC 1.53 C=C 1.34 CC 1.53 CCl 1.77
CC= 1.50 C=C= 1.31 CN 1.47 CBr 1.94 CC 1.46 =C=C= 1.28 CO 1.43 CI
2.14 =CC= 1.48 CF 1.38 =CC 1.4 CC 1.20 C=O 1.22 CC 1.38 CC (in
C6H6) 1.39
Bond length is defined as the distance between two nuclei.
Distortion hardly affects bond length.
(b) Bond angle Bond angle is defined with the positions of three
nuclei. Typically, the bond angles involved with sp-, sp2-, and
sp3-hybridized carbons are 180, 120, and
109.5, respectively. Distortion hardly restricts the bond
angles. Therefore, the CCC bond angle in cyclopropane is
allowed to be 60. However, the strain does not highly distort
the angle of two sp3 orbitals. The CC bond in cyclopropane is
constituted with a banana shaped orbital.
(c) Dihedral angle
Bond angle is defined with the positions of four nuclei. Shape
of molecule can be defined with bond lengths, bond angles, and
dihedral angles. In stable conformation, each dihedral angle should
be 60, 180, or 120 (if the molecule have
sp2-hybridized atom). (see Conformation of organic
molecules)
(d) Van der Waals radius Bondi, A. J. Phys. Chem. 1964, 68, 441.
atom H C N O F P S Cl Br I radii () 1.20 1.70 1.55 1.52 1.47 1.80
1.80 1.75 1.85 1.98
CH3 2.0 C6H6 (thickness) 1.7 Generally, van der Waals radius is
useful for considering the
bulkiness of substituent. However, van der Waals volume, which
is calculated from the radii,
does not contains the effect of bond rotation. Solvent
accessible surface area is sometimes used for evaluating
the accessibility of a reagent to a substrate.
e
Cf dC
b a
c
e
f d
b a
c
dihedral angle
-
2
(e) A-value
R A-value R A-value R A-value R A-value R A-value H 0.00 CCH
0.41 F 0.25 OMe 0.55 CHO 0.56 Me 1.74 CH=CH2 1.49 Cl 0.53 O(t-Bu)
0.75 COMe 1.02 Et 1.79 Ph 2.8 Br 0.48 OSiMe3 0.74 CO2H 1.4 i-Pr
2.21 SiH3 1.45 I 0.47 NHMe 1.29 CO2Me 1.2 Cy 2.2 SiMe3 2.5 OH 0.60
NMe2 1.53 CN 0.2 t-Bu 4.7 SnMe3 1.0 NH2 1.23 PMe2 1.5 CF3 2.4
Sn(i-Pr)3 1.10 NH3+ 1.7 PPh2 1.8
A-value is widely used for discussing the steric effect of
substituent. In general, A-value correlates with the size of
substituent. Furthermore, the value includes the
effect of bond rotation. Therefore, the value reflects the
steric environment around the atom bearing the substituent.
A-value is affected by bond length (CR) as well as by van der
Waals radius.
(f) Tips to consider steric effect of a substituent i) Where is
the most important for the related steric repulsion (near or
far)?
If you will consider the steric effect around the atom , t-Bu or
2,6-xylyl must be larger than
-CC(t-Bu) group. If you would like to create a steric hindrance
far from , -CC(t-Bu) should be larger than t-Bu
and 2,6-xylyl. ii) Snapshot or motion blur? (in the case of aryl
group)
(top view) (side view) (snapshot) (motion blur) Snapshot may be
preferable when you consider the steric hindrance in dynamic
phenomena. Motion blur may be suitable for thermodynamic phenomena.
In snapshot steric effect, phenyl group can be regarded as a
smaller substituent than methyl one. In motion blur steric effect,
phenyl group can be regarded as a larger substituent than
secondary
alkyl ones.
(2) Chiral Compounds and Enantiomers Chiral molecule can not
overlap with its mirror image. Therefore, chiral compounds have
no
symmetry plane () or rotation-reflection axis (Sn). Achiral
compounds are the compounds that are not chiral. "Chiral molecule"
means the molecule possessing any chirality. "Chiral compound"
means the mass of chiral molecules. "Racemic compound (racemate)"
means the 1:1 mixture of both enantiomers (R and S). Each
molecule constituting a racemic compound should be "chiral
molecule". "Optically active compound" means the chiral compound
other than racemate. A mixture of
enantiomers is often categorized as optically active compounds,
even if R:S is 51:49. However, the term often indicates pure
enantiomer (enantiopure compound or optically pure compound).
"Enantiomer" originally means the mirror image of a chiral
molecule (e.g. (S)-2-octanol is the enantiomer of (R)-2-octanol.).
The term often indicates the enantiopure compound, whose absolute
configuration has been known.
"Diastereomer" means any stereoisomers other than enantiomer.
"Epimer" means stereoisomers bearing only one chiral center with
the opposite absolute
configuration. The configuration of other chiral centers in the
epimer must be identical to the original compound.
(a) Central chirality
The chirality caused by asymmetric atom is called "central
chirality". Asymmetric atom is not limited to carbon (e.g. N, S, P,
etc.). Lone pair can function as a
substituent and is regarded as atomic number 0 in CIP rule (see
35).
Spiro compound 6 is chiral, although they seem to have no
asymmetric atom. However,
compound 7 is achiral because its tetrahydrofuran ring is
symmetry plane.
