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NMR Spectroscopy forNMR Spectroscopy for
StudyingStudying ChiralityChirality
Thomas J. WenzelThomas J. WenzelDepartment of ChemistryDepartment of Chemistry
Bates CollegeBates College
Lewiston, Maine 04240Lewiston, Maine [email protected]@bates.edu
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ChiralChiral DiscriminationDiscriminationNMR SpectroscopyNMR Spectroscopy
ChiralChiral derivatizingderivatizing agentsagents
ChiralChiral solvating agentssolvating agents
Metal complexesMetal complexes
Liquid crystalsLiquid crystals
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ChiralChiral DerivatizingDerivatizingAgentsAgents
Form a covalent bond between anForm a covalent bond between anoptically pure reagent and the compoundoptically pure reagent and the compound
of interestof interest
CDA + (CDA + (RR))--Sub = CDASub = CDA--((RR))--SubSub
CDA + (CDA + (SS))--Sub = CDASub = CDA--((SS))--SubSub
Resulting compounds areResulting compounds are diastereomersdiastereomers
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ChiralChiral Discriminating AgentsDiscriminating Agents
NoNo racemizationracemization
No kinetic resolutionNo kinetic resolution
Need 100% optical purity of the reagent ifNeed 100% optical purity of the reagent ifusing for the determination ofusing for the determination ofenantiomericenantiomeric excessexcess
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ChiralChiral Solvating AgentsSolvating Agents
Form nonForm non--covalent interactions between ancovalent interactions between anoptically pure reagent and the compound ofoptically pure reagent and the compound ofinterestinterest
CSA + (CSA + (RR))--Sub = CSASub = CSA--((RR))--SubSubCSA + (CSA + (SS))--Sub = CSASub = CSA--((SS))--SubSub
Resulting compounds areResulting compounds are diastereomersdiastereomers
KKRR and Kand KSS are likely differentare likely different causes differentcauses differenttimetime--averagedaveraged solvationsolvation environmentsenvironments
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ChiralChiral Solvating AgentsSolvating Agents
Preferable to have fast exchangePreferable to have fast exchange
High concentration of CSA usually leads toHigh concentration of CSA usually leads tolarger discriminationlarger discrimination
Often see enhancedOften see enhanced enantiomericenantiomericdiscrimination at lower temperaturesdiscrimination at lower temperatures
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Assigning Absolute StereochemistryAssigning Absolute Stereochemistry
Mechanism of discrimination is understood andMechanism of discrimination is understood andcharacteristic shifts occur in the spectrumcharacteristic shifts occur in the spectrum More common with certain families ofMore common with certain families ofchiralchiral
derivatizingderivatizing agentsagents
Possible with somePossible with some chiralchiral solvating agentssolvating agents
Empirical trendEmpirical trend
Best if use known model compounds as close asBest if use known model compounds as close as
possible in structural features to the unknownpossible in structural features to the unknown
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ArylAryl--containing Carboxylic Acidscontaining Carboxylic Acids
--Alcohols and AminesAlcohols and Amines
C COH
CH3O
F3C
O
H3CO
OH
O
OHHC3CO
O
O
C
F
CN
COOHH3C
OH
HN
O
OCH3
O
OH
H3CO
OH
O
CH3C
OCH3
COOH
MTPA MPA (O-MMA) O-AMACFTA
N-Boc PG MNP
2-AMA/9-AMA
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ArylAryl--containing Carboxylic Acidscontaining Carboxylic Acids
MTPA =MTPA = --methoxymethoxy----trifluoromethylphenylacetictrifluoromethylphenylacetic acidacid
MPA =MPA = --methoxyphenylaceticmethoxyphenylacetic acidacid
OO--AMA =AMA = OO--acetylacetyl mandelicmandelic aciedacied CFTA =CFTA = --cyanocyano----fluorofluoro--pp--tolylacetictolylacetic acidacid
NN--BocBoc PG =PG = NN--bocboc phenylglycinephenylglycine
MMNPNP = 2= 2--methoxymethoxy--22--(1(1--naphthyl)propionic acidnaphthyl)propionic acid 22--/9/9--AMA =AMA = --(2(2--anthryl)anthryl)----methoxyacetic acidmethoxyacetic acid
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L2O
CF3
L1
H O
Ph OMe
(OMe) (Ph) (R)-MTPA
(S)-MTPA
Mosher Method/Modified Mosher Method
-Prepare derivatives with (R)- and (S)-forms ofthe reagent
-Syn-periplanararrangement of HC-O-C(O)-Catoms (secondary alcohols)
-Calculate RS values negative for L1, positive
for L2
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10
RO
8 9
Me(10) Me(8) Me(9)
MTPA 0.07 -0.017 -0.04
MPA 0.05 -0.021 -0.26
RS H1'
H1
H2
OH
3
45
67
8
Position MTPA MPA PPA
1 0.07 0.19 0.431' 0.03 0.12 0.202 0.09 0.14 0.183 0.04 0.02 0.034 0.03 0.07 0.144' 0.03 0.06 0.138 0.03 0.04 0.10
PPA = -phenyl-propionic acid
RS depends on:
-Degree of conformational preference/how itinfluences the shielding
