Download NMR Spectroscopy for Studying Chirality

NMR Spectroscopy for
Studying Chirality
Thomas J. Wenzel
Department of Chemistry
Bates College
Lewiston, Maine 04240
[email protected]
Chiral Discrimination
NMR Spectroscopy
• Chiral derivatizing agents
• Chiral solvating agents
• Metal complexes
• Liquid crystals
Chiral Derivatizing Agents
• Form a covalent bond between an
optically pure reagent and the compound
of interest
CDA + (R)-Sub = CDA-(R)-Sub
CDA + (S)-Sub = CDA-(S)-Sub
• Resulting compounds are diastereomers
Chiral Discriminating Agents
• No racemization
• No kinetic resolution
• Need 100% optical purity of the reagent if
using for the determination of
enantiomeric excess
Chiral Solvating Agents
• Form non-covalent interactions between an
optically pure reagent and the compound of
interest
CSA + (R)-Sub = CSA-(R)-Sub
CSA + (S)-Sub = CSA-(S)-Sub
• Resulting compounds are diastereomers
• KR and KS are likely different – causes different
time-averaged solvation environments
Chiral Solvating Agents
• Preferable to have fast exchange
• High concentration of CSA usually leads to
larger discrimination
• Often see enhanced enantiomeric
discrimination at lower temperatures
Assigning Absolute Stereochemistry
• Mechanism of discrimination is understood and
characteristic shifts occur in the spectrum
– More common with certain families of chiral
derivatizing agents
– Possible with some chiral solvating agents
• Empirical trend
– Best if use known model compounds as close as
possible in structural features to the unknown
Aryl-containing Carboxylic Acids
-Alcohols and Amines
CH 3 O
F3 C
C
O
O
O
HC3 CO
H3 CO
COH
F
OH
OH
O
H 3C
C
COOH
CN
MTPA
MPA (O-MMA)
CFTA
O-AMA
OCH3
OH
O
OCH 3
H
N
OH
H3C
C
O
COOH
O
H3 CO
OH
N-Boc PG
MαNP
2-AMA/9-AMA
Aryl-containing Carboxylic Acids
• MTPA = α-methoxy-α•
•
•
•
•
•
trifluoromethylphenylacetic acid
MPA = α-methoxyphenylacetic acid
O-AMA = O-acetyl mandelic acied
CFTA = α-cyano-α-fluoro-p-tolylacetic acid
N-Boc PG = N-boc phenylglycine
MαNP = 2-methoxy-2-(1-naphthyl)propionic acid
2-/9-AMA = α-(2-anthryl)-α-methoxyacetic acid
Mosher Method/Modified Mosher Method
-Prepare derivatives with (R)- and (S)-forms of
the reagent
-Syn-periplanar arrangement of HC-O-C(O)-C
atoms (secondary alcohols)
-Calculate ∆δRS values – negative for L1, positive
for L2
L1
(OMe)
(Ph)
Ph
OMe
O
L2
CF 3
H
O
(R)-MTPA
(S)-MTPA
H1
OH
8
9
∆δ RS
RO
8
6
4
H2
Me(10) Me(8) Me(9)
MTPA 0.07 -0.017 -0.04
MPA
10
0.05 -0.021 -0.26
H1'
3
5
7
Position
MTPA
MPA
PPA
1
1'
2
3
4
4'
8
0.07
0.03
0.09
0.04
0.03
0.03
0.03
0.19
0.12
0.14
0.02
0.07
0.06
0.04
0.43
0.20
0.18
0.03
0.14
0.13
0.10
PPA = α-phenylpropionic acid
∆δRS depends on:
-Degree of conformational preference/how it
influences the shielding
-Size of the shielding (anthryl > naphthyl > phenyl)
Secondary Alcohols
• MPA > MTPA (conformational preference
that produces greater difference in
shielding)
• MPA – early synthetic procedures – high
degree of racemization
• Better procedures for MPA derivatization
now exist
• Mix and shake method
MPA derivative
I
OH
2.7 Hz differential shielding for the methyl group
9-bonds removed From the chiral center
Effect of temperature
• For MPA derivatives of secondary alcohols,
•
•
•
lowering the probe temperature by about 100 K
(to 175-200K) approximately doubles the ∆δRS
values
Alters conformational preference further toward
the sp form
Can measure ∆δT1T2 values as a confirmation of
stereochemical assignment
Effect not as pronounced with MTPA or AMA
Barium Method
MPA/secondary alcohols
ap
sp
MeO
H
Ph
O
α
O
Ph
O
H
α'
O
MeO
L2
L2
L1
L1
Barium binds in a chelate
manner with the ester and
alters the conformation
preference toward the sp
conformer.
