Stereochemistry: Part II

1
Stereochemistry Part II
Chem 313Spring Semester 2009
2
Enantiomers and Diastereoisomers
Structural representations
Fischer Projections
(.)-Lactic Acid
()-Lactic Acid
S
R
R
S
R
S
(2R,3R)- ()- Tartaric Acid
meso- or (2R,3S)- Tartaric Acid
(2S,3S)- (-)- Tartaric Acid
meso compound number such that .-chiral
centre precedes .-chiral centre!
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Structural Representations (cont.)
Relationship between Fischer, Newman, sawhorse,
other projections
(2R,3R)- ()- Tartaric Acid
R
R
R
S
R
R
."
"
D-Glucose
..' or ' projections used for
depicting stereostructures of reaction products
or natural products!
4
Structural Representations (cont.)
..' and '
Use .' and to describe relative
stereochemistry of substituents attached to
adjacent chiral centres and projecting out on
opposite sides from 'zig-zag' backbone

..
..
.....' both substituents projecting 'forward'
or 'back' .' one substituent 'forward', the
other 'back'
R
S
R
S
S
R
R
S
..
..
..

note relative stereochemistry only is described
by ..' and ' (used later to describe
relative stereochemistry of products from
stereoselective reactions).
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Nomenclature of Ligands and Faces
Ligand any atom or group attached to a reference
atom Face the 'space' above and below a
reference plane
Ligands, enantiomers and diastereoisomers
(diastereomers)
R
R
R
S
r
s
0
0
S
S
R
S
Diastereomers (both are meso compounds!!)
Enantiomers
.. ligands' consist of atoms or groups
identically linked to a chiral centre with the
same absolute configuration
.. ligands' consist of atoms or groups
identically linked to a chiral centre with the
opposite absolute configuration
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1. .. Ligands
Substitution criterion If two or more identical
ligands are sequentially replaced by a third
ligand to generate the same structure, the
ligands are .
Products are .. Ha and Hb are .
ligands'
Products are Ha, Hb and Hc are .
ligands'
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1. .. Ligands (cont.)
S
R
0
R
S
S
R
R
S
S
R
0
(2S,4S)- pentane-2,4-diol
R
(2R,3R)- ()- Tartaric Acid
S
identical Ha, Hb
identical! Ha, Hb .
Note that .. ligands are chemical shift
equivalent ('isochronous') in the NMR spectrum.
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2. Faces
Addition criterion Two corresponding faces of a
molecule are ..when addition of the same
reagent to either face gives the same product
Nucleophilic addition to carbonyl compound
attack on 'top' face
attack on 'bottom' face
Products are identical faces are '
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Heteretopic Ligands and Faces 3. .. Ligands
Heterotopic 'different' heterotopic includes
'enantiotopic' or 'diastereotopic'
Substitution criterion Two ligands are
if replacement of each by a third non-chiral
ligand generates a pair of enantiomeric products
R
Products are enantiomers Ha and Hb are
..'
S

• The starting structure (CH2BrCl) is 'prochiral'
• Ha is called the 'pro-' hydrogen atom
• Hb is called the 'pro-.' hydrogen atom

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3. Enantiotopic Ligands (cont.)
R
Hb and Hc .
enantiomers
S
identical
R
Ha and Hc ..
enantiomers
S
.
chiral

