WelcometoChemistry421

UseofPhysicalMethodstodetermine
structuresinOrganicChemistry
Dr.CharlesDeBrosse
232BeuryHall(acrossfromDept.office)
NMRlab001BeuryHall
2152041082

CourseOrganization
LecturesTuesdayevenings69pm.Attendanceisstrongly
encouraged.Youshouldreadtheassignedmaterialanddothe
homeworkproblemspriortothelecture.
Textbook,OrganicStructuralSpectroscopy,byLambert,
Shurvell,LightnerandCooks
Gradebasedon3Inclassquizzes,homeworksetsandFinal
exam
CoursenoteswillbeavailableonBlackboardgenerallythe
Mondaybeforethelecture.
IwillreserveMonday1011amasofficehour,andam
accessibleothertimesinmylaboroffice

SpectroscopyinOrganic
Chemistry.

TheChemistsEyes,EarsandNose
Howdoweknowwhatwehave?
Readlabels(sometimeslabelslie)
Whoseworddowehavetotakeonit?
Checkitoutforyourself!(Getaspectrum!)
Aspectroscopist.(neverthehero,justthe
herosbestfriend)

Chemistry421
Goalofthecourseistogiveyouthetoolstoanswer
partsofthesequestions.
OrganicStructuredeterminationbyspectroscopic
methods
NMR(nuclearmagneticresonancespectroscopy)
MassSpectrometry(MS)
InfraredSpectroscopy(IRandothervibrationalclasses
likeNearIR,Raman)
ElectronicSpectra(Ultravioletandchiroptical
methods)

StructuralFeatureswecan
addressSpectroscopically

Molecularweight
ChemicalFormula
Functionalgroups
SkeletalConnectivity,structuralisomers
Spatialgeometricarrangements,stereoisomerism,
symmetry
Presenceandlocationofchromophores
Chiralityissues
Someofthesearemorecentralthanothers.Sometimes
wecanstopwhentheanswerisfittopurpose.

Techniqueswewillstudyinthis
Course
NMRlooksatbatomsbymeansoftheirnuclei.
Connectivitypathways,spatialarrangementsofatomsand
1:1correspondencebetweensignalsandatoms
MassSpecmeasuresmolecularweight,most
fundamentallyusefulforunknowns.Controlable
fragmentationcandistinguishamongrivalpossibilities
IRandRamanVibrationscharacteristicofbonds,
particularyforfunctionalgroupidentification.Excellent
fingerprint
UVreportsonconjugationandmultiplebonds.Provides
entretochiropticalprobestoassymetricconfigurations

Chemistry421
Goalisforyoutogainaconversational
levelofknowledge
Baseleveloftheory,aspictoralaspossible
shouldhelpyourealizethescopeand
limitationsofthesemethods.
Surveyofrepresentativedataandhowto
interpretit.
Applyingtherighttooltotherightquestion
Integratingdatafromvarioustoolsandsources(i.e.we
shouldbeabletoexplainallourobservations.Alsowe
shouldbeabletoobservefeatureswepredict,knowing

ourchemistry)

ComplementarySpectroscopies
Therearestrengthsandweaknessesinallthevariousspectroscopymethods
BlindSpots(seestoryofthreeblindmendescribinganelephant)
NMRe.g.;hasNMRsilentnuclei;fullysubstitutedcarbonsasblocks;blind
toinorganics,nearlyblindtopolymericmtls.
IRe.g.;robustforfunctionalgroups;greatifyouhaveacompoundmatchina
library(fingerprint);shakyonquantitativeresponse,samespectrummight
explainmultiplecompounds;subjecttoselectionrulesgovernedbydipole
momentinvibration(complementsomewhatwithRaman)
UV;needschromophores
MassSpec;compoundsdifferinionizability.

Asmartchemistwillbeattunedtopossibleblindspotsbefore
makingconclusions.Bestsolutionistomarryupcomplementary
data.Allthedataneedstoagreeoratleast,notconflictwithing

thevariousmethods.