Ba +2
Ba +2
Ba +2
MeO
H
Ph
O
α
O
Ph
H
α'
L2
L1
sp-Ba
+2
complex
O
Me
O
O
L2
Ba +2
ap-Ba
+2
L1
complex
Leads to enhancement in
the shielding and get larger
∆δRS values.
La(hfa)3 method with MTPA
Secondary alcohols
R2
R2
MeO
R1
OMe
R1
X
X
CF3
CF3
H
H
O
O
sp
sp
R2
R2
CF3
R1
F 3C
R1
X
X
OMe
H
O
OMe
M
H
O
M
Chelate bonding of the
La reverses the
orientation of the
phenyl ring and the
shifts of the hydrogen
resonances
sp'
sp'
(S)-MPTA derivative
(R)-MPTA derivative
X = O or NH
(b)
∆δ0S,R < 0
M
∆δ0S,R > 0
OMTPA
R1
R2
M
H
∆δMS,R > 0
MTPA plane
∆δMS,R < 0
This reversal in shifts
can be used to confirm
the stereochemical
assignment
2-AMA/9-AMA – Linear vs cyclic
secondary carbinols
Me
Me
H
O
MeO H
R1
R2
H
O
O
H
MeO H
MeO
R1
R2
H
MαNP (secondary alcohols)
OCH 3
H 3C
C
COOH
-∆δRS about 4-times greater than with MTPA
-Less prone to racemization with methyl group
on chiral carbon
CFTA (secondary alcohols)
F
H 3C
C
COOH
CN
• The ∆δRS values are typically 2-times greater
•
•
than MTPA
Much faster reaction than MTPA with
hindered compounds
1H and 19F NMR can be used
CFTA - Conformational Preference
syn-periplanar arrangement
Me
N
C
O
RR
RS
F
O
H
CFTA ester plane
Secondary Diols and Polyols
• If groups are far enough apart, can
determine the configuration of each group
independently
• If groups are close together, bound
reagent may influence the shielding or
deshielding at more than one site
MPA for Diols
• Analysis of (syn and anti):
– 1,2– 1,3– 1,4– 1,5-diols with known configurations
• Observe reproducible trends that can be applied
to compounds with unknown configurations
Primary Alcohols
• MTPA – C2 chiral
• CFTA
O
OMOM
OMe
O
∗
∗
EtOOC
OH
OH
2.116
• 9-AMA
O
HO
N
Cl
MeO
N
1'
α
O
N
H
2'
N
MPA - Unreliable
H
Ar
L2
L1
Tertiary Alcohols
2-NMA
MTPA
(a)
HC
HB
(H)
HA
(Nap)
Nap
OH
H
(S)-2NMA
(R)-2NMA
CH 2
HX
HY
O
HZ
OMe
CH 2
Me
O-2NMA
HX
(b)
HY
HZ
∆δ < 0
H2
C
C
Me
H2
C
2NMA plane
O
HC
∆δ > 0
HB
HA
Secondary Amines
• MTPA
O
N
MTPA
N
N
MTPA
2
CF 3
Ph
OMe
• H2 had a ∆δRS of 2.44 ppm!
• Values so large only need one MTPA
derivative (use (R)-acid chloride since more
reactive than (S)-acid chloride)
Primary Amines – α-substituted
• MTPA gives larger ∆δRS values than MPA or
9-AMA - MTPA amides have greater
preference for the sp conformer than
observed with esters.