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3. . Ligands (cont.)
R
S
R
S
R
meso- or (2R,3S)- Tartaric Acid
S
Enantiomers Ha, Hb ..
Enantiomers Ha, Hb .
Note that ligands are chemical shift
equivalent ('isochronous') in the NMR spectrum
in an achiral environment.
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4. Faces
Addition criterion Two faces are .. if
addition of the same achiral reagent to each
face generates a pair of enantiomeric products
Enantiomers 'top' and 'bottom' faces of
aldehyde are
S
R
Enantiomers 'top' and 'bottom' faces of
?,?- unsaturated ketone at C-3 are
R
S
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4. . Faces (cont.)
Nomenclature of enantiotopic (and diastereotopic)
faces use .' and ', assigning priorities
to groups attached to designated (sp2) atom
within trigonal plane.
.. face
face
face
.. face
It is important to define face with reference to
point of attack by the reagent.
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5. Ligands
Substitution criterion Two ligands are
if replacement of each by a third non-chiral
ligand generates a pair of diastereoisomeric
products
R
Z
R
R
S
E
R
Diastereomers Ha, Hb ..
Diastereomers Ha, Hb
Ha is pro-R Hb is pro-S
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5. Ligands (cont.)
S
S
R
r
R
S
0
R
R
S
R
s
Citric acid
meso- or (2R,4S)- pentane-2,4-diol
R
Diastereomers Ha, Hb ..
Diastereomers Ha, Hb
Note that .. ligands are chemical shift
non-equivalent ('anisochronous') in NMR
spectrum.
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6. .. Faces
Addition criterion Two faces are .. if
addition of the same achiral reagent to each face
generates a pair of . products
..-face attack
R
S
S
-face attack
S
S
S
.. 'top' and 'bottom' faces of
unsaturated lactone are ..
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Homotopic and Heterotopic Ligands and Faces
Significance

• Spectroscopic identification of organic compounds
  ? CHEM 312
• Stereoselective reactions to be considered
  later
• Enzyme catalysed reactions.

Consider metabolism of ethanol in the human body!

• Catalysed by enzyme 'liver alcohol dehydrogenase'
  LAD
• Requires cofactors nicotinamide adenine
  dinucleotide (NAD), and Zn2

C2H5OH
CH3CHO
H
NADH
NAD
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Metabolism of Ethanol Stereochemistry
Which hydrogen atom of ethanol is transferred to
NAD?

• H atoms at C1 of ethanol are ...

S
R

• In a chiral environment (enzyme binding site),
  the atoms are ......
• Stereoselective transfer of one atom will take
  place.
• Need to prepare deuterated ethanol to establish
  which atom is transferred.

()-(-)-1-deutero ethanol
(..)-()-1-deutero ethanol

• Each of the chiral deuterated ethanol is
  incubated with the enzyme, and the product
  acetaldehyde is analysed by mass spectrometry.

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Metabolism of Ethanol Stereochemistry (cont.)
pro-..-H atom at C-1 abstracted from ethanol!
(.)-(-)-1-deutero ethanol
..-face of NAD receives H from ethanol!
(..)-()-1-deutero ethanol
Note that reaction is reversible if large excess
of acetaldehyde is presented to enzyme,
reduction to ethanol will occur by reverse of
above pathway
Which face of acetaldehyde receives the hydrogen
atom?
..-face!
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Conformational Analysis
Conformational aspects of six-membered rings
Chair-chair inversion by half-chair and twist
boat conformations
.
.
.
is highest-energy conformer ( 11 kcal
mol-1above energy of chair) two chair forms are
degenerate equally populated at 25 C
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1. Monosubstituted Cyclohexanes
Newman projection . methylcyclohexane
Newman projection methylcyclohexane
Analyze for presence of butane gauche
interactions involving methyl group in .
conformer
- . butane gauche interactions (includes both
torsional, and steric strain)
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1. Monosubstituted Cyclohexanes (cont.)
Now analyze for presence of butane gauche
interactions involving methyl group in .
conformer
There are ! However, two 'anti' orientations
(. torsional or steric strain!)

• Axial methylcyclohexane is less stable than
  equatorial by 2 x 0.9
• kcal mol-1 1.8 kcal mol-1
• From relationship ?G -RT lnK (see slide 9
  Part I), at 25 C,
• equilibrium concentration of conformers is
• 95 equatorial, 5 axial!
• The energy difference represents preference for
  methyl group to be
• equatorial the 'A-value' or 'conformational
  energies'.