The molecules possessing symmetry plane (see 8, 9) or
rotation-reflection axis (see 10) must be
achiral, even if they have asymmetric atoms (e.g. meso
compound).
Metal complexes are possible to be chiral when they are
tetrahedral, trigonal bipyramidal, or
octahedral.
RR
Geq GaxA value = G0 = Gax Geq (in kcal/mol)
MeMe
Me
Me
Me
Me
MeMevs vs
Me
Me
Cl
d
Ca
bc
d
Ca
bc =
d
Ca
cb
180
NH2Me CO2HH
+N
Ph MePh
N
N
1 2 3
Me PPh
OMe:
Ph SMe
O
:
4 5
O O OO=180
OO
6O7
Me MeOH
OHMe Me
OHOH =Me Me
HO OH
8 9O
OO
Me O
Me
10
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3
(b) Axial chirality Axial chirality takes two forms:
atropisomerism and isomerism in allenes. Atropisomerism
Atropisomerism is caused by inhibition of free rotation of a single
bond. The inhibition of free
rotation is often observed in the biaryl compounds bearing four
ortho-substituents or some sterically hindered carboxamides.
A racemate of axially chiral compound can be resolved into each
enantiomer when the rotation
barrier is over 20 kcal/mol. Axial chirality will be stable at
room temperature when the rotation barrier is over 30 kcal/mol.
Herical chirality is originated from the accumulation of axial
chirality.
Isomerism in allenes Each terminal carbon in C=C=C is plane
because it is sp2-hybridized. One of the planes is
perpendicular to another because the internal carbon in C=C=C is
linear and hybridized in sp manner to form two CC double bonds.
Therefore, substituted allenes are possible to be chiral as with
biaryls.
The chirality is seen in some spiro bicyclic compounds and
alkylidene cycloalkanes.
(c) Planar chirality
Planar chirality appears when a planar molecule loses its
symmetry plane by bridging with short tether or forming
-complex.
The chirality is seen in some cyclophanes, metallocenes, and
trans-cycloalkenes.
(d) Notations of absolute configuration 1) R/S notation
According to CIP rule, determine the priority of each
substituent involved with the chirality. Central chirality
(in the case of spiro compounds)
Axial chirality
i) Determine the priority of the two substituents on each atom
involved with the chiral axis. ii) The sequence of substituents
becomes a > b > c > d or c > d > a > b. Both
sequences result
in the same configuration. iii) Put the substituent with the
lowest priority (d or b) on the location far from you. Confirm
the
direction of a b c (or c d a).
iv) To distinguish the axial chirality from others, prefix 'a'
(or sufix 'a') is sometimes attached to the
chiral descriptor R or S (e.g. (aS)-2,3-pentadiene or
(Sa)-2,3-pentadiene) Planar chirality (cyclophanes,
trans-cycloalkenes etc.)
i) Determine 'pilot atom' from the bridging tether. The pilot
atom is out of the plane and closest to the plane. There are two
candidates in general. The pilot atom is the candidate binding to
the in-plane atom with higher priority in CIP rule.
ii) Among the atoms in the chiral plane, the atom binding the
pilot atom is assigned to 'a'. The next atom is 'b', and the third
atom is 'c'. If there are two candidates, the atom with higher
priority is assigned to 'c' (or 'b').
iii) View the molecule from the pilot atom.
iv) To distinguish the planar chirality from others, prefix 'p'
(or sufix 'p') is sometimes attached to
the chiral descriptor R or S (e.g. (pS)-(E)-cyclooctene or
(Sp)-(E)-cyclooctene) Planar chirality (metallocenes) Three rules
have been proposed to assign the stereochemical descriptor, R or S,
for the planar
chiral metallocenes. One is based on central chirality and
proposed by Prelog, Cahn, and Schloegl (Rule 3). Others are based
on planar chirality and proposed by Ugi and Schloegl,
b
aa
bb
aa
b
=180
a
ba
b a b
OHOH
N
O
Pht-Bu
NO
Me
Me
a
b
ab
a b
CO2H
HH
HO2CHMe
HO2C
H
FeCO2Me
BrCO2H
=
aCbcd
a > b > c > d
a
b c
d
a C a'b b'
a > b
1 2
3 4
a
b a'
b'
d
ca
b a > b, c > d
=a
b dc
b
acd
Br cb a
Br: pilot atom
a b c clockwise R anticlockwise S
a a' b clockwise R anticlockwise S
a b c clockwise R anticlockwise S
a b c clockwise R anticlockwise S
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4
independently (Rule 1 and 2). Unfortunately, the rules 1 and 2
resulted in configuration different from each other. However,
rules 2 and 3 reach the same result in most cases. Rule 1 (i)
View the substituted Cp ligand from the side opposite to the metal
atom. (ii) Confirm the direction of a b.
I. Ugi et al., J. Am. Chem. Soc. 92, 5389 (1970).
Rule 2 (i) Assign the metal atom to the pilot atom. (ii) Regard
the centroid of the substituted Cp ligand as atom 'a'. (iii) The
cyclopentadienyl atom bearing the substituent with the highest
priority is 'b'. (iv) The ortho-atom with higher priority is
assigned to 'c'. (v) View the Cp ring from the pilot atom, and then
confirm the direction of a b c.