• BPG – preference for ap conformer – typical
∆δRS values are 2- to 3-times larger than with
MTPA
O
H
N
OH
Aryl Methoxy Reagents - Summary
• Want larger ∆δRS values – either through
high conformational preference or larger
aromatic ring (shielding)
• Values should all be positive for one
substituent (L1) and negative for the other
(L2)
• Need resonances in both substituents
O
O
Camphanic Acid
HO
O
• pro-(R) and pro-(S) positions of α-deuterated
primary and secondary alcohols
D
O
H
D
D
H
H
R
HO
Ph
H
D
N
O
• Primary amines as well
OH
OH
D
H Ph
H
2-(2,3-Anthracenedicarboximido)cyclohexane carboxylic acid
O
N
HOOC
O
Analysis of primary and secondary alcohols –
especially effective for compounds with
remotely disposed chiral centers
O
O
(Me) (Me)
N
Me
∗
O
O
Me
O
O
O
N
O
2,2,2-Trifluoro-1-(9-anthryl)ethanol
(TFAE) (Pirkle’s Alcohol)
F3 C
H
C
OH
Versatile chiral solvating agent
-Can determine optical purity
-Can assign absolute configurations for
certain classes of compounds
Absolute Configurations - TFAE
Sulfoxides
H
H
O
O
C
S
C 6H 5
CF 3
H
i-propyl
CH3
C 6H 5
O
O
C
S
CF 3
H
(R, R)
N-oxides
CH 3
i-propyl
(R, S)
H
O
Amino Acids
H
H
H H 3C
N
C
H
N
C
C
OCH 3
H
O
O
CH3
C
C
H
CH 2
H H
H
CF3
CH3
O
O
CF3
O
H
CH3
C
OCH 3
C
N
H
CF3
Absolute Configurations - TFAE
Oxaziridines
Imines
H
H
H
R
O
CA, B
CF3
C
CF3
O
Ph
R1
R1
O
C
H
H
Me2
Me2
O
H
C
C
N
Ph
Me1
CH 3
Ar
F3 C
H
O
R1
C
O
R2
H
Ph
(R, S)
Lactams
Lactones
C
CH 3
C
H
(R, R)
O
N
Me1
C
H
H
O
N
CA, B
Ph
H
CF3
C
C
R
O
N
H
CF3
Ar
F3 C
O
O
C
R2
C
O
R1
H
N
O
TFAE – Enantiomeric Purity
2,3-diamino succinate – methine
signals for meso versus dl-isomers
Epoxides
R1
C
H
-O
C
O
O-
R3
O
Axial Chiral Compounds
O
R
OCH 3
R
R
N
N
X
O
O
CH 3
NH2
Slow Rotation
R
N
O
H
O
NH2
R2
N
R1
R2
2
3
1
R1= Cl CH3 CH3
R2= H H
CH 3
N
a
b
(R = i-Pr)
(R = Et)
X = Cl
X = NO 2
X = CH3
TFAE – Enantiomeric Purity
Metal Complexes
Cl
Cl
O
Nb
1
S
Nb
S
S
S
Pd
O
N
Cl
Ar
Phosphine Oxides
Pr
O
Ph
P(OCH 2 CH 3) 2
O
N
Ph
Ar
Calixarenes
O
O
N
Pr
O
PrO
PrO
P(OCH 2 CH 3) 2
O
N
Cr(CO) 3
Alcohols as CDAs for Carboxylic Acids
O
• Methyl mandelate
H
C
COCH 3
OH
O
• Menthol
HO
N
HO
O
• 2-(2,3-anthracenedicarboximido)-1-cyclohexanol
Glycosidation Shifts
• React secondary alcohol with D-glucose or
D-mannose
• Pronounced differences in the 13C NMR
spectrum that correlate with absolute
configuration – see trends in both sugar
and alcohol resonances
• Also see differences in the 1H NMR
spectrum of secondary alcohols with tetraO-acetylglucose
β-D- and β-L-Fucofuranoside and
Arabinofuranoside
OH
HO
• Use tetraacetate derivative of sugar
•
•
•
•
(arabino easier to prepare)
React with secondary or tertiary
alcohol
Also works with 1,2-glycols
Alkaline hydrolysis of acetate groups