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1. Monosubstituted Cyclohexanes (cont.)
A-values
R A-value (kcal mol-1) -CH3 1.74 -CH2CH3
1.79 -CH(CH3)2 2.21 -C(CH3)3 4.7-4.9 -C6H5 2.8 -C
OOH 1.4 -COO- 2.0 -COOCH3 1.2-1.3
R A-value (kcal mol-1) -C?N 0.2 -F 0.25-0.42
-Cl 0.53-0.64 -Br 0.48-0.67 -I 0.47-0.61 -OH
0.60 (C6H12 solvent) -OH 1.04 (CS2) -SH 1.21

• A-value expressed as - ?G 0
• value is function both of van der Waals radius
  (steric strain) and bond length.
• -COO- is 'solvated' effective 'larger' size.
• tert-butyl group serves as a 'conformational
  anchor' over 99.9 of equilibrium
• mixture of tert-butylcyclohexane conformers is
  the equatorial conformer!

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2. Disubstituted Cyclohexanes
cis-1,2-dimethylcyclohexane
Ring inversion barrier ? 12 kcal mol-1 rapid
at room temperature!

• .. ..!

axial methyl group . x gauche interactions
axial methyl group .. x gauche interactions
Equilibrium concentration of conformers at 25 C
is 50 of each . ? . mixture!
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2. Disubstituted Cyclohexanes (cont.)
trans-1,2-dimethylcyclohexane
relationship between conformers?

• .. ..!

trans-diaxial
trans-diequatorial
axial methyl x gauche interactions!
equatorial methyls . x gauche interaction!
axial methyl x gauche interactions!
Difference in energy between trans-diaxial and
trans-diequatorial conformer ( x 0.9)-(. x
0.9) . kcal mol-1.
Equilibrium concentration of .. at 25 C is
99 diequatorial, 1 diaxial!
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2. Disubstituted Cyclohexanes (cont.)
cis-1,3-dimethylcyclohexane

• ....
• both !

relationship between conformers?
cis-diaxial methyls .. x gauche interactions!
cis-diequatorial methyls . x gauche
interaction!
For cis-diaxial conformer - additional steric
or van der Waals interaction torsional strain
"1,3-diaxial interaction" - between axial methyl
groups - 1.8 kcal mol-1.
Difference in energy between trans-diaxial and
trans-diequatorial conformer (. x 0.9) 1.8
.. kcal mol-1.
Equilibrium concentration of conformers at 25 C
is 99.99 diequatorial, 0.01 diaxial!
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2. Disubstituted Cyclohexanes (cont.)
trans-1,3-dimethylcyclohexane
S
S
relationship between conformers?

• ..!

S
S
conformational equilibrium displaying
residual stereoisomerism at 25 C!
R
R
For enantiomers
R
R
The (S,S) and the (R,R)-enantiomers .
interconverted!
cis-1,4-dimethylcyclohexane

• !

relationship between conformers?
conformational equilibrium at 25 C!
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2. Disubstituted Cyclohexanes (cont.)
trans-1,4-dimethylcyclohexane
relationship between conformers?

• .
• !

trans-diequatorial methyls x gauche
interaction
trans-diaxial methyls . x gauche interactions
Difference in energy between trans-diaxial and
trans-diequatorial conformer (. x 0.9)
.. kcal mol-1.
Equilibrium concentration of conformers at 25 C
is 99.6 diequatorial, 0.4 diaxial!
conformation analysis is very important in
predicting conformation preferences and
reactivity of cyclic compounds, and predicting
preferences for selection of 'cyclic transition
states' later!
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Conformation and Reactivity Steric Effects

• Two effects
• steric effects normally refers to a steric (van
  der Waals) interaction as
• reactants approach each other, or as a reaction
  moves through a transition
• state.