K. Schloegl, J. Organomet. Chem. 300, 219 (1986).
Rule 3 (i) Treat chirality of metallocene as central chirality
of the cyclopentadienyl carbon with the
highest priority. (ii) Consider the metal atom to bond to the
carbons in Cp ring. (iii) The absolute configuration can be
similarly assigned to R or S with the rule for central
chirality.
K. Schloegl, Forschr. Chem. Forsch. 6, 479 (1966).
2) P/M notation P/M notation is based on the chirality of helix
(helicity). The descriptor P is used for right-handed helicity, and
M is used for left-handed helicity (from
before backward).
The notation can be applied to axial and planar chiralities. In
the case of planar chirality, pR and pS configurations correspond
to P and M, respectively.
3) D/L notation
D/L notation is sometimes used for the stereochemistries of
carbohydrates and -amino acids. Descriptors D and L strongly relate
to the stereochemistries of (R)-(+)- and (S)-()-glyceraldehyde,
respectively. D and L, must be smaller in size than other
characters.
4) Notations based on the direction of optical rotation
Descriptor (+) or () corresponds to the direction of optical
rotation. (+) and () are used for dextrorotatory and levorotatory
compounds, respectively.
Descriptors d and l are equivalent to (+) and (), respectively.
dl notation is not related to D/L notation.
(e) Characteristic properties of chiral compounds Most
properties of an enantiopure compounds are identical to those of
its enantiomer.
Exceptionally, the direction of optical rotation is different.
However, an enantiopure compound is different in most properties
from its racemate. 1) Crystals of racemate
Three types of crystalline racemate are known, as follows:
racemic conglomerate, racemic compound, and psudoracemate. Most
racemates preferentially to form racemic compounds.
Racemic conglomerate Racemic conglomerate is a mechanical 1:1
mixture of R crystals and S crystals. Each crystal in
the mixture is homochiral (constits of a sole enantiomer).
Preferential formation of racemic conglomerate requires that the
interaction between R and R (or
S and S) is stronger than that between R and S. Racemic
conglomate is much rarer than racemic compound.
Feb
a Fe b
a
90
a > b
FeBr
Mec b BrMe
a
FeBr
MeC Br
Me
Fe2
1
3
4FeC
BrCC4
3Me
1
2
(P)-[6]helicene (M)-[6]helicene
c dd
ca
ba > b, c > d
a
b
90a
bd cor
For axial chirality
For planar chirality
ab
dc
Br
The abcd unit can be regarded as a helix. View the helix from a.
Confirm the direction of the helix.
HOOH
CHO
D-glyceraldehyde
HOOH
CHO
L-glyceraldehyde
CHOOHH
CH2OH
CHOHHO
CH2OH
CHOHH2N
CH2OHL-serine
OOH
HOHOHO
OH
CHOOHH
HO HH OH
HO HOH
=
D-glucose
a b clockwise R anticlockwise S
a b c clockwise R anticlockwise S
1 2 3 clockwise R anticlockwise S
from before backward clockwise P anticlockwise M
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5
Chiral compounds, which preferentially form racemic
conglomerate, can be resolved into each enantiomer through
preferential crystallization without any other chiral source.
Racemic compound In racemic compound (true racemate), each
crystal contains R and S molecules in 1:1 ratio.
The both enantiomers form a racemic pair in a unit cell. Most
chiral compounds prefer the formation of racemic compound to that
of racemic
conglomerate. In many cases, a chiral molecule has stronger
affinity for its enantiomer than for itself.
Nevertheless, homochiral crystals are preferentially obtained
from the compound with relatively high enantiomeric excess
Psudoracemate In crystals of psudoracemate, both enantiomers
coexist in an unordered manner. This type of chiral compound is
very rare.
2) Melting point
Melting point of chiral compound is affected by its enantiomeric
excess. Each type of crystalline racemate exhibits characteristic
behavior in solid-liquid phase transition.
In racemic compound, racemate is generally higher in melting
point than its enantiopure form.
Binary phase diagrams describing the melting behavior of a)
3-fluoromandelic acid (racemic compound); b) 2,3-diacetoxybutane
(psudoracemate); c) 1.2-diphenylethane-1,2-diol (racemic
conglomerate).
(f) Resolution of chiral compounds 1) Use of resolving agent
Although an enantiomer is impossible to be separated from its
racemate, an epimer is physically separable from the mixture of
diastereomers.
Therefore, formation of diastereomers with an optically active
resolving agent is very useful for the optical resolution of
racemates.
Crystallization of diastereomeric salts This method is useful
for resolution of chiral carboxylic (phosphonic or sulfonic) acids,
amines,
and phosphine oxides. Acidic functional group (e.g. -CO2H,
-SO3H) can readily form salts with basic functional groups
(e.g. -NH2). The acidbase pair is easier to crystallize from
organic solvent than each compound, because the salt is generally
less soluble.
Treating racemic carboxylic acid 1 with stoichiometric
enantiopure amine 2 gives the mixture of
ammonium salt 3RR and 3SR. If 3RR is less soluble than 3SR, 3RR
can selectively be obtained through crystallization. Purity of the
crystals can be enhanced by recrystallization. Enantiopure (R)-1
will be obtained by decomposing the pure 3RR in hand with acid.
Equimolar resolving agent (to racemate) is requires for the
resolution controlled by type 1
thermodynamics. Halfmolar resolving agent may be enough for an
efficient resolution, if it is controlled by type 2 or 3
thermodynamics.