See differences in the 1H and 13C
spectra of product that correlate with
absolute configuration
O
HO
CHOH
CH3
2,2’-Dihydroxy-1,1’binaphthalene
(BINOL)
• Potential chiral solvating
agent for several classes of
substrates including alcohols,
sulfoxides, selenoxides,
amines, ketones, amides,
and amino alcohols
OH
OH
OH
OH
O
O
OH
OH
S
CH3
Ph
(S)
S
CH3
Ph
(R)
Butane-2,3-diol/Butane-2,3-thiol
• Chiral derivatizing agent for the analysis of
chiral ketones – produce diastereomeric ketals
Me
O
Me
O
O
RS
RS
• For cyclohexanones in the chair conformation,
the 13C shifts correlate with absolute
stereochemistry
X = CH2
O
S
O
O
X
PEA, NEA and AEA
CH 3CH
CH 3CH
NH 2
NH 2
CH 3CH
NH 2
Useful with carboxylic acids
-chiral solvating agent – formation of diastereomeric salts
-chiral derivatizing agent – formation of amides – can assign
absolute stereochemistry with certain compounds
Me
H
O
H
H
Et
O
H
N
H
H
Ph
Me
Me
N
H
H
H
i (major)
H
H
N
H
H
Et
H
Ph
H
Ph
Me
H
N
H
H
H
O
H
H
Me
Et
O
H
Me
Me
N
H
H
Ph
iii (minor)
Me
Et
O
H
ii (major')
O
Me
Me
Me
Et
Et
H
Ph
Me
H
N
H
H
H
Ph
PEA, NEA and AEA
R
Me
• Phosphorus thioacids
P
S
OH
O
• Phosphonic acids
R
H
C
P
OH
OH
OH
• Sulfonyl chlorides
O
• Isocyanates
CH 2SO 2Cl
O
OCN
OR'
R
PEA, NEA and AEA - Ketones
• Method 1
– Convert to acid oxime using NH2OCH2COOH
– Add NEA to form salt – see discrimination
• Method 2
– Reductively aminate the enone with PEA
perchlorate – see discrimination in products
Phenylglycine methyl ester and dimethyl
amide (PGME)
O
H3 CO
C
H
C
NH 2
Absolute configuration of
carboxylic acids – ∆δRS values
α-Substituted
HA
HB
HC
(H)
(Ph)
( R)
Ph
H
( S)
O
HZ
HY
HX
Z
PGME (PGDA) plane
H
H
O
β,β-substituted acids
H
R1
O
N
R2
OMe
H
O
PGME plane
H
PGME - examples
HOOC
O
O
H
Me
COOMe
OH
O
H
O
Me
OH
H
Me
O
H
Me
O
H
O
O
H
OH
O
Me
H
H
O
H
Me
H
O
H
H
Me
COOH
Me
O
H
OH
H
HO
H
HO
HO
O
H
H
Me
O
HO
H
O
Me
H
H
O
O
COOH
1,2-Diphenyl-1,2-diaminoethane
H 2N
NH 2
CH HC
3-substituted cyclohexanones and cyclopentanones
-forms the corresponding aminal
-can determine enantiomeric purity
Ph
Ph
Ph
Ph
O
Ph
*
n
H 2N
Ph
HN
NH
HN
NH
NH2
R
n
*
R
n
*
R
N,N’-Substituted 1,2-diphenyl-1,2diaminoethane
Reacts with Aldehydes
-forms the corresponding imidazolidine
-can be used to determine enantiomeric purity
Ph
Ph
Ph
*
N
*
N
*
*
RCHO
R
NH
HN
Ph
Amides as Chiral Solvating Agents
Soluble Pirkle LC Phases
N-(3,5-Dinitrobenzoyl)-
O2 N
O
CH 3
C
1-phenylethylamine (DNB-PEA)
NH
C
H
O 2N
N-(3,5-Dinitrobenzoyl)-L-leucine
O2 N
O
(DNB-Leu)
O
C
H
C
NH
COH
CH 2
O 2N
CH
H 3C
N-(3,5-Dinitrobenzoyl)-4-amino3-methyl-1,2,3,4-tetrahydrophenAnthrene (Whelk-O-1)
CH3
NO2
O 2N
H
N
O
CH3
Phosphorus-based Reagents
• P(V) reagents (P=O or P=S) group
• P(III) reagents