-Size of the shielding (anthryl > naphthyl > phenyl)
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Secondary AlcoholsSecondary Alcohols
MPA > MTPA (conformational preferenceMPA > MTPA (conformational preferencethat produces greater difference inthat produces greater difference inshielding)shielding)
MPAMPA early synthetic proceduresearly synthetic procedures highhighdegree ofdegree ofracemizationracemization Better procedures for MPABetter procedures for MPAderivatizationderivatization
now existnow exist Mix and shake methodMix and shake method
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I
OH
MPA derivative
2.7 Hz differential shielding for the methyl group9-bonds removed From the chiral center
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Effect of temperatureEffect of temperature
For MPA derivatives of secondary alcohols,For MPA derivatives of secondary alcohols,lowering the probe temperature by about 100 Klowering the probe temperature by about 100 K(to 175(to 175--200K) approximately doubles the200K) approximately doubles the RSRS
valuesvalues
Alters conformational preference further towardAlters conformational preference further towardthethe spsp formform
Can measureCan measure TT11TT22 values as a confirmation ofvalues as a confirmation ofstereochemicalstereochemical assignmentassignment
Effect not as pronounced with MTPA or AMAEffect not as pronounced with MTPA or AMA
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Barium MethodBarium Method
MPA/secondary alcoholsMPA/secondary alcohols
O
O
MeO
H
Ph
L1
L2
Ba+2
'
O
O
MeO
H
Ph
L1
L2
'
Ba+2
sp
sp-Ba+2 complex
O
OMeO
H
Ph
L1
L2
Ba+2
O
OO
H
Ph
L1
L2
ap
ap-Ba+2 complex
Ba+2Me
Barium binds in a chelate
manner with the ester andalters the conformationpreference toward the spconformer.
Leads to enhancement inthe shielding and get largerRS values.
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La(hfa)La(hfa)33 method with MTPAmethod with MTPA
Secondary alcoholsSecondary alcohols
X
CF3
MeO
H O
R1
R2
sp
X
OMe
H O
R1
R2CF3
sp'
M
X
OMe
F 3C
H O
R1
R2
sp'
XCF3
H O
R1
R2OMe
sp
M
(S)-MPTA derivative (R)-MPTA derivative
X = O or NH
(b)
OMTPA
H
R1 R2
MTPA plane
0S,R < 0
M
S,R > 0
0S,R > 0
M
S,R < 0
M M
Chelate bonding of theLa reverses theorientation of the
phenyl ring and theshifts of the hydrogenresonances
This reversal in shiftscan be used to confirmthe stereochemicalassignment
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22--AMA/9AMA/9--AMAAMA LinearLinear vsvs cycliccyclicsecondarysecondary carbinolscarbinols
O
Me
Me
H
OO
H
MeO
HMeO
HR1 R2
HMeO
HR1 R2
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MMNPNP (secondary alcohols)(secondary alcohols)
CH3C
OCH3
COOH
-RS
about 4-times greater than with MTPA
-Less prone to racemization with methyl groupon chiral carbon
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CFTA (secondary alcohols)CFTA (secondary alcohols)
TheThe RSRS values are typically 2values are typically 2--times greatertimes greaterthan MTPAthan MTPA
Much faster reaction than MTPA withMuch faster reaction than MTPA withhindered compoundshindered compounds
11H andH and 1919F NMR can be usedF NMR can be used
C
F
CN
COOHH3C
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H
O
RSRR
O
F
C
MeN
CFTA ester plane
CFTA - Conformational Preferencesyn-periplanararrangement
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SecondarySecondary DiolsDiols andand PolyolsPolyols
If groups are far enough apart, canIf groups are far enough apart, candetermine the configuration of each groupdetermine the configuration of each groupindependentlyindependently
If groups are close together, boundIf groups are close together, bound
reagent may influence the shielding orreagent may influence the shielding or
deshieldingdeshielding at more than one siteat more than one site
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MPA forMPA for DiolsDiols
Analysis of (Analysis of (synsynandand antianti):): 1,21,2--
1,31,3--
1,41,4-- 1,51,5--diols with known configurationsdiols with known configurations
Observe reproducible trends that can be appliedObserve reproducible trends that can be appliedto compounds with unknown configurationsto compounds with unknown configurations
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Primary AlcoholsPrimary Alcohols MTPAMTPA CC22 chiralchiral
CFTACFTA
99--AMAAMA
OH
O
O
OMeEtOOC
OH
OMOM
2.116
HO
N
N
N
N
Cl
MeO
O
H
L1ArL
2H
O
1'
2'
MPA - Unreliable
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Tertiary AlcoholsTertiary Alcohols
OHCH2
HC HB HA
CH2
HX HY HZ
Me
O
O
OM e
HNap (R)-2NMA
(H) (Nap) (S)-2NMA
2NMA plane
(a)
(b)
HY
HX
HZ
< 0H2C C
Me
H2C HB
HA
HC
> 0
O-2NMA
MTPA
2-NMA
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Secondary AminesSecondary Amines MTPAMTPA
HH22 had ahad a RSRS of 2.44of 2.44 ppmppm!!