Representative resolving agents
Crystallization or chromatographic separation after
derivatization This method is useful for the resolution of chiral
alcohols and ketones. It is applicable for the
resolution of chiral (secondary or primary) amines and acids. In
the resolution of a racemic alcohol 4 (e.q. R and S), the racemate
is esterified with an
enantiopure acid anhydride 5 (e.g. R), which is the resolving
agent. The esterification will give a mixture of diastereomeric
esters 6RR and 6SR (RR and SR). Both diastereomers can be separated
by column chromatography or crystallization. Each pure diastereomer
in hand can be transformed to (R)- or (S)-alcohol through
hydrolysis.
RRRRRR
SSSSSS
RSRSRS
SRSRSR
racemic conglomerate racemic compound
RRSRSS
SRRSSR
psudoracemate(true racemate)
CO2HMeO
PhH
CO2HMeO
HPh
+ H2NH
MePh
R
R
S
CO2MeO
PhHR H2N
H
MePh
R+
CO2MeO
HPhS H2N
H
MePh
R+
3RR
3SR
(R)-1
(S)-12
(crystallize)
(in solution)
H3O+ CO2HMeO
PhHR
(R)-1
R + S
S + S
RS (less soluble)
(more soluble)
Type 1R + S
S + S
RS (less soluble)
(soluble)
Type 2
SS SS
R + S
S + S
RSType 3
SS
N
O
O
N
H
H
HH
R
R
for acids
brucine (R = OMe)strychnine (R = H)
N
NOH
OMe
quinine
NOH
N
OMequinidine Me
NH2
Me
NH2
for bases
HO2C CO2HOH
OH
tartaric acid
HO2C CO2HOBz
OBz
HO2C CO2H
OH
malic acid
CO2H
OH
mandelic acid
O
Me Me
HO3Scamphorsulfonic acid
OP
O OOH
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6
A racemic chiral ketone or aldehyde can be resolved through the
reaction with an enantiopure
primary amine, which gives a mixture of diasteromeric imines.
Representative resolving agents
2) Chiral HPLC
A racemate is resolved to each enantiomer through the column
chromatography with a chiral stationary phase, which is typically
composed of a chiral compound and silica gel.
Information of each chiral column can be obtained from the
following web sites.
Daicel: http://www.daicelchiral.com Sumichiral:
http://www.scas.co.jp/service/apparatus/
hplc/sumichiral_introduction.html Astec:
http://www.sigmaaldrich.com/japan/
analytical-chromatography/hplc/chiral-astec.html 3) Preferential
crystallization
Racemic conglomerate can be resolved through recrystallization
without resolving agent, if you have its homochiral single
crystal.
To a saturated hot solution of the racemate, its homochiral
crystal (e.g. R) is installed. The same enantiomer (R) will be
crystallized in preference to the antipode (S). The resulting
mother liquor
will be S-enriched. The recrystallization of the mother liquor
will preferentially form the crystals of S-compound.
4) Kinetic resolution In general, chiral reagents and catalysts
exhibit different reaction rate for each enantiomer of
substrates. If the reaction of the R-enantiomer is faster than
that of S-isomer, the recovered substrate should be S-enriched.
Therefore, the reaction of a racemate with a chiral reagent (or
through asymmetric catalysis) is usable for the resolution.
The efficiency of kinetic resolution (s) is expressed by the
ratio of the reaction rate of each
enantiomer (kR/kS). s = kR/kS = ln[(1C)(1-ee)]/ln[(1C)(1+ee)] =
ln[1C(1+ee')]/ ln[1C(1ee')]
C: conversion ee = enatiomeric excess of unreacted substrate ee'
= enatiomeric excess of product
Examples
Marshall, J. A. Org. Synth. 2005, 82, 43.
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(g) How to determine absolute configuration 1) Chemical
transformation
a) The target molecule is reacted with a known optically active
compound. If the product, which must have two chiral centers, is
crystalline solid, it is subjected to X-ray crystal structure
analysis. The absolute configuration of the target is found through
the resulting structure, because the absolute configuration of one
of its chiral centers is known.
b) The target molecule is transformed to a known optically
active compound. Possibility for
racemization must be considered during the transformation. The
specific rotation of the resulting product is compared with the
reported []D. Comparison of the retention times in the chiral HPLC
analyses is also useful for the assignment of absolute
configuration.
MeOH
PhHO
H
H
O
OMe
OHHPh
R
S
RR+
(R)-4
(S)-4HO2C
O
O
PhMeH
5HO2C
O
O
PhHMe
R S
6RR 6SR
(separable with chromatography or crystallization)
hydrolysis(R)-4 (S)-4
for alcohols
O
O
O
H
H
O
O
OH
H
H
Me
Me Me
NCO
(for urea derivatization)
(for lactor derivatization)(for ester derivatization)
O
O
CO2HMe Me
Me OH
O
OMe
MeMe Me Me Me
H
for ketones and aldehydes
Noe reagent
EtO2C CO2EtOH
OH
diethyl tartarate
NNH2 OMe
SAMPMeHN NHMe
Ph Ph
kR R&S
(50:50)
+ aR + a R a
kSS + a S a(fast)
(slow)
if kR >> kS R a&S (almost enantiopure)
Me
OH
TMS
Amano Lipase AKOAc , pentane Me
OH
TMS49%
Me
OAc
TMS47%
C6H13
OH Ti(O-i-Pr)4 & (+)-DIPTt-BuOOH C6H13
OH
C6H13
OH
Os = 83
R1 R2
OH
(target)
Ph COCl
OMe
S
Ph O
O
R1R1MeO
SX-ray crystal structure
a
b Compare the stereochemistry of chiral center a with that of
chiral center b.