• P(V) reagents are more stable than P(III)
reagents but usually have smaller enantiomeric
discrimination
• 31P signal usually monitored – splits into two
singlets for the two diastereomers for
derivatizing agents
P(V) Reagents - Examples
CH 3
CH 3
N
S
H
P
Ph
O
Cl
O
Cl
N
O
P
Ph
O
P
CH 3
CH 3
O
Ph
O
Ph
O
Cl
P
O
P
O
N
O
O
P
Cl
Cl
Cl
-Alcohols and amines react at the chlorine atom
-Primarily used for determining enantiomeric purity
N
Ph
Configurational analysis of thiophosphate
monoester that is chiral by virtue of
different oxygen isotopes
S
P
O
O
Me
Cl
P
H
+
P
O
N
Me
H
OEt
O
18O
O
P
P
Ph
S
OEt
O
N
Me
H
S
O
Ph
H
+
Me
O
P
P
H
O
N
Me
H
Ph
O
P
H
H
OEt
O
Ph
Me
N
Me
OEt
S
Ph
Me
=18 O
O =16O
O
O
+
P
O
Me
H
S
OEt
=18 O
O =16O
P
H
N
Me
S
O
OEt
O
P
and 16O in the
bridging position have
different effects on the
shift of the phosphorus
resonance
Phosphinothioic Acids
S
Ph
S
Ph
P
P
Me
S
Ph
H
O
R
P
R
Bu t
OH
H
S
S
Ph
O
Ph
Ph
R
P
O
Effective chiral solvating agents for:
-Phosphine oxides
-Phosphonates
-Sulfoxides
-Amine oxides
H
P
P
O
OH
-Alcohols/Diols
-Amines
-Thiols
-Amino alcohols
H
S
R
P(III) Reagents
R1
R1
R2
CF3
R2
N
Me
Me
Me
NH
NH
NH
NH
NH
NH
Me
Me
Me
N
CF3
CH 3
P
R2
N
R1
P
Cl
R2
Phos13
N
Phos14
Phos15
CH3
N
R1
CH3
-Primary, secondary and
tertiary alcohols
-Thiols
-Carboxylic acids
-α-hydroxyphosphonates
CH3
CH3
N
N
N
N
N
N
CH3
Phos16
Phos18
Phos17
CH3
N
NH
NH
NH
CH3
Phos19
CH3
CH3
Phos20
CO2 R
HO
P(III) Reagents
OH
O
OH
CO 2R
HO
OH
O
HO
R = Et or iPr
R
O
Phos21
P
R
Phos22
Phos23
Cl
O
O
OH
OH
OH
H3 C
OH
O
-Primary, secondary and
tertiary alcohols
-Primary amines
-Carboxylic acids
OH
OH
H 3C
Phos24
Phos25
O
(CH 3) 2NC
OH
(CH 3)2 NC
OH
O
Phos27
Phos26
[5] HELOL Phosphite
MeO
OMe
OMe
O
Cl
P
OMe
MeO
O
MeO
OMe
-Primary and secondary
alcohols
-Phenols
-Amines
-Carboxylic acids
after coupling to
2-aminophenol
MeO
CH3
OH
Ph
TRISPHAT, BINPHAT, BINTROP
Cl
Cl
Cl
Cl
O
Cl
Cl
O
Cl
P
O
Cl
O
O
Cl
Cl
Cl
Cl
O
O
Cl
O
O
Cl
P
O
O
Cl
Cl
O
Cl
Cl
Cl
Cl
O
O
O
P
O
O
O
Useful for ionic compounds
TRISPHAT – Metal Complexes
2+
N
N
O
Pd
(OC) 3Cr
N
Cl
Fe
O
O
py
N
(R)
7.62
N
3
R1
O
O
O
R2
(S)
Ru
Mn(CO)3
+
Ru
O
N
R''
(depe)2 Ru
S
I
Me
Cp*M
Cr(CO) 3
R
TRISPHAT, BINPHAT – Other Cations
N
Me
N
O
P
D2
S4
X
CH 3
CD 3
X
X = Br, H
N
N
N
N
Pr
N
N
Pr
N
S
N
MeO
Me
OMe
BF4
BINTROP
– Limited studies on anions
R
t-Bu
O
O
B
O
R
O
O
t -Bu
O
O
O
O
N
O
N
O
N
N
O
O
O
Configuration of Phosphates
∅CH3
O
• React (cyclize) with
∅
O
P
P
O
O
OCH 3
O
propane-1,2-diol
∅CH3
O
∅
O
P
P
O
O
OCH 3
O
• React (cyclize) with
P
O
∅
∅ = 17O
H
Ph
H
O
Ph
O
H
P
OH
Ph
O
P
P
ØMe
OMe
Me
S
Ø
∅CH 3
= 18O
H
O
S
S
O
S P
Ø
H
Ph
H
O
OMe
Ph
S
H
O
ØMe
P
Ph
O
O
Me
P
P
S
O
O
P
O
(S)-2-iodo-1phenylethanol
Ph
OCH3
O
Ø
S
Selenium-containing Reagent