Values so large only need one MTPAValues so large only need one MTPAderivative (use (derivative (use (RR))--acid chloride since moreacid chloride since morereactive than (reactive than (SS))--acid chloride)acid chloride)
N
MTPA
N
MTPA
N
O
CF3
PhOMe
2
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Primary AminesPrimary Amines --substitutedsubstituted MTPA gives largerMTPA gives larger RSRS values than MPA orvalues than MPA or
99--AMAAMA-- MTPA amides have greaterMTPA amides have greater
preference for thepreference for the spsp conformer thanconformer thanobserved with esters.observed with esters.
BPGBPG preference forpreference for apap conformerconformer typicaltypicalRSRS values are 2values are 2-- to 3to 3--times larger than withtimes larger than with
MTPAMTPA
OH
HN
O
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ArylAryl MethoxyMethoxy ReagentsReagents -- SummarySummary
Want largerWant larger RSRS
valuesvalues either througheither throughhigh conformational preference or largerhigh conformational preference or larger
aromatic ring (shielding)aromatic ring (shielding)
Values should all be positive for oneValues should all be positive for onesubstituentsubstituent (L(L11) and negative for the other) and negative for the other
(L(L22))
Need resonances in bothNeed resonances in both substituentssubstituents
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CamphanicCamphanicAcidAcid
propro--((RR) and) and propro--((SS) positions of) positions of--deuterateddeuteratedprimary and secondary alcoholsprimary and secondary alcohols
Primary amines as wellPrimary amines as well
O
O
OHO
DH
Ph
HD
HO N
O
O
OH
D H
H Ph
D
D
R
H
OH
H
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22--(2,3(2,3--Anthracenedicarboximido)Anthracenedicarboximido)--
cyclohexane carboxylic acidcyclohexane carboxylic acidN
O
O
HOOC
N
O
O
(Me)(Me)
Me
MeO
O
N
O
O
O
O
Analysis of primary and secondary alcohols especially effective for compounds withremotely disposed chiral centers
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2,2,22,2,2--TrifluoroTrifluoro--11--(9(9--anthryl)ethanolanthryl)ethanol
(TFAE) ((TFAE) (PirklePirklessAlcohol)Alcohol)
HCF
3
C OH
Versatile chiral solvating agent
-Can determine optical purity-Can assign absolute configurations forcertain classes of compounds
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Absolute ConfigurationsAbsolute Configurations -- TFAETFAE
O
H
C
O
Si-propyl
CH3
C6H5
CF3 H
O
H
C
O
SCH3
i-propyl
C6H5
CF3 H
(R, R) (R, S)
N
CH3
CH2
CH3
O
H
C
CF3H
O
C
H
O
CF3
H
C
H
C
O
OCH3
N
H3CH H
C
H
O
CF3
H
C
CH3
C
O
OCH 3
N
HH H
Sulfoxides
N-oxides
Amino Acids
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Absolute ConfigurationsAbsolute Configurations -- TFAETFAE
O
C
Ph
CF3
H
H
N
O
CA, B
R
O
C
Ph
CF3
H
H
N
O
CA, B
R
C N
C
CH3H
Ph
Me2
Me1
H
O
C
R1
H CF3
C N
C
PhH
CH3
Me2
Me1
H
O
C
R1
H CF3
(R, R) (R, S)
H O
O
C
H
Ar
F3C
O
C R1
R2
H O
O
C
H
Ar
F3C
O
C R2
R1
Oxaziridines Imines
Lactones
N
O
Lactams
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TFAETFAE EnantiomericEnantiomeric PurityPurity
C C
O
R2
R3
R1
HO
-O
O
O-
NH2
NH2
N
R2R1
H CH3
OCH3
O
1 2 3
Cl CH3 CH3
H H CH3
R1=
R2=
O
N N
RR R R
O O
a (R = i-Pr)
b (R = Et)
N
N
X
X = Cl
X = NO2X = CH3
Epoxides2,3-diamino succinate methinesignals for mesoversus dl-isomers
Axial Chiral Compounds Slow Rotation
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TFAETFAE EnantiomericEnantiomeric PurityPurity
Cl
Nb
S
SO
Cl
Nb
S
S
O
N N
Pd
Cl
Ar Ar
1
O N
Ph P(OCH2CH3)2
O
O N
Ph P(OCH2CH3)2
O
OOPr
Pr
PrOPrO
Cr(CO)3
Metal Complexes
Phosphine OxidesCalixarenes
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GlycosidationGlycosidation ShiftsShifts React secondary alcohol with DReact secondary alcohol with D--glucose orglucose or
DD--mannosemannose Pronounced differences in thePronounced differences in the 1313C NMRC NMR
spectrum that correlate with absolutespectrum that correlate with absolute
configurationconfiguration see trends in both sugarsee trends in both sugar
and alcohol resonancesand alcohol resonances
Also see differences in theAlso see differences in the11
H NMRH NMRspectrum of secondary alcohols with tetraspectrum of secondary alcohols with tetra--
OO--acetylglucoseacetylglucose