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7
c) The authentic sample of the target molecule is synthesized
from a known optically active
compound. The specific rotation or the chiral HPLC retention
time of the authentic sample allow us to assign the absolute
configuration.
2) Crystallography (Bijvoet method)
Commonly, X-ray single crystal analysis gives no information
about the absolute configuration of the chiral compound. However,
the configuration can be determined with the crystallography, when
the compound has one heavy-weight atom.
The heavy-weight atom induces anomalous X-ray scattering, which
caused that intensity F(h k l) is not equal to that of F(h k l) in
a chiral crystal.
Flack parameter (x) is widely used for estimating the absolute
configuration of crystal structure. I(h k l) = (1x)|F(h k l)|2 +
x|F(h k l)|2
x: Flack parameter I: the square of the scaled observed
structure factor F: the calculated structure factor
If x is near 0, the crystal structure has the correct absolute
configuration. If the crystal structure has the inverted
configuration, x is near 1.
Bijvoet method is applicable for chiral compounds bearing no
heavy-weight atom. In this case, a protective group containing a
heavy-weight atom (e.g. p-bromobenzoyl) is installed to the target
molecule.
3) Advanced Mosher method and its related methods see: Riguera,
R. Chem. Rev. 2004, 104, 17. Advanced Mosher method Advanced Mosher
method is empirical, but very useful for determining the absolute
configuration
of an unknown chiral secondary alcohol. This method is
applicable for the chiral secondary alkyl primary amines.
(original) Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(alcohol) Kusumi, T.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092. (amine) Kusumi, T.; Kakisawa, H. Tetrahedron Lett. 1991, 32,
2939.
Prepare two samples of the secondary alcohol. Each Sample is
esterified with (R)- or (S)-MTPA to prepare (R)- and (S)-MTPA
esters (MTPA is 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid).
For each proton in the secondary alcohol moiety, calculate the
difference between the 1H NMR chemical shifts of (S)- and (R)-MTPA
esters ( = S R) as shown in above figure.
In MTPA esters, their CF3 groups are located at the pseudo
eclipse of the proton attaching to the chiral carbon of the
secondary alcohol. The aromatic ring in MTPA induces upfield shift
of the resonances of the protons in the secondary alcohol moiety.
Therefore, if is negative, the proton should be located over the
aromatic ring of (S)-MTPA.
Trost method Trost method uses O-methylmandelic acid instead of
MTPA. The procedure is very similar to
advanced Mosher method. O-Methylmandelic acid is easier to react
with secondary alcohols than MTPA, but may be
racemized during the esterification. In the O-methylmandelates,
their OMe groups are located at the pseudo eclipse of the
proton
attaching to the chiral carbon of the secondary alcohol.
Trost, B. M. J. Org. Chem. 1986, 51, 2370.
PGME method PGME (phenylglycine methyl ester) method is useful
for determining the absolute configuration of
the chiral -carbon of carboxylic acid. In the PGME amides, their
CO2Me groups are located at the pseudo eclipse of the -proton of
the
chiral carboxylic acid.
Kusumi, T. Tetrahedron Lett. 1995, 36, 1853; J. Org. Chem. 2000,
65, 397.
4) Circular dichroism (CD) spectrum Circular dichroism is active
for only optically active compounds. Positive Cotton effect means
that an enantiomer gives a positive peak in its CD spectrum. Octant
rule This method is empirical and useful for determining the
absolute configuration of cyclic ketones. First, consider the most
stable conformation for the target molecule. Geometry optimization
with
MO or MM may be useful for the consideration.
target other compound(Its []D has been reported.)
Measure its optical rotation and caluculate []D.
Compare it with the []D reported in the literature.
other compound(Its []D has been reported.)
authenticsample optical rotation.retention time in chiral
HPLC.Measure its
Compare the value with that of the target.
R1H
O
O
OMeCF3
R2S
(S)-MTPA ester
upfield shift
R1H
O
O
MeOCF3
R2R
(R)-MTPA ester
upfield shift
= S RIf > 0, the proton belongs to R2.If < 0, the proton
belongs to R1.
R1H
O
O
HOMe
R2R
(R)-O-methylmandelate
upfield shift
R1H
O
O
HOMe
R2S
upfield shift
= S RIf > 0, the proton belongs to R1.If < 0, the proton
belongs to R2.
(S)-O-methylmandelate
R1H
R2
(S)-PGME amide
upfield shift
R1H
NH
HCO2Me
R2R
upfield shift
NH
HCO2Me
O O
S
(R)-PGME amide
= S RIf > 0, the proton belongs to R2.If < 0, the proton
belongs to R1.
-
8
Space around the carbonyl group is divided into eight sectors as
shown in figure (a).
In octant rule, the atoms in the + sectors induces a positive
Cotton effect. The atoms in the sectors induces a negative Cotton
effect.
The Cotton effect can be predicted as above. Compare the
prediction with the observed CD spectrum (n* (C=O), ca. 300
nm).