77Se NMR
Se
H
N
O
Ph
-Carboxylic acids – react at NH group
-Alcohols and alkyl halides react at selenium
atom
-Amines with triphosgene react at the NH
group
R
O
Se
S
Se
H
S
OH
N
R-OH or R-Br
O
N
O
H
Ph
Effective for compounds with remotely disposed chiral
centers – because of shift range of 77Se NMR
Ph
α-, β- and γ-Cyclodextrins
HO
OH
3
2
4
1
O
5
O
6
OH
Native – underivatized
-Water-soluble
-Effective for water-soluble substrates
-Determination of enantiomeric purity
-Substrates usually contain an aromatic ring
(phenyl or bicyclic)
Cyclodextrins
Permethylated cyclodextrins
-β-Derivative is more water-soluble than native β-CD
-Organic-soluble as well
-Broadly applicable for determining enantiomeric purity
-Especially useful for the analysis of allenes
R1
R3
C
R2
C
C
H
Carboxymethylated (-CH2CO2-) cyclodextrins - Anionic
-Especially useful for organic cations
-Can add paramagnetic lanthanides – these
associate at the carboxy group and cause shifts in
the spectra that enhance the enantiomeric
discrimination
Crown Ethers
(18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
HOOC
O
O
COOH
HOOC
O
O
COOH
O
Useful for primary amines
-As hydrochloride salts
-As neutral amines (neutralization
reaction with crown ether)
-In methanol, acetonitrile, or water
(usually best in methanol)
R
N
H
O
O
O
H
H
O
O
O
Crown Ethers
(18-Crown-6)-2,3,11,12-tetracarboxylic acid
Useful for secondary amines
-As neutral amines (neutralization reaction with
crown ether)
-In methanol
-Effective for pyrrolidines, piperidines, piperazines,
alkyl aryl amines
R
R'
N
O
O
HOOC
O
O
O
H
H
O
O
HOOC
O
COOH
Calix[4]resorcarenes
Sulfonated analog with L-proline
groups
-Water-soluble
-Effective for mono or bicyclic
aromatic compounds – singly or
ortho-substituted
OH
O
N
CH 2
HO
OH
R
R
R
H
C
CH 2
CH 2
SO 3
4
(b)
(a)
R
(c)
R
(d)
Lanthanide tris(β-diketonates)
CF3
tfc
O
dcm
O
O
CF2 CF 2CF3
O
O
O
hfc
Organic-soluble
• Suitable for a wide range of hard Lewis bases –
oxygen- and nitrogen-containing compounds –
metal complexes with binding groups in ligands
• Paramagnetism of lanthanide ions does cause
broadening – worse at higher field strengths
–
–
–
–
–
Use a lower field instrument (300 MHz or lower)
Run 13C spectra
Use Sm(III) chelates
Use a polar solvent
Warm the sample (50-75oC)
“Chiralization” of Xenon
MeO
O
O
O
(CH 2) 2
(CH 2) 2
OMe MeO
O
OMe MeO
O
(CH 2 )2
O
OMe
-Racemic cryptophane binds xenon in the cavity
-Addition of Eu(hfc)3 causes the appearance of
two 129Xe signals
Lanthanides - Absolute Configuration
Empirical Trends
• Alkyl aryl carbinols
• Benzhydrols
• 2-Aryloxypropionyl derivatives
• Amino acid methyl esters
• Menthyl butanoates
• N-phthaloyl-α-methylcyanoglycinates