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--DD-- andand --LL--FucofuranosideFucofuranoside andand
ArabinofuranosideArabinofuranoside
UseUse tetraacetatetetraacetate derivative of sugarderivative of sugar
((arabinoarabino easier to prepare)easier to prepare)
React with secondary or tertiaryReact with secondary or tertiaryalcoholalcohol
Also works with 1,2Also works with 1,2--glycolsglycols
Alkaline hydrolysis of acetate groupsAlkaline hydrolysis of acetate groups
See differences in theSee differences in the 11H andH and 1313CCspectra of product that correlate withspectra of product that correlate with
absolute configurationabsolute configuration
O
HO
HO
OH
CHOH
CH3
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2,22,2--DihydroxyDihydroxy--1,11,1binaphthalenebinaphthalene
(BINOL)(BINOL)
PotentialPotential chiralchiral solvatingsolvating
agent for several classes ofagent for several classes of
substrates including alcohols,substrates including alcohols,
sulfoxidessulfoxides,, selenoxidesselenoxides,,
amines,amines, ketonesketones, amides,, amides,and amino alcoholsand amino alcohols
OH
OH
OH
OH
O
S
CH3 Ph
OH
OH
O
S
CH3 Ph
(S) (R)
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ButaneButane--2,32,3--diol/Butanediol/Butane--2,32,3--thiolthiol
ChiralChiral derivatizingderivatizing agent for the analysis ofagent for the analysis ofchiralchiral ketonesketones produceproduce diastereomericdiastereomeric ketalsketals
ForFor cyclohexanonescyclohexanones in the chair conformation,in the chair conformation,thethe 1313C shifts correlate with absoluteC shifts correlate with absolute
stereochemistrystereochemistry
O
RSRS
O
O
Me
Me
X
O
O
X = CH2OS
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PEA, NEA and AEAPEA, NEA and AEACH3CH NH 2 CH3CH NH 2 CH3CH 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
Et N
H
H
Ph
Me
H
Me
HO
H
Me N
Et
H
Ph
H
H
Me
HO
H
H N
Me
H
Ph
Et
H
Me
HO
H
Et N
Me
H
Ph
H
H
Me
HO
H
Me N
H
H
Ph
Et
H
Me
HO
H
H N
Et
H
Ph
Me
H
Me
HO
H
i (major) ii (major') iii (minor)
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PEA, NEA and AEAPEA, NEA and AEA
PhosphorusPhosphorus thioacidsthioacids
PhosphonicPhosphonic acidsacids
SulfonylSulfonyl chlorideschlorides
IsocyanatesIsocyanates
P
OH
SMe
R
P OH
OH
HC
O
R
OH
CH2SO 2Cl
O
OCN
OR'
O
R
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PEA, NEA and AEAPEA, NEA and AEA-- KetonesKetones
Method 1Method 1 Convert to acidConvert to acid oximeoxime using NHusing NH22OCHOCH22COOHCOOHAdd NEA to form saltAdd NEA to form salt see discriminationsee discrimination
Method 2Method 2
ReductivelyReductively aminateaminate thethe enoneenone with PEAwith PEAperchlorateperchlorate see discrimination in productssee discrimination in products
PhenylglycinePhenylglycine methyl ester andmethyl ester and dimethyldimethyl
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PhenylglycinePhenylglycine methyl ester andmethyl ester and dimethyldimethyl
amide (PGME)amide (PGME)Absolute configuration ofAbsolute configuration of
carboxylic acidscarboxylic acids RSRS valuesvalues
H3CO CHC
O
NH2
HA HB HC
HZ HY HX
H
Z
O Ph H
H O
(H) (Ph) (R)
(S)
PGME (PGDA) plane
-Substituted
,-substituted acids NOMe
H O
H O
R2
R1
H
PGME plane
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PGMEPGME -- examplesexamples
OO
H
OH
O
Me H
HOOC
O
COOMe
O
O
H
COOH
HO
COOH
OH
O
O
O
O
O
MeMe
OH
Me
H
H
Me
H
OH
H
H
H
MeH
O
H
H
O
O
OHO
HO
O
Me
Me
H
H
H
Me
H
H
H
H
HO
OMe
H
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1,21,2--DiphenylDiphenyl--1,21,2--diaminoethanediaminoethane
CH HC
NH2H2N
O
Rn*
H2N NH2
PhPhNHHN
PhPh
n*
R
NHHN
PhPh
n*
R
3-substituted cyclohexanones and cyclopentanones
-forms the corresponding aminal-can determine enantiomeric purity
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NN,,NN--Substituted 1,2Substituted 1,2--diphenyldiphenyl--1,21,2--
diaminoethanediaminoethane
RCHO
Ph Ph
NH HN
N
N
R
Ph
Ph
* **
*
Reacts with Aldehydes-forms the corresponding imidazolidine-can be used to determine enantiomeric purity
Amides as Chiral Solvating Agents
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N-(3,5-Dinitrobenzoyl)-1-phenylethylamine (DNB-PEA)
N-(3,5-Dinitrobenzoyl)-L-leucine(DNB-Leu)
N-(3,5-Dinitrobenzoyl)-4-amino-
3-methyl-1,2,3,4-tetrahydrophen-Anthrene (Whelk-O-1)