Energy
?G A
?G B
?G ref
GSB
GSA
GSref
?G Blt ?G ref
?G Agt ?G ref
Case A steric effects have small effect on
energy of ground state (GS), but raise energy
of TS relative to a reference reaction (higher ?G
relative to reference 'steric
hindrance') Case B steric effects raise energy
of GS, and but have little effect on energy of
TS (lower ?G relative to reference -'steric
assistance').
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Revision hydrolysis of esters
Base-induced hydrolysis saponification
i. addition usually RDS
ii. .
iii .
Reaction is brought to completion equilibrium in
step iii lies to the right
pKa ROH gtgt pKa RCOOH ROH much weaker acid
than RCOOH RO- much stronger base than RCOO-
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Conformation and Reactivity Steric Effects
(cont.)
Case A 'Steric ..'
Base hydrolysis of ester rate determining step
(RDS) is formation of tetrahedral intermediate
equatorial ester no relative change in steric
effects in going from 'ground state' (structure
1) to transition state leading to intermediate
axial ester steric effects are enhanced in going
from GS to TS leading to intermediate (sp2 ?sp3
centre, developing negative charge - solvation!)
larger 'butane'-gauche interactions.
Note that tert-butyl group has overwhelming
preference to be equatorial (A value 4.7-4.9)
krel equatorialaxial 8.50.43
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Conformation and Reactivity Steric Effects
(cont.)
Case B 'steric ..'
Oxidation of axial and equatorial cyclohexanols
by Cr(VI) rate determining step is conversion
of intermediate chromate ester into ketone
steric crowding raises GS energy of axial ester-
lower activation energy reaction to ketone is
faster 'steric assistance' due to relief of
steric strain (2 x gauche interactions) in axial
chromate ester.
krel axialequatorial 13.04.0
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Conformation and Reactivity Stereoelectronic
Effects
Effects involving spatial disposition of
non-bonding and bonded electron pairs.
The anomeric effect D-glucose (Fischer
projection Slide 3)
Equilibrating mixture of cyclic hemiacetals and
open chain aldohexose in aqueous solution

• ?- and ?-isomers - diastereomers - 'epimers' or
  'anomers C1 'anomeric centre'
• Crystallization from water below 50 C ?
  ?-D-glucopyranose, ?D20 112.2 evaporation
  of water at 115 C ? ?-D-glucopyranose, ?D20
  17.5
• Each anomer dissolved in water ? equilibrating
  mixture, ?D20 52.7 - 'mutarotation' to give
  mixture 64 ?, 36 ?-epimer.
• ?- or equatorial epimer favoured - K 1.34, ?G
  -0.34 kcal mol-1.

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Stereoelectronic Effects The Anomeric Effect
(cont.)
D-glucose (cont)

• ?- or equatorial epimer favoured K 1.34, ?G
  -0.34 kcal mol-1.

• For cyclohexanol, equatorial epimer is more
  favoured K 4.5

• For glucose methyl acetal, the ?- (axial)
  epimer is favoured in methanol or water K
  1.5

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Stereoelectronic Effects The Anomeric Effect
(cont.)
Other cyclic pyranose systems
Chlorocyclohexane
2-Chlorotetrahydropyran
-Cl A value 0.53 kcal mol-1 (Slide 23) ?
equatorialaxial ? 7327
?G 1.8 kcal mol-1 equatorialaxial 595!
Substituent must be 'electronegative' (that is,
'electron-accepting')!
?G -1.8 kcal mol-1 equatorialaxial 955!
The anomeric effect When there is a heteroatom
in the ring attached to the C atom bearing an
'electronegative' substituent, the effect is to
lower the energy of the axial conformer!
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Stereoelectronic Effects The Anomeric Effect
(cont.)
Examples
K (neat liquid) 32 at 40 C axialequatoria
l gt964
K 3.4, CCl4 axialequatorial gt7723
K gt 49 at 25 C, CDCl3 axialequatorial
gt982!
Only axial conformer is observed (X-ray
crystallography)!!
37
Stereoelectronic Effects The Anomeric Effect
(cont.)
Anomeric Effect due to i. dipole-dipole
repulsion?
Approximately anticlinal arrangement of partial
and bond dipoles
Approximately syn-periplanar arrangement of
partial and bond dipoles

• Overall lower molecular dipole for axial isomer
• electrostatic effect, will show solvent effect!

Solvent ? axialequatorial CCl4 2.2
8317 C6H6 2.3 8218 CHCl3 4.7
7129 (CH3)2CO 20.7 7228 CH3OH 32.6
6931 CH3CN 37.5 6832 H2O 78.5 5248
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Stereoelectronic Effects The Anomeric Effect
(cont.)
Anomeric Effect due to i. dipole-dipole
repulsion? - problem axial and equatorial
tetrahydropyrans have significantly different
bond lengths!
1.428 Å
1.366 Å
1.895 Å
1.754 Å
1.409 Å
1.395 Å
1.409 Å
1.415 Å
1.394 Å
1.819 Å
1.781 Å
1.425 Å
A remarkable effect! Explained as due to
hyperconjugation
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Stereoelectronic Effects The Anomeric Effect
(cont.)
Anomeric Effect hyperconjugation - overlap of ?
C-Cl orbital with n orbital on O in axial
conformer (check McMurry p. 19 for ?)