Exciton chirality method This method is theoretical and useful
for determining the absolute configuration of
cycloalkanediol or diamine. Two equivalent chromophores (e.g.
p-Me2NC6H4CO2-) in a molecule are required for the assignment.
The two chromophores cause the split of their CD peak. One is
negative and the other is positive.
When the longer wavelength band of the split peak describes a
positive Cotton effect and the shorter one describes a negative
Cotton effect, the two chromophores arranged in a right-handed
helix.
(h) How to analyze enantiomeric excess
Percentage of enantiomeric excess (% ee) is commonly used for
representing the ratio of enantiomers. (% ee (R-enriched) = ([R]
[S])/([R] + [S]) 100)
1) Specific rotation Specific rotation is usable for measuring
enantiomeric excess, if specific rotation of enantiopure
compound has been reported. % ee = [a]D (sample)/[a]D (100% ee)
100
However, the specific rotation is significantly affected by
inpurity, solvent, and temperature. Sometimes, concentration of the
sample affects the specific rotation.
2) Chiral HPLC and GC Chiral HPLC or GC analysis is commonly
used for measuring enantiomeric excess. Chiral HPLC is effective
for relatively polar compounds (alcohol, ketone, ester, amide etc.)
with a
UV active moiety (-bond). Chiral GC is usable for less polar
compounds (hydrocarbon, ether etc.) as well as above
compounds. UV active moiety is not required, but the sample must
be volatile. 3) Chiral shift reagent
Prepare NMR sample of the target compound in CDCl3 or C6D6 and
measure 1H NMR. Add a small amount of a shift reagent to the NMR
sample, and then measure 1H NMR again. Repeat the process several
times until a proton signal completely splits. The enantiomeric
excess of the sample is calculated from the ratio of the integrals
of each split peak.
Representative chiral shift reagents
OH
NMe2
OO
Ar
O
O
ArOHOH
Ar
O
Cl==
HO
HO
NMe2
O
OM
Rf
Me
Me
Me 3
Rf = CF3 (tfc) or C3F7 (hfc)M = Yb or Eu
NO2
HNO
OHN
N
N
O
O
HN
HN
O
OM(tfc)3 or M(hfc)3
Octant rule for standard ketones. (a) Signs of the sectors in a
left-handed Cartesian coordinate system; (b) projection of the rear
sectors (z < 0).
-
9
(3) Diastereomers (a) Notations of diastereomeric
stereochemistry
1) E/Z notation for alkenes As with R/S notation, E/Z notation
unambiguously defines the geometrical configuration of
alkenes. The notation is based on CIP rule. i) Determine the
priority of the two substituents on each atom involved with the CC
double bond. ii) Confirm the positional relationship of each
substituent with higher priority.
2) cis/trans notation
Cis/Trans notation is ambiguous, but often used for indicating
the geometrical configuration of alkenes or the relative
configuration of cyclic skeletons including two chiral centers.
Priority of each substituent is determined with common sense,
which causes the ambiguity (CIP priority or main chain in IUPAC
nomenclature?).
In the case of alkene geometry, cis and trans configurations
correspond to Z and E, respectively.
3) erythro/threo notation for relative configuration
Erythro/threo notation is ambiguous, but often used for
indicating the relative configuration of acyclic vicinal chiral
centers. Erythro and threo forms are strongly related to the
stereochemistry of erythrose and threose.
If the substituents on each chiral carbon are arranged in a
similar manner, the configuration is threo. Otherwise, the
configuration is erythro.
4) syn/anti notation for relative configuration
Syn/anti notation is less ambiguous than erythro/threo notation
and applicable to various acyclic compounds.
Draw the structure of the target compound with zig-zag
projection. If two substituents are arranged on the same face, the
configuration is syn. Otherwise, the configuration is anti.
5) R*/S* (or RS/SR) notation for relative configuration R/S
notation is applicable in relative configuration. This notation is
unambiguous. Assign the absolute configurations of all chiral
center in an enantiomer. Attach an asterisk to
each R or S descriptor. (2R*, 3S*) is equivalent to (2S*,
3R*).
6) l/u notation for relative configuration
Determine the absolute configurations (R/S or P/M) of all chiral
centers, and then arrange them according to the numbering rule in
IUPAC nomenculture.
If the absolute configurations of two neighboring chiral centers
are identical or similar each other, the relative configuration is
l (like). Otherwise, u (unlike) must be used as the stereochemical
descriptor. For example, uu-1,2,3,5-hexanetetraol is equivalent to
(2R*,3S*,5R*)-1,2,3,5-hexanetetraol.
(b) Treatment of stereochemistry in CIP rule
In CIP rule Atomic number larger higher priority Isotope atomic
mass: larger higher priority Alkene stereochemistry priority: Z
> E (cis > trans)
In most cases, the priority of two geometrically isomeric groups
can be determined by Z/E system. However, the system is useless to
4-substituted alkylidenecyclohexanes, although they can be regarded
as axially chiral molecules. In this case, the alkene configuration
is determined from the substituent bearing the chiral center.
Diastereomeric groups priority: l > u ( Enantiomeric groups R
> S or M > P?)
