NMRNMR SpectroscopySpectroscopy forfor StudyingStudying ChiralityChirality ThomasThomas J.J. WenzelWenzel DepartmentDepartment ofof ChemistryChemistry BatesBates CollegeCollege Lewiston,Lewiston, MaineMaine 0424004240 [email protected]@bates.edu ChiralChiral DiscriminationDiscrimination NMRNMR SpectroscopySpectroscopy •• ChiralChiral derivatizingderivatizing agentsagents •• ChiralChiral solvatingsolvating agentsagents •• MetalMetal complexescomplexes •• LiquidLiquid crystalscrystals ChiralChiral DerivatizingDerivatizing AgentsAgents •• FormForm aa covalentcovalent bondbond betweenbetween anan opticallyoptically purepure reagentreagent andand thethe compoundcompound ofof interestinterest CDACDA ++ (( RR))--SubSub == CDACDA --((RR))--SubSub CDACDA ++ (( SS))--SubSub == CDACDA --((SS))--SubSub •• ResultingResulting compoundscompounds areare diastereomersdiastereomers ChiralChiral DiscriminatingDiscriminating AgentsAgents •• NoNo racemizationracemization •• NoNo kinetickinetic resolutionresolution •• NeedNeed 100%100% opticaloptical puritypurity ofof thethe reagentreagent ifif usingusing forfor thethe determinationdetermination ofof enantiomericenantiomeric excessexcess ChiralChiral SolvatingSolvating AgentsAgents •• FormForm nonnon --covalentcovalent interactionsinteractions betweenbetween anan opticallyoptically purepure reagentreagent andand thethe compoundcompound ofof interestinterest CSACSA ++ (( RR))--SubSub == CSACSA --((RR))--SubSub CSACSA ++ (( SS))--SubSub == CSACSA --((SS))--SubSub •• ResultingResulting compoundscompounds areare diastereomersdiastereomers •• KKR andand KK S areare likelylikely differentdifferent –– causescauses differentdifferent timetime --averagedaveraged solvationsolvation environmentsenvironments ChiralChiral SolvatingSolvating AgentsAgents •• PreferablePreferable toto havehave fastfast exchangeexchange •• HighHigh concentrationconcentration ofof CSACSA usuallyusually leadsleads toto largerlarger discriminationdiscrimination •• OftenOften seesee enhancedenhanced enantiomericenantiomeric discriminationdiscrimination atat lowerlower temperaturestemperatures AssigningAssigning AbsoluteAbsolute StereochemistryStereochemistry •• MechanismMechanism ofof discriminationdiscrimination isis understoodunderstood andand characteristiccharacteristic shiftsshifts occuroccur inin thethe spectrumspectrum – More common with certain families of chiral derivatizing agents – Possible with some chiral solvating agents •• EmpiricalEmpirical trendtrend – Best if use known model compounds as close as possible in structural features to the unknown ArylAryl --containingcontaining CarboxylicCarboxylic AcidsAcids --AlcoholsAlcohols andand AminesAmines CH3O O O O F H3CO HC3CO OH F3C C COH OH H3C C COOH O CN CFTA MTPA MPA (O-MMA) O-AMA OCH3 OH O OCH3 O H N H3C C COOH OH O H3CO OH N-Boc PG MαNP 2-AMA/9-AMA ArylAryl --containingcontaining CarboxylicCarboxylic AcidsAcids •• MTPAMTPA == αα--methoxymethoxy --αα-- trifluoromethylphenylacetictrifluoromethylphenylacetic acidacid •• MPAMPA == αα--methoxyphenylaceticmethoxyphenylacetic acidacid •• OO--AMAAMA == OO--acetylacetyl mandelicmandelic aciedacied •• CFTACFTA == αα--cyanocyano --αα--fluorofluoro --pp--tolylacetictolylacetic acidacid •• NN--BocBoc PGPG == NN--bocboc phenylglycinephenylglycine •• MMααNPNP == 22 --methoxymethoxy --22--(1(1 --naphthyl)propionicnaphthyl)propionic acidacid •• 22--/9/9 --AMAAMA == αα--(2(2 --anthryl)anthryl) --αα--methoxyaceticmethoxyacetic acidacid 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) ∆δ RS -Calculate values – negative for L 1, positive for L 2 (OMe) (Ph) (R)-MTPA L1 Ph OMe (S)-MTPA O L2 CF3 H O OH H1 8 9 ∆δRS 7 5 3 H1' 8 6 4 RO Me(10) Me(8) Me(9) H2 MTPA 0.07 -0.017 -0.04 Position MTPA MPA PPA 1 0.07 0.19 0.43 MPA 0.05 -0.021 -0.26 1' 0.03 0.12 0.20 2 0.09 0.14 0.18 3 0.04 0.02 0.03 10 4 0.03 0.07 0.14 4' 0.03 0.06 0.13 8 0.03 0.04 0.10 PPA = α-phenyl- propionic acid ∆δ RS depends on: -Degree of conformational preference/how it influences the shielding -Size of the shielding (anthryl > naphthyl > phenyl) SecondarySecondary AlcoholsAlcohols •• MPAMPA >> MTPAMTPA (conformational(conformational preferencepreference thatthat producesproduces greatergreater differencedifference inin shielding)shielding) •• MPAMPA –– earlyearly syntheticsynthetic proceduresprocedures –– highhigh degreedegree ofof racemizationracemization •• BetterBetter proceduresprocedures forfor MPAMPA derivatizationderivatization nownow existexist •• MixMix andand shakeshake methodmethod MPA derivative I OH 2.7 Hz differential shielding for the methyl group 9-bonds removed From the chiral center EffectEffect ofof temperaturetemperature •• ForFor MPAMPA derivativesderivatives ofof secondarysecondary alcohols,alcohols, loweringlowering thethe probeprobe temperaturetemperature byby aboutabout 100100 KK (to(to 175175 --200K)200K) approximatelyapproximately doublesdoubles thethe ∆δ∆δ RS valuesvalues •• AltersAlters conformationalconformational preferencepreference furtherfurther towardtoward thethe spsp formform ∆δ∆δ •• CanCan measuremeasure T1T2 valuesvalues asas aa confirmationconfirmation ofof stereochemicalstereochemical assignmentassignment •• EffectEffect notnot asas pronouncedpronounced withwith MTPAMTPA oror AMAAMA BariumBarium MethodMethod MPA/secondaryMPA/secondary alcoholsalcohols sp ap MeO O Ph O H H α α' O Ph O MeO L2 L2 L1 L1 Ba+2 Ba+2 Barium binds in a chelate manner with the ester and Ba+2 alters the conformation MeO O Ph O preference toward the sp H H α α' O conformer. Ph O O L2 Me L2 Ba+2 L L 1 1 Leads to enhancement in +2 +2 sp-Ba complex ap-Ba complex the shielding and get larger ∆δ RS values. La(hfa)La(hfa) 3 methodmethod withwith MTPAMTPA SecondarySecondary alcoholsalcohols R2 MeO R2 OMe R R1 1 X X CF CF3 3 Chelate bonding of the H O H O sp sp La reverses the orientation of the phenyl ring and the R2 R2 F3C CF3 R1 R1 shifts of the hydrogen X X OMe OMe resonances H O M H O M sp' sp' (S)-MPTA derivative (R)-MPTA derivative X = O or NH This reversal in shifts (b) can be used to confirm ∆δ S,R ∆δ S,R 0 < 0 OMTPA 0 > 0 M R1 R2 M the stereochemical H assignment ∆δ S,R > 0 ∆δ S,R < 0 M MTPA plane M 22--AMA/9AMA/9 --AMAAMA –– LinearLinear vsvs cycliccyclic secondarysecondary carbinolscarbinols Me Me O MeO H H R1 R2 H O O H MeO H MeO R1 