O2N
O2N
C
O
NH CH
CH3
O2N
O2N
C
O
NHHC COH
O
CH2
CH
H3C CH3
CH3
N O
O2N NO2
H
Amides as Chiral Solvating Agents
Soluble Pirkle LC Phases
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PhosphorusPhosphorus--based Reagentsbased Reagents P(V) reagents (P=O or P=S) groupP(V) reagents (P=O or P=S) group
P(III) reagentsP(III) reagents
P(V) reagents are more stable than P(III)P(V) reagents are more stable than P(III)
reagents but usually have smallerreagents but usually have smaller enantiomericenantiomericdiscriminationdiscrimination
3131
P signal usually monitoredP signal usually monitored
splits into twosplits into two
singletssinglets for the twofor the two diastereomersdiastereomers forforderivatizingderivatizing agentsagents
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P(V) ReagentsP(V) Reagents -- ExamplesExamples
O
P
NCH3
Ph
S
Cl
O
P
NCH3
Ph
O
Cl
CH 3
CH 3
P
O
OO
ClP
Ph
Cl
O
O
O
P
O
Cl
Ph
N
P N
H
PhO
Cl
-Alcohols and amines react at the chlorine atom
-Primarily used for determining enantiomeric purity
Configurational analysis of thiophosphate
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Me
NH
Ph
O
H
Me
PCl
O
+ P
S
OEtO
Me
NH
Ph
O
H
Me
P
O
P
O
S
OEt
Me
NH
Ph
O
H
Me
PO
P
OEtS
O
+
+
Me
NH
Ph
O
H
Me
PO
O
P
S
OEt
Me
NH
Ph
O
H
Me
P
O
O
P
S
OEt
=18O
O =16O
Configurational analysis of thiophosphate
monoester that is chiral by virtue ofdifferent oxygen isotopesP
S
OEtO
=18O
O =16O
18O and 16O in thebridging position have
different effects on theshift of the phosphorusresonance
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PhosphinothioicPhosphinothioicAcidsAcidsP
SPh
Me OH
P
SPh
Bu t OH
R
P
O
Ph S
H S
P
OH R
Ph R
P
O
Ph S
H S
P
OH Ph
R
Effective chiral solvating agents for:
-Phosphine oxides -Alcohols/Diols-Phosphonates -Amines-Sulfoxides -Thiols-Amine oxides -Amino alcohols
P(III) R tP(III) R t
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P(III) ReagentsP(III) ReagentsNH
NH
Me
Me
Phos13
NH
NH
Me
Me
Phos14
NH
NH
Me
Me
Phos15
CF3
CF3
N
CH3
N
CH3
Phos16
N
CH3
N
CH3
Phos17
N
CH3
N
CH3
Phos18
NH
NH
CH3
CH3
Phos19
N
NH
Phos20
N
N
P Cl
R1
R1
R2
R2 N
N
P N
R1
R1
R2
R2
CH3
CH3
-Primary, secondary andtertiary alcohols
-Thiols
-Carboxylic acids--hydroxyphosphonates
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P(III) ReagentsP(III) Reagents
O
P
OR
R
Cl
HO CO2R
CO2RHO
R = Et or iPr
Phos21 Phos22
OH
OH
O
O
OH
HO
Phos23
H3C OH
OHH3
C
Phos24
OH
OH
Phos25
O
O
OH
OH
Phos26
OH
OH
Phos27
(CH3)2NC
O
(CH3)2NC
O
-Primary, secondary andtertiary alcohols
-Primary amines
-Carboxylic acids
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[5] HELOL[5] HELOL PhosphitePhosphite
Cl P
O
O
OMe
OMe
MeO
MeO
MeOOMe
OMe MeO
Ph
OH
CH3
-Primary and secondary
alcohols-Phenols-Amines
-Carboxylic acidsafter coupling to2-aminophenol
TRISPHAT BINPHAT BINTROPTRISPHAT BINPHAT BINTROP
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TRISPHAT, BINPHAT, BINTROPTRISPHAT, BINPHAT, BINTROP
O P
O
O
O
O O
ClCl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
ClCl
O
P
O
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
P
O
O
O
O
Useful for ionic compounds
TRISPHATTRISPHAT Metal ComplexesMetal Complexes
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TRISPHATTRISPHAT Metal ComplexesMetal Complexes
NN
N N
Fe
3
2+
7.62
Cp*M
O
R
+
Mn(CO)3
R2
R1
R''
Cr(CO)3
Ru S
Me
I(depe)2
N
(OC)3CrPd
Cl
py
NRu
Ru
O
O
O
O
OO
(R)
(S)
TRISPHAT BINPHATTRISPHAT BINPHAT OtherOther CationsCations
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TRISPHAT, BINPHATTRISPHAT, BINPHAT OtherOther CationsCations
N N
S4 D2
P CH3
CD3
O
Me
N
N
N N
X
N N
X
X = Br, H
N NPrPr
OMeMeO
BF4
S
Me
BINTROPBINTROP
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BINTROPBINTROP
Limited studies on anionsLimited studies on anions
R
R
O
O
B
t-Bu
t-Bu
O
O O
O
OO
O
O
O
OO
O
N
N
N
N
Configuration of PhosphatesConfiguration of Phosphates
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Configuration of PhosphatesConfiguration of Phosphates
React (React (cyclizecyclize) with) withpropanepropane--1,21,2--dioldiol
React (React (cyclizecyclize) with) with
(S)(S)--22--iodoiodo--11--phenylethanolphenylethanol
O
PO
CH3O
OCH 3
PO
O
O
PO
CH3O
OCH 3
PO
O
PO
OCH3O
CH3
PO
OO
= 17O = 18O
S P
OHH
Ph
O
S
P
OH
PhO
MeS
P
OH
