Nmr Short Course

8/6/2019 Nmr Short Course

1/92

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


2/92


3/92

ChiralChiral DiscriminationDiscriminationNMR SpectroscopyNMR Spectroscopy

ChiralChiral derivatizingderivatizing agentsagents

ChiralChiral solvating agentssolvating agents

Metal complexesMetal complexes

Liquid crystalsLiquid crystals


4/92

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


5/92

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


6/92

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


7/92

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


8/92

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


9/92

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


10/92

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


11/92

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


12/92

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)


13/92

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


14/92

I

OH

MPA derivative

2.7 Hz differential shielding for the methyl group9-bonds removed From the chiral center


15/92

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


16/92

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.


17/92

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


18/92

22--AMA/9AMA/9--AMAAMA LinearLinear vsvs cycliccyclicsecondarysecondary carbinolscarbinols

O

Me

Me

H

OO

H

MeO

HMeO

HR1 R2

HMeO

HR1 R2


19/92

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


20/92

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


21/92

H

O

RSRR

O

F

C

MeN

CFTA ester plane

CFTA - Conformational Preferencesyn-periplanararrangement


22/92

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


23/92

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


24/92

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


25/92

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


26/92

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


27/92

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


28/92

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


29/92

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


30/92

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


31/92

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


32/92

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


33/92

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


34/92

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


35/92

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


36/92


37/92

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


38/92

--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


39/92

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)


40/92

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


41/92

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)


42/92

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


43/92

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


44/92

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


45/92

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


46/92

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


47/92

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


48/92

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


49/92

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


50/92

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


51/92

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


52/92

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


53/92

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


54/92

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


55/92

[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


56/92

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


57/92

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


70/92

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


73/92

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


75/92

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)


76/92

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


77/92

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


78/92

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


80/92

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))


81/92

p yp y (( ))

Zn

NN

N N

ZnNN

N NO

O

O

O

Especially effective for bifunctional substrates (diamines)


82/92

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


83/92

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


84/92

C or H Database -subtract chemical shiftof particular nucleusin one stereoisomer

from average of valuein all eight

DMBA database


85/92

-Difference in 13Cshifts between (R)-and (S)-DMBA

BMBA-pMe For assigning the stereochemistry


86/92

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)


87/92

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


88/92

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


89/92

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


90/92

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


91/92

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


92/92

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

Documents

Nmr Short Course