• Lactones
• Epoxides and arene oxides
Secondary and Tertiary Carbinols
• Use Pr(hfc)3
• Measure 13C NMR spectrum
• Examine shifts of neighboring carbons
• Works for diols as well if separated by two or
more carbons
R
HO
OH
Y
X
∆∆δ = ∆δ(R)-Pr(tfc)3 - ∆δ(S)-Pr(tfc)3
Y
Me
OH
X
β-orientation
∆∆δ = positive
α-orientation
∆∆δ = negative
Me
R
Me
OH
Me
OH
Me
OH
Me
Me
OH
4
Binuclear Lanthanide-Silver
Reagents
Ln(β-dik)3 + Ag(β-dik) = [Ln(β-dik)4]Ag
• Effective for soft Lewis bases
– Olefins
– Aromatics
– Alkynes
– Phosphines
– Halides (iodide and bromide)
Binuclear Lanthanide-Silver
Reagents – Organic Salts
[Ln(β-dik)4]Ag + R+X- = [Ln(β-dik)4]R + AgX(s)
• Ammonium salts
• Isothiouronium salts
• Sulfonium salts
Lanthanide Complexes
Water-soluble
• Chelates of pdta (anionic ligand)
CO2 H
HO2 C
N
N
CO2 H
HO2 C
• Chelates of tppn (neutral ligand)
N
N
N
N
N
N
H3 C
• Effective for carboxylic acids – absolute
configurations of amino acids
Palladium-Amine Dimers
Me
Me 2N
NMe 2
Me
Me
Me
NMe2
Me2 N
Cl
Cl
Pd
Pd
Pd
Pd
Cl
Cl
cis
Me
cis
NMe 2
Me
Cl
Pd
NMe2
Cl
Pd
Pd
Pd
Cl
Cl
Me 2N
Me 2N
trans
Me
Me
trans
-Mono- and diphosphines bind to the palladium
-Can use for enantiomeric purity and absolute
configuration (often with NOE data)
H
Me
Me2
N
P
Pd
*
P
Cl -
Palladium/Platinum Complexes
O
Ph 2
Ph 2
P
P
Pt
M
O
P
P
Ph2
Ph 2
-Alkenes and alkynes can displace the
ethylene ligand
-Enantiomeric purity
Platinum-Amine Complexes
Covalent and Ionic
H2
N
Cl
Pt
Cl
H
C
Ph
Cl
Cl
CH3
Pt
[AmH]+
Cl
-Olefins and allenes displace the ethylene group
-Measure 195Pt signal - used for enantiomeric purity
-Substrates have two prochiral faces
-If only one face binds – two 195Pt signals
-If both faces bind – four 195Pt signals
Platinum-Amine
Complexes
Ph
Cl
Am
Pt
unsaturated ethers
H
Cl
Me
NH2
cis
Ph
Am
Cl
Pt
selected cases of allenes
H
Me
Cl
NH2
trans
1 - Np
Me
H
Me
Cl
Cl
AmH
Pt
enantiodiscriminated
substrates
Am
CDA
allenes, olefins, vinyl and allyl
ethers
H
N
H
1 - Np
+
Cl
ionic
β-olefins
NH
Am
Cl
α-olefins
Pt
Cl
tr ans
NH
Rhodium Dimer with MTPA
R
R
O
O
O
Rh
O
O
Rh
O
O
O
R
RO2 = MTPA
R
R
O
R
O
Rh
O
O
+L
Rh
O
O
R
Rh
O
O
R
+L
L
L
Rh
O
Rh
O
O
R
R
O
O
-L
O
R
O
O
O
-L
O
R
O
O
Rh
O
R
R
O
R
O
O
R
L
Rhodium Dimer with MTPA
•
•
•
•
•
•
•
•
•
•
•
Olefins
Phosphines
X = O, S, Se
Aryl alkyl selenides
Phosphine selenides (P=Se)
Phosphorus thionates (P=S)
Phospholene and phospholane chalcogenides
Spirochalcogenuranes
Alkyl iodides, diiodobiphenyls
Nitriles
Oxiranes
Oxatriazoles, thiatriazoles, tetraazoles
R
H 3C
CH 3
P
X
O
Ph
Ch
R
O
X
H 3C
CH 3
Ch = S, Se, Te
Ph
N
H 3C
I
R
H3
'
H3
CH 3
N
O
I
X'
N
N
H 3C
HC
O
R
H2
Zinc Porphyrins (Tweezer)
N
N
O
Zn
N
N
O
N
N
Zn
N
O
N
O
Especially effective for bifunctional substrates (diamines)