Ph
OMeS
P
OH
Ph
Me
S
P
OH
PhOMe
S
P
OH
PhMe
O
S
P
OH
Ph
Me
SeleniumSelenium-containing Reagentcontaining Reagent
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SeleniumSelenium--containing Reagentcontaining Reagent7777Se NMRSe NMR
N O
H
Se
Ph
R-OH or R-BrN O
Se
Ph
R
N OH
Se
Ph
-Carboxylic acids react at NH group-Alcohols and alkyl halides react at selenium
atom-Amines with triphosgene react at the NH
group
S
S
OH
O
H
Effective for compounds with remotely disposed chiralcenters because of shift range of77Se NMR
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CyclodextrinsCyclodextrins
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Permethylated cyclodextrins--Derivative is more water-soluble than native -CD-Organic-soluble as well-Broadly applicable for determining enantiomeric purity-Especially useful for the analysis of allenes
C CC
R3
H
R1
R2
Carboxymethylated (-CH2CO2-) cyclodextrins - Anionic
-Especially useful for organic cations
-Can add paramagnetic lanthanides theseassociate at the carboxy group and cause shifts inthe spectra that enhance the enantiomericdiscrimination
Crown EthersCrown Ethers
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C o t e s
(18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
O
O
OO
O
COOH
COOH
HOOC
HOOC
O
O
O
OO
O
H H
N
R
H
Useful for primary amines-As hydrochloride salts-As neutral amines (neutralization
reaction with crown ether)-In methanol, acetonitrile, or water
(usually best in methanol)
Crown EthersCrown Ethers
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Crown EthersCrown Ethers(18-Crown-6)-2,3,11,12-tetracarboxylic acid
O
O
O
OO
O
H H
N
HOOC
HOOC COOH
O
O
R R'
Useful for secondary amines
-As neutral amines (neutralization reaction withcrown ether)
-In methanol-Effective for pyrrolidines, piperidines, piperazines,alkyl aryl amines
Calix[4]resorcarenesCalix[4]resorcarenes
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Calix[4]resorcarenesCa [ ] eso ca e es
RR R
RR
(a) (b)
(c) (d)
CH2
N
OH
O
HO OH
HC
CH2
CH2
SO 3 4
Sulfonated analog with L-prolinegroups
-Water-soluble
-Effective for mono or bicyclicaromatic compounds singly orortho-substituted
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LanthanideLanthanide tristris((--diketonatesdiketonates))
O
CF3
O
O O
O
CF2CF2CF3
O
tfc
hfc
dcm
Organic-soluble
Suitable for a wide range of hard Lewis basesSuitable for a wide range of hard Lewis bases
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Suitable for a wide range of hard Lewis basesSuitable for a wide range of hard Lewis basesoxygenoxygen-- and nitrogenand nitrogen--containing compoundscontaining compoundsmetal complexes with binding groups inmetal complexes with binding groups in ligandsligands
ParamagnetismParamagnetism of lanthanide ions does causeof lanthanide ions does causebroadeningbroadening worse at higher field strengthsworse at higher field strengths
Use a lower field instrument (300 MHz or lower)Use a lower field instrument (300 MHz or lower)
RunRun 1313C spectraC spectra
UseUse Sm(IIISm(III)) chelateschelates
Use a polar solventUse a polar solvent
Warm the sample (50Warm the sample (50--7575ooC)C)
ChiralizationChiralization of Xenonof Xenon
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ChiralizationChiralization of Xenonof Xenon
MeO O
O MeO
(CH2)2
O OMe
(CH2)2
O OMe
OMe MeO O O
(CH2)2
-Racemic cryptophane binds xenon in the cavity-Addition of Eu(hfc)3 causes the appearance of
two 129Xe signals
LanthanidesLanthanides -- Absolute ConfigurationAbsolute Configuration
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LanthanidesLanthanides Absolute ConfigurationAbsolute Configuration
Empirical TrendsEmpirical Trends
Alkyl arylAlkyl aryl carbinolscarbinols
BenzhydrolsBenzhydrols
22--Aryloxypropionyl derivativesAryloxypropionyl derivatives
Amino acid methyl estersAmino acid methyl esters MenthylMenthyl butanoatesbutanoates
NN--phthaloylphthaloyl----methylcyanoglycinatesmethylcyanoglycinates
LactonesLactones EpoxidesEpoxides andand arenearene oxidesoxides
Secondary and TertiarySecondary and Tertiary CarbinolsCarbinols
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Seco da y a d e t a yy y Ca b o s
Use Pr(hfc)Use Pr(hfc)33 MeasureMeasure 1313C NMR spectrumC NMR spectrum