TotalSynthesisasaStructural
Proof
Useofallourknowledge
Generallytheproductofareactionis
rationallyrelatedtotheingredientswehave
used.
Nonambiguousroutefromknown
compounds
Oxidativedegradationtoknown
compoundsandhistoryofchemistry

TheElectromagneticSpectrum
Lightcomesindifferentcolors
Nomatterwhatpartofrange,therearesomefeaturesin
common,thatyoushouldknow.
B

1wavelength,
isadistance.

isfrequency,Hz,1/sec

Amplitude

PhotonE=h

=c/;|c=3x1010cm/sec
h=Plancksconstant=6.624x1034Jsec
/c=1/=wavenumber,cm1

Peakspertime;
frequency

Propagationofe,bfields,time

ChemicalPropertiesasrelatedto
thedifferentcolorsoflight
Spacings
betweenatomic
nucleiincrystals

Micro
X UV IR+Ramanwaves NMR
RayElectron

higherE,
higher
smaller
15

lowerE,
lower
larger

vibrationsof
orbital
bonds
transitions

10

5
100
kcal/mol

rotational nuclear
states
spinflips

5
106
kcal/mol

10
kcal/mol

Log,
meters

WhataboutMassSpec?
Thepropertiesmeasureddonotdirectlybearonabsorptionof
light
Moreproperlytermedmassspectrometry
Wedohoweverinquadrupolemassspectrometryscanan
electricfieldthatinduceddifferentcurvepathsfordifferent
masses
RadiofrequencyalsodoesshowupinFTmassspec(ion
cyclotronresonance)

Sensitivityofthemethodswe
willstudy
NMRisworst,typicallyneeding10sofg
to10sofmgfor13C.
MassSpecisgenerallyabout103104x
moresensitivethanNMR
UVisabout100xmoresensitivethan
NMR

Questions,Questions.

Whatsinthisflask?
Whathaveyoujustsynthesized?
DidmyreactionWork?
Whatispresentinthatsample?
HowcouldthisreactionhavepossiblyFailed?
Isolatedmaterials?
Purity?Mixture?Whatkindofmixture?
Isthismaterialsuitableforthenextstep?
BesttoAskYourselfthesequestions!(Betterthanmaking
yourBossask,ornottobeabletoansweraCustomer

Answers!
BadAnswer:becausethisalwaysworksinour
lab
BadAnswer#2..becausemyProfessor(orsome
slightlyoldergradstudent,postdoc)saidso..
SlightlylessBadAnswer#3thiswasdoneinthe
literature
GoodAnswerbecauseallthespectralandother
analyticaldataagreewithme
AnalyticalChemistry.Ifyoudoitright,nobodyhas
totakeyourwordontheanswers!

FeaturesinCommonforall
Spectroscopy
SomePhysical
Property

Energy
Transitions

Measuring
Scheme

Light,
(Frequency
Dispersion)
Akeyforushereis,weuse
instrumentstoDisperseenergy
acrossascaleappropriatetoa
chemicalproperty

Data
Analysis,
Interpretation

Knowledge

Wisdom(orProgress)

ThereforewehavePrecise
AnalyticalInstrumentsthatcan
DisperseEnergy
Accurate,precise,reproducible
Combinetheenergydispersionschemewithadetection
scheme.
Generallythesamplesitsphysicallybetweenthesource
andthedetector.
Detectorprovidesselectivityinresponse,usuallygenerates
avoltage.WerecordvoltageresponsesasDATA

Thedispersioniseasytoachieve
withordinarylight
Lightsource

Monochromatorrotates
Prismordiffraction
grating
Spacingsongrating
appropriateto
wavelength

Recorder

Schemesuseslitsto
admitaselectregionof
spectrum

Sample

Prettyineffectivefor
radiowaves

Detector

SpectroscopySpreadsoutVision
Allthetechniqueswewilldiscusshavesomefeaturesin
common
Datawillhavearunningvariable(xaxis)thatisinsomesense,
aenergyscale.(notatleastdirectly,atimeaxis.Thereforea
snapshotintimeofamolecule)

Instrument
Response

Theresponsevariable(anabsorptionorotherintensity)is
relatedtothechemicalpreponderanceofsomefeaturethatcause
theresponse.

Energy

Thereisapeakhere
Butnothere

Thepositioninformsus
aboutsomechemical
propertyinthesample
Thepeakheight
informsusabouthow
muchofthatproperty
isinthesample

FourierTransformMethods
AnalternativetoEnergy
Dispersivemethods
AllmodernNMRandIRisdonethisway
Measuresallfrequenciesatsametime.Moreefficientat
signalgatheringinagivetime(betterS/N)
Thefrequenciespresentaredeconvoluted(ordispersed)after
dataiscollected.
FourierAnalysisisthemathematicalmethodfordoingthis.
Itisbasedonthetheorythatanycomplexperiodic(repeats
overtime)wavecanbedecomposedintoalinear
combinationofsinusoids

Instrument