R2 H MMααNPNP (secondary(secondary alcohols)alcohols) OCH3 H3C C COOH -∆δ RS about 4-times greater than with MTPA -Less prone to racemization with methyl group on chiral carbon CFTACFTA (secondary(secondary alcohols)alcohols) F H3C C COOH CN •• TheThe ∆δ∆δ RS valuesvalues areare typicallytypically 22 --timestimes greatergreater thanthan MTPAMTPA •• MuchMuch fasterfaster reactionreaction thanthan MTPAMTPA withwith hinderedhindered compoundscompounds •• 1HH andand 19 FF NMRNMR cancan bebe usedused CFTA - Conformational Preference syn-periplanar arrangement N Me C O RR RS F O H CFTA ester plane SecondarySecondary DiolsDiols andand PolyolsPolyols •• IfIf groupsgroups areare farfar enoughenough apart,apart, cancan determinedetermine thethe configurationconfiguration ofof eacheach groupgroup independentlyindependently •• IfIf groupsgroups areare closeclose together,together, boundbound reagentreagent maymay influenceinfluence thethe shieldingshielding oror deshieldingdeshielding atat moremore thanthan oneone sitesite MPAMPA forfor DiolsDiols •• AnalysisAnalysis ofof (( synsyn andand antianti ):): –– 1,21,2 -- –– 1,31,3 -- –– 1,41,4 -- –– 1,51,5 --diolsdiols withwith knownknown configurationsconfigurations •• ObserveObserve reproduciblereproducible trendstrends thatthat cancan bebe appliedapplied toto compoundscompounds withwith unknownunknown configurationsconfigurations PrimaryPrimary AlcoholsAlcohols •• MTPAMTPA –– CC2 chiralchiral •• CFTACFTA O OMOM OMe O EtOOC ∗ OH ∗ OH 2.116 •• 99--AMAAMA O HO N Cl 1' MeO H N α 2' O N N H L2 MPA - Unreliable Ar L1 TertiaryTertiary AlcoholsAlcohols 2-NMA MTPA (a) (H) (Nap) (S)-2NMA HC HB HA Nap (R)-2NMA OH H CH2 O HX HY HZ OMe CH2 2NMA plane Me O HX O-2NMA (b) HC H2 H2 ∆δ ∆δ HY < 0 C C C > 0 HB HZ Me HA SecondarySecondary AminesAmines •• MTPAMTPA O N N CF3 N MTPA OMe MTPA Ph 2 ∆δ∆δ RS •• HH2 hadhad aa ofof 2.442.44 ppmppm !! •• ValuesValues soso largelarge onlyonly needneed oneone MTPAMTPA derivativederivative (use(use (( RR))--acidacid chloridechloride sincesince moremore reactivereactive thanthan (( SS))--acidacid chloride)chloride) PrimaryPrimary AminesAmines –– αα--substitutedsubstituted •• MTPAMTPA givesgives largerlarger ∆δ∆δ RS valuesvalues thanthan MPAMPA oror 99--AMAAMA -- MTPAMTPA amidesamides havehave greatergreater preferencepreference forfor thethe spsp conformerconformer thanthan observedobserved withwith esters.esters. •• BPGBPG –– preferencepreference forfor apap conformerconformer –– typicaltypical ∆δ∆δ RS valuesvalues areare 22 -- toto 33 --timestimes largerlarger thanthan withwith MTPAMTPA O H N OH ArylAryl MethoxyMethoxy ReagentsReagents -- SummarySummary •• WantWant largerlarger ∆δ∆δ RS valuesvalues –– eithereither throughthrough highhigh conformationalconformational preferencepreference oror largerlarger aromaticaromatic ringring (shielding)(shielding) •• ValuesValues shouldshould allall bebe positivepositive forfor oneone substituentsubstituent (L(L 1)) andand negativenegative forfor thethe otherother (L(L 2)) •• NeedNeed resonancesresonances inin bothboth substituentssubstituents O O CamphanicCamphanic AcidAcid O HO •• propro --((RR)) andand propro