Examine shifts of neighboring carbonsExamine shifts of neighboring carbons Works forWorks for diolsdiols as well if separated by two oras well if separated by two or
more carbonsmore carbons
Me OH
Me MeMe Me Me MeOH OH OH OH
4
R OH
Y X
-orientation
= negative
HO R
Y X
-orientation
= positive
= (R)-Pr(tfc)3 - (S)-Pr(tfc)3
Binuclear LanthanideBinuclear Lanthanide--SilverSilver
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ReagentsReagents
Effective for soft Lewis basesEffective for soft Lewis bases OlefinsOlefins
AromaticsAromatics
AlkynesAlkynes
PhosphinesPhosphines Halides (iodide and bromide)Halides (iodide and bromide)
Ln(-dik)3 + Ag(-dik) = [Ln(-dik)4]Ag
Binuclear LanthanideBinuclear Lanthanide--SilverSilver
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ReagentsReagents Organic SaltsOrganic Salts
Ammonium saltsAmmonium salts
IsothiouroniumIsothiouronium saltssalts
SulfoniumSulfonium saltssalts
[Ln(-dik)4]Ag + R+X- = [Ln(-dik)4]R + AgX(s)
Lanthanide ComplexesLanthanide Complexes
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WaterWater--solublesoluble ChelatesChelates ofofpdtapdta (anionic(anionic ligandligand))
ChelatesChelates ofoftppntppn (neutral(neutral ligandligand))
Effective for carboxylic acidsEffective for carboxylic acids absoluteabsoluteconfigurations of amino acidsconfigurations of amino acids
N
N
CO2H
CO2H
HO2C
HO2C
N N
NN
N N
H3C
PalladiumPalladium--AmineAmine DimersDimers
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Pd
Cl
NMe 2Me
Pd
Cl
Me2N Me
Pd
Cl
NMe 2Me
Pd
Cl
Me2N Me
cis
trans
Pd
Cl
Pd
Cl
cis
NMe2 Me2N
Me Me
Pd
Cl
trans
NMe2
Me
Cl
Pd
Me2N
Me
Pd
N
P
P
M e2
H
Me
* Cl-
-Mono- and diphosphines bind to the palladium-Can use for enantiomeric purity and absolute
configuration (often with NOE data)
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Palladium/Platinum ComplexesPalladium/Platinum Complexes
P
PO
O
M
Ph2
Ph2
P
P
Pt
Ph 2
Ph 2
-Alkenes and alkynes can displace the
ethylene ligand-Enantiomeric purity
PlatinumPlatinum--Amine ComplexesAmine Complexes
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Covalent and IonicCovalent and Ionic
Pt
Cl
Cl
H2N HC
Ph
CH3 Pt
Cl
Cl
Cl
[AmH]+
-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
PlatinumPlatinum--AmineAmineCDA Am enantiodiscriminated
substrates
Pt
Am Cl
H
Ph
unsaturated ethers
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ComplexesComplexesPt
Cl
cisNH2
H
Me
Pt
Cl
Cl Am
transNH2
H
Me
Ph
selected cases of allenes
Pt
Cl
Cl Cl
ionic
AmH+
NH
Me N 1 - Np
Me
H
H
1 - Np
H allenes, olefins, vinyl and allylethers
-olefins
Pt
Cl
Cl Am
trans
NH
-olefins
RhodiumRhodium DimerDimer with MTPAwith MTPA
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O
Rh
O
O O
R
R
OO
R
O
O
R
Rh
O
Rh
O
O O
R
R
OO
R
O
O
R
Rh
O
Rh
O
O O
R
R
OO
R
O
O
R
RhL
+ L
- L
+ L
- LL L
OO
Rh
O
Rh
O O
OO
R
R
R
O
R
RO2 = M TPA
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RhodiumRhodium DimerDimer with MTPAwith MTPA OlefinsOlefins
PhosphinesPhosphines Aryl alkylAryl alkyl selenidesselenides PhosphinePhosphine selenidesselenides (P=Se)(P=Se) PhosphorusPhosphorus thionatesthionates (P=S)(P=S)
PhospholenePhospholene andand phospholanephospholane chalcogenideschalcogenides SpirochalcogenuranesSpirochalcogenuranes Alkyl iodides,Alkyl iodides, diiodobiphenylsdiiodobiphenyls NitrilesNitriles OxiranesOxiranes OxatriazolesOxatriazoles,, thiatriazolesthiatriazoles,, tetraazolestetraazoles
PR
PhX
X = O, S, Se
O
Ch
O
CH3H3C
H3C CH3
Ch = S, Se, Te
H3C
X
R
H3C
X'
R
I
I
OR
H2
H3'
H3
N
NO
N
N
Ph
HC
CH3
ZincZinc PorphyrinsPorphyrins ((TweezerTweezer))
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p yp y (( ))
Zn
NN
N N
ZnNN
N NO
O
O
O
Especially effective for bifunctional substrates (diamines)
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Database TechniquesDatabase Techniques
1313C orC or 11H shiftsH shifts
NN,,--DimethylbenzylamineDimethylbenzylamine (DMBA)(DMBA)
BisBis--1,31,3--methylbenzylaminemethylbenzylamine--22--methylpropane (BMBAmethylpropane (BMBA--pMepMe))
H3CHC N
CH3
CH3
HN
HN
Me
Me
M e
Structural MotifsStructural Motifs
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OH OH
Me Me
OH OH OH
AcO
OAc
OAc OAc
OH
Me
OH OAc
Me
OAc
HO Me
OH
Me
OH
Me
Prepare and examine allpossible stereoisomers
13 1