Database Techniques
• 13C or 1H shifts
CH 3
H 3C
• N,α-Dimethylbenzylamine (DMBA)
• Bis-1,3-methylbenzylamine-2methylpropane (BMBA-pMe)
Me
H
N
Me
H
N
Me
H
C
N
CH 3
Structural Motifs
OH
OH
OH
HO
Me
Me
Me
OH
Me
Me
Me
OH
OH
OH
OAc
OH
OH
OAc
OAc
Me
Prepare and examine all
possible stereoisomers
AcO
OAc
OAc
13C
or 1H Database subtract chemical shift
of particular nucleus
in one stereoisomer
from average of value
in all eight
DMBA database
-Difference in 13C
shifts between (R)and (S)-DMBA
BMBA-pMe – For assigning the stereochemistry
of secondary and tertiary alcohols
Me
A
OH
saturated secondary
alcohols
(acyclic and cyclic)
Ph
N
H
H
O
N
H
Me
Ph
Binding of BMBA-pMe
to a secondary alcohol
∆δ =
negative
C
B
C
∆δ =
positive
C
∆δ =
negative
C
∆δ =
negative
OH
biaryl alcohols &
benzyl alcohols
∆δ =
positive
C
C
OH
saturated tertiary
alcohols
∆δ =
positive
C
Me
Observed trends
Liquid Crystals
poly(γ-benzyl-L-glutamate) (PBLG)
• Forms ordered material in a magnetic field
• Pair of enantiomers have different
molecular orientations in PBLG
• Three discrimination mechanisms
– Chemical shift anisotropy (least useful)
– Different dipolar coupling constants (1H-13C)
– Differences in quadrupolar splitting (2H) (most
useful)
Quadrupolar Splitting
• Not observed in solution because of rapid
•
tumbling
Observed in ordered media and extent of
splitting depends on orientation relative to the
applied magnetic field
Proton-decoupled
deuterium NMR
spectrum
PBLG - Incredible Versatility
• Only need different packing orders
• Do not need specific interactions between
the substrate and the liquid crystal
• Effective for virtually any class of
compound
– Includes aliphatic hydrocarbons
• Especially effective for resonances of
nuclei remote to the chiral center
Deuterium Labeling
• Only need deuterium as a signal – better
to use achiral reagents so no concern
about kinetic resolution or racemization
– Convert CO2H to CO2CD3
– Add perdeutero benzoyl group (have o-, mand p-protons as potential probes
• Provides a single, strong signal (or a few
easily assigned signals) for the analysis
Examples
S
S
O
D
D
OH
D
D
D
4
HO
D
(R,R)-, (S,S)- and (R,S)-(meso)isomer distinguished
O
D
D
HO
D
D
OH
D
-Remote chiral center
-2H signal for the para-position
showed different quadrupolar
splitting
D
OH
Can distinguish (R,R,R)-,
(R,R,S)-, (S,S,R)- and (S,S,S)isomers
Perdeuterated/Natural Abundance 2H
• Complicated spectra
– each 2H signal is a doublet
– each 2H signal may be two doublets if the
enantiomers have different quadrupolar
splitting
– can’t predict a priori the magnitude of the
quadrupolar splitting
• Procedures have been devised to aid in
the assignment of 2H spectra