• Lone pair of electrons on O antiperiplanar to
  axial Cl!
• 'Hyperconjugation' gives double bond character
  to O-C bond ? shorter bond!
• C-Cl bond has 'ionic character ? longer bond!
• Equivalent to a resonance contributor!
• Compare antiperiplanar arrangement to TS of E2
  reactions!

The effect implies different chemical reactivity
for axial, equatorial groups also controls
stereochemical outcome of certain reactions!
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Stereoelectronic Effects The Anomeric Effect
(cont.)
Consider the following reaction involving
formation of cyclic acetal

• Acid-catalyzed formation of acetal from ketone
  and alcohol - see McMurry Ch. 19, pp. 702-705
• Above reaction is intramolecular example -
  stereochemistry of most stable product?

ax
ax
ax
eq
eq
ax
eq
eq
Examine axial-equatorial relationship of C-O bond
with respect to other tetrahydropyran ring! -
Axial-axial isomer most stable!
41
The Anomeric Effect Problem
Predict the major product obtained in the
following reaction

• Reaction involves oxonium-stabilized cation as
  intermediate

Axial addition is kinetically preferred to give
axial product
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Stereoelectronic Effects SN2 Reactions
SN2 rate k RXY, R 1, 2 alkyl group X
Cl, Br, I, OH2 or other leaving group Y
nucleophile (uncharged, or negatively charged)
i. via bimolecular trigonal bipyramidal
pentacoordinated TS

ii. Concerted no intermediate
iii. Nucleophile attacks carbon bearing LG
(leaving group) along axis of C-LG bond on
opposite side (backside attack).
iv. For basic, hindered nucleophile, competing E2
reaction for alkyl halides with ?-hydrogen
atoms
increasing E2
(CH3)3CO- gt(CH3)2CHO- gtCH3CH2O- gtCH3O-
increasing SN2
43
Stereoelectronic Effects SN2 Reactions (cont.)
SN2 Concerted no intermediate
Reaction Profile
Energy
Reaction Coordinate
44
Stereoelectronic Effects SN2 Reactions (cont.)
SN2 reaction in cyclohexyl systems
krel axialequatorial 311
Stereoelectronic effect 'backside attack' by
nucleophile along axis of C-OTs bond in
equatorial tosylate, trajectory of attack by
C6H5S- engenders severe steric interactions with
axial H steric effect 'steric assistance' in
displacement of axial tosylate
45
Stereoelectronic Effects E2 Reactions
E2 reaction Rate k RXB
Bimolecular antiperiplanar transition state
('anti elimination')

?
?
Concerted reaction no intermediate
Transition State
?-Carbon atom bearing leaving group X attached
to ?-carbon atom with at least one hydrogen atom
?
- ?-elimination reaction
46
Stereoelectronic Effects E2 Reactions (cont.)
Reaction profile concerted reaction - no
intermediate

Energy
Reaction Coordinate
47
Stereoelectronic Effects E2 Reactions (cont)
E2 elimination in bromocyclohexane
antiperiplanar pathway
For Br equatorial, no antiperiplanar arrangement
of Br, H required for elimination.
Change to other chair conformer generates
antiperiplanar arrangement of Br, H required for
elimination.
48
Stereoelectronic Effects Lactonization
Formation of lactone from 3-hydroxycyclohexane
carboxylic acid only takes place in cis-diaxial
conformer (eeaa at 25 C 99.40.6)
49
Stereoelectronic Effects Grob Fragmentation
Grob fragmentation 1,3-relationship of
e-donating (EDG or electrofuge) and e-withdrawing
groups (EWG or nucleofuge)
cis-diequatorial isomer
trans-axial-equatorial isomer less effective!
50
Stereoelectronic Effects Grob Fragmentation
(cont.)
Grob fragmentation (cont.) 1,3-relationship of
EDG, EWG
Fragmentation easy to carry out brilliantly
exploited in the total synthesis of Cecropia
juvenile hormone (Slide 44, Introduction)
51
Stereoelectronic Effects Grob Fragmentation
(cont.)
Can be induced by the formal equivalent of a
nucleophilic displacement process
check hydroboration McMurry p. 215
This kind of reaction was used in the synthesis
of thapsigargin, a potent Ca2-transport
inhibitor!
52
Stereoelectronic Effects Problems
Problem a. Explain as concisely as possible the
observation that solvolysis of the
cis-disubsituted cyclohexane 1a in aqueous
ethanol rapidly yields the iminium salt 1b.
i. You must draw correct conformational
representation of the cyclohexane 1b. ii. Grob
fragmentation electron donating group
(CH3CH2)2N- - and leaving group - OTs
associated with favourable arrangement of
participating bonds in 'W' arrangement (your
drawing should show this).
53
Stereoelectronic Effects Problems (cont.)
Problem (cont.) b. The iminium salt 1b undergoes
a slower hydrolysis under the reaction conditions
to give the aldehyde 1i. Draw the mechanism.
Hydrolysis of iminium salt simplify structure so
it is easier to draw
54
Stereoelectronic Effects Problems (cont.)
Problem c. Explain as concisely as possible why
compound 1c on solvolysis in aqueous ethanol
reacts much more slowly than the
cis-disubstituted cyclohexane 1a, and only gives
a small amount (11-13) of compound 1b, and the
products 1d-1h.
First, draw out 1c in correct conformation

• A values for p-toluenesulfonate group (-OTs or
  -OSO2C6H4CH3-p) is 0.50 kcal mol-1 and
  N,N-diethylamino group N(CH2CH3)2 is 2.8 kcal
  mol-1- N(CH2CH3)2 prefers to be equatorial
• Bonds between electron donating group
  (CH3CH2)2N- - and leaving group -OTs in 1c
  are not in 'W' arrangement suitable for Grob
  fragmentation. Thus, whilst a small amount of
  Grob fragmentation takes place, other reactions
  compete

55
Stereoelectronic Effects Problems (cont.)
Problem c. (cont.) The competing reactions are
- i. E2 elimination leading to products 1d and
1e. B is base this may be the tertiary amino
group in compound 1c itself or product 1d or 1e,
or hydroxide ion produced by equilibration of the
basic amino group of 1c-1e in the water in the
reaction mixture (CH3CH2)2N-R H2O ?
(CH3CH2)2NH-R HO-
Axial tosylate and axial hydrogen on adjacent C
atoms enables E2 reaction to proceed via
antiperiplanar TS check review of first year
elimination reactions!
56
Stereoelectronic Effects Problems (cont.)
Problem c. (cont.) competing reactions are- ii.
hydrolysis of tosylate by water or HO- to produce
p-toluenesulfonic acid (TsOH) and alcohol no
need to write mechanism H2O p-CH3C6H4-SO2-OR
? p-CH3C6H4-SO2-OH H-OR remember that TsOH
will protonate amine in the reaction mixture
e.g. (CH3CH2)2N-R TsOH ? (CH3CH2)2NH-R
TsO-.
iii. SN2 substitution of the tosylate group by
HO- produced in equilibrium CH3CH2)2N-R H2O ?
(CH3CH2)2NH-R HO- (alkylamines are basic in
aqueous solution)
57
Stereoelectronic Effects Problems (cont.)
Problem c. (cont.) competing reactions are- iv.
formation of compound 1f via intramolecular SN2
reaction, probably via a twist boat conformer
Note that compound 1f can also undergo SN2
substitution by HO- produced in equilibrium
CH3CH2)2N-R H2O ? (CH3CH2)2NH-R HO- to give
compound 1g!
58
Conformation and Reactivity
Steric and Stereoelectronic Effects (conclusion)

• Many other examples
• considered later in the context of synthetic
  transformations be aware of them!
• extremely important in predicting reactivity of
  cyclic systems, and acyclic systems which
  involve 'cyclic transition states'.