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C or H Database -subtract chemical shiftof particular nucleusin one stereoisomer
from average of valuein all eight
DMBA database
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-Difference in 13Cshifts between (R)-and (S)-DMBA
BMBA-pMe For assigning the stereochemistry
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saturated secondaryalcohols(acyclic and cyclic)
=negative
=positiveC C
OHA
biaryl alcohols &benzyl alcohols
=
positive
=
negativeC C
OHB
saturated tertiaryalcohols
=positive
=negativeC C
OHC
Me
H
O
H
N
H
N
Ph
Ph
Me
Me
of secondary and tertiary alcohols
Binding of BMBA-pMeto a secondary alcohol
Observed trends
Liquid CrystalsLiquid Crystals
l (l ( b lb l l ) ( G)l ) ( G)
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poly(poly(--benzylbenzyl--LL--glutamate) (PBLG)glutamate) (PBLG)
Forms ordered material in a magnetic fieldForms ordered material in a magnetic field
Pair ofPair ofenantiomersenantiomers have differenthave differentmolecular orientations in PBLGmolecular orientations in PBLG
Three discrimination mechanismsThree discrimination mechanisms Chemical shift anisotropy (least useful)Chemical shift anisotropy (least useful)
Different dipolar coupling constants (Different dipolar coupling constants (11HH--1313C)C)
Differences inDifferences in quadrupolarquadrupolar splitting (splitting (22H) (mostH) (mostuseful)useful)
QuadrupolarQuadrupolar SplittingSplittingN t b d i l ti b f idN t b d i l ti b f id
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Not observed in solution because of rapidNot observed in solution because of rapidtumblingtumbling
Observed in ordered media and extent ofObserved in ordered media and extent ofsplitting depends on orientation relative to thesplitting depends on orientation relative to theapplied magnetic fieldapplied magnetic field
Proton-decoupleddeuterium NMR
spectrum
PBLGPBLG I dibl V tilitI dibl V tilit
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PBLGPBLG -- Incredible VersatilityIncredible Versatility
Only need different packing ordersOnly need different packing orders
Do not need specific interactions betweenDo not need specific interactions betweenthe substrate and the liquid crystalthe substrate and the liquid crystal
Effective for virtually any class ofEffective for virtually any class of
compoundcompound
Includes aliphatic hydrocarbonsIncludes aliphatic hydrocarbons
Especially effective for resonances ofEspecially effective for resonances ofnuclei remote to thenuclei remote to the chiralchiral centercenter
D t i L b liD t i L b li
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Deuterium LabelingDeuterium Labeling
Only need deuterium as a signalOnly need deuterium as a signal betterbetterto useto use achiralachiral reagents so no concernreagents so no concernabout kinetic resolution orabout kinetic resolution or racemizationracemization
Convert COConvert CO22H to COH to CO
22CDCD
33AddAdd perdeuteroperdeutero benzoylbenzoyl group (have ogroup (have o--, m, m--
and pand p--protons as potential probesprotons as potential probes
Provides a single, strong signal (or a fewProvides a single, strong signal (or a feweasily assigned signals) for the analysiseasily assigned signals) for the analysis
E lE lD
HO
D
OH
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ExamplesExamples
O
SS
O D D D
D
D
D
D
4
D
D D
OH
HOOH
-Remote chiral center-2H signal for the para-position
showed different quadrupolarsplitting
(R,R)-, (S,S)- and (R,S)-(meso)-
isomer distinguished
Can distinguish (R,R,R)-,(R,R,S)-, (S,S,R)- and (S,S,S)-isomers
PerdeuteratedPerdeuterated/Natural Abundance/Natural Abundance 22HH
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Complicated spectraComplicated spectra
eacheach22
H signal is a doubletH signal is a doublet eacheach 22H signal may be two doublets if theH signal may be two doublets if the
enantiomersenantiomers have differenthave different quadrupolarquadrupolarsplittingsplitting
cancant predict a priori the magnitude of thet predict a priori the magnitude of thequadrupolarquadrupolar splittingsplitting
Procedures have been devised to aid inProcedures have been devised to aid inthe assignment ofthe assignment of22H spectraH spectra