(c) How to determine stereochemistry of diastereomer 1)
Crystallography
If the sample is crystalline solid, its X-ray crystal structure
analysis is the most reliable. 2) NMR
i) 1,2-Disubstituted alkene nOe (nuclear Overhauser effect)
difference spectrum Positive nOe will be observed between two
substituents, which are located in the cis position
a
b
c
da > b, c > d
a
b
c
d
a
b
c
da > b, c > d
a
b
c
d
a
d
bc
a
d
bc
CHOOH
OHD-erythrose HO
CHOOH
OHD-threose HO
==
==
CH2OH
H OH
OHC
H OH
CH2OH
H OH
OHC
HO H
b'
c' a'
b
c a
b'
c' a'
b
a c
2
13
3
1
2
2
13
3
1
2
Me
OH OH
OH2 4
5 Me 2,4-syn, 2.5-anti
Me OHOH
OHOH(2R*,3S*,5R*)-1,2,3,5-hexanetetraol
= (2S*,3R*,5S*)-1,2,3,5-hexanetetraol
O OHOH
HOHOHO
CHO
OH
OH
OH
OHHO RRR S
D-glucose uul-2,3,4,5,6-pentahydroxyhexanal
CO2H
H MeH Me
HO2C
CO2Hcistrans
12
34S
positional relationship between a and c the same side Z opposite
side E
positional relationship between a and c the same side cis
opposite side trans
a b c vs a' b' c' the same direction erythro opposite direction
threo
-
10
each other. NOESY should be avoid to use for the purpose.
Vicinal HH coupling (3JHH) In general, the coupling constant
between the two alkenyl the alkenyl protons is 1013 Hz when
the protons are arranged with cis configuration. In the trans
isomer, the coupling constant is 1517 Hz.
The above rule is useful only when a carbon atom attaches to
each alkenyl carbon. Heteroatom substituents causes decrease in the
coupling constant.
ii) Saturated four- and five-membered ring
NOESY or nOe difference spectrum Use only transannular nOe.
Sometimes, nOe is observed between vicinal hydrogens with
trans configurations, because these protons couple with each
other.
iii) Saturated six-membered ring
Chemical shift In general, an axial proton appears in higher
field (ca. 0.5 ppm) than its corresponding
equatorial proton. Vicinal HH coupling Karplus equation: 3JHH =
A cos2 + B cos + C (: dihedral angle)
(e.g. A = 9.4, B = 1.4, C = 0.4 (for hydrocarbons)) 3JHaxHax is
814 Hz, because dihedral angle for HaxCCHax is 180. 3JHaxHeq and
3JHeqHeq
is 24 Hz, because the related dihedral angles are 60. Higher
magnetic field NMR spectrometer should be used for assigning the
relative configuration
of cyclohexane derivative. Assign as many paeks as possible by
using not only 1D-NMR but also HH cosy, HMBC. HSQC etc.
Assign the stereochemistry by using each coupling constant in a
similar way to solving a puzzle.
iv) Acyclic compound see: Bifulco, G.; Riccio, R. Chem. Rev.
2007, 107, 3744. General methods JBCA (J-based configuration
analysis) see, Murata, M. J. Org. Chem. 1999, 64, 866. UDB
(Universal NMR Database) see, Kishi, Y. Org. Lett. 1999, 1, 2177
and 2188. Use of quantum mechanical calculation 1,2- or 1,3-diols
(diamine) Protect the diol with acetone (or 2,2-dimethoxy propane,
phosgene etc.) to give the
corresponding acetonide. Analyze the resulting cyclic acetal
with NOESY, nOe difference spectrum, HH coupling constrants
etc.
1,3-diols Acetonides of syn-1,3-diols have chair conformation,
while those of anti-1,3-diols prefer twist
boat conformation. Therefor, the relative configuration of
1,3-diols can be elucidated with the 13C NMR resonances of the
methyl groups of their acetonides.
H H H CHR2 R2HC CHR2 H OCH3
HOCH3
O?
CH3OCH3
O?
H H
C C3JHH = 1013 Hz
H C
C H3JHH = 1517 Hz
abd
c
The nOe between a and d (red) is reliable for determing the
relative configulation. The nOe between a and b (blue) should be
avoid to use for the purpose, because an nOe is sometimes observed
between a and c.
R1 R2OH OH
R1 R2O O
Me Me
R1 R2OH OH
R1 R2O O
Me Me
==
==
OO
R1
R2 Me
Me
OO
R1
R2Me
MeOOR2R1
H
H
MeMe 24.6 0.76
19.4 0.21
30.0 0.15
98.1 0.83
100.6 0.25syn-1,3-diol
anti-1,3-diol
-
11
(4) Conformation of organic compounds (a) Acyclic saturated
compounds
1) Ethane The staggered conformer ( = 60 or
180) is more stable than the eclipsed one ( = 0 or 120) (E = 2.9
kcal /mol).
The ecripsed conformer is a transition state and not energy
minimum.
The CH*CH interaction stabilizes the staggered conformer.
The steric repulsion between the vicinal protons scarcely
contributes to rotational barrier.
2) Butane Butane has two energy minima: one is anti, and the
other is gauche. Anti conformer is more stable than gauche one
(E =
0.9 kcal /mol). Each conformer, including unstable conformers,
can be
named with the dihedral angle as shown below.
3) Pentane
In the conformational analysis of pentane, the free rotations of
C2C3 and C3C4 should be considered.
Conformer aa is the most stable conformer of pentane. Conformers
g+g and gg+ are the least stable. The energies of these
conformers has been estimated to lie over 3.3 kcal/mol above
that of conformer aa.
The steric repulsion is called 'syn-pentane interaction'.
4) Effect of * or n* interaction Conformation involved with
C(sp3)C(sp3) bond is affected by the hyperconjugation between
vicinal CX bonds. In the hyperconjugation, one of the orbital of
CX bond donates electrons to *-orbital of another CX.
Electron donating ability: nN > nO > CC, CH > CX (X: N
> O > S > Hal) Electron accepting ability: C=O > *CHal
> *CO > *CN > *CC, *CH Gauche effect: In some compounds,
gauche conformer is preferable to anti conformer.
Anomeric effect: The ratio of - and -glucose is 38:62 in water.
The unusual ratio (A value of
OH is 0.60) is caused by anomeric effect, the interaction
between nO and *CO orbital.
(b) Acyclic unsaturated compounds
1) XCH2CH=Y (Y = CH2, O) Energy minima appear when the C(sp3)X
(or H) bond overlaps to the C=Y bond in the Newman
projection. Another conformer, in which the CX bond overlaps to
the C(sp2)H bond, is a torsional barrier.
Steric repulsion between X and Y is often considerable in the
eclipsed conformer (1,3-allylic strain). Therefore, the gauche
conformer is generally preferable to the eclipsed one.
The gauche or ecripsed conformation is stable in substituted
benzenes. Allylic strain:
2) X=CHCH=Y
In general, s-trans conformer is more stable than s-cis, when
there is no steric repulsion in the conjugated molecule.
However, gauche conformer is preferable to s-cis one, if X
and/or Y have a substituent and both double bonds have
Z-configuration.
Ra
bb
ccd
RC A
B
a: synperiplanar (ecripsed, 30 < < 30)b: synclinal
(gauche, 30 < < 90 ())c: anticlinal (90 < < 150 ())d:
antiperiplanar (anti, 150 < < 180 ())
CH2FCH2F:
F
FHH H
H F
HHH H
FE = 2.02.6 kcal/mol
OHOHO
HOOH
HO OHOHO
HOOH
HO
-glucose -glucoseOH
OnO
*CO
X
HH
Y
H
H
XH
Y
HH
XH
Y
Hbisecting
(rotational barrier)gauche
(a stable confomer)eclipsed
(less stable than gauche)
XH
H Y
HFelkinAnh-type
(not stable)
RR
HHHRH
HHR
1,3-allylic strain (A(1,3)-strain)
R
HH
H
RH
RR1,2-allylic strain (A(1,2)-strain)
The * interation between the vicinal CH bonds.
syn-pentane interaction
-
12
3) Carboxamides
CN bond of carboxamide possesses double bond character, because
structure 2 remarkably contributes to the resonance hybrid.
Therefore, the rotation of CN bond is relatively slow.
In NMR analysis, a set of signals are often observed because the
ZE isomerization of amide is slow in NMR time scale.
(c) 4-Membered rings
In 4-membered rings, planar structure is unfavorable because
torsional strain is maximum. Puckered structure is preferable to
planar one in order to escape the strain. The 4-membered
ring is released from the ecripsed conformation. The angle of
pucker is 28 and the barrier of ring inversion is 1.45 kcal/mol in
cyclobutane.
(d) 5-Membered rings
Conformation analysis of 5-mambered rings is significantly
complicated as compared to those of 4- and 6-membered rings,
because their conformation is very flexible.
Stable conformations of cyclopentane are envelope and half-chair
conformations. The former is more stable than latter, but the
energy difference of both conformers is very small (0.5
kcal/mol).
The envelope conformer is Cs-symmetry, and the half-chair
conformer is C2-symmetry. Equilibrium between envelope and
half-chair conformers is remarkably affected by substituents.
(e) 6-Membered rings
1) Saturated rings Stable conformations of saturated 6-membered
rings are chair and twist boat. Boat
configuration is the transition state of the interconversion
between two twist boat conformers. In most cases, chair conformer
is more stable than twist boat conformer. Rarely, twist boat is
preferable to chair in order to avoid large 1,3-diaxial
interaction.
Stability of conformer of substituted 6-membered rings is
affected by A-value, 1,3-diaxial interaction, and the presence of
gauche conformation etc.
Fused ring systems Bicyclic system of cis-fused cyclohexane,
such as cis-decaline, is possible to invert. In contrast,
ring inversion of the trans-isomer is impossible.
2) Cyclohexene
The most stable conformation of cyclohexene is half-chair.
In 1,6-disubstituted cyclohexenes, substituent R' at the
6-position induces considerable
A(1,2)-strain if it occupies the pseudo-equatorial position. To
avoid the strain, R' tends to occupy the psudo-axial position.
3) Cyclohexanone
Cyclohexanones prefer chair conformation. Their conformations
are affected by the dipole and planar structure of carbonyl
group.
Y
H
X
H
X YH
Y
X
H
XY
s-ciss-trans
Y
H
X
H
X Y
gauche
O
R1N
R2
R3 O
R1N+
R2
R3
1 2
ON
H
Me
HE = 20.6 kcal/mol
ON
Me
Me
HE = 21.3 kcal/mol
5
67
84
3
1
2
2
14
37
8
6
5
E = 1.45 kcal/mol
envelope
C2
half-chair
chair half-chair twist boat boatR
R
axialequatorial
cis-decaline trans-decaline
==
half-chair
pseudo-axialpseudo-equatorial
R'R'
H HR RA(1,2)-strain
more stable
R R 1,3-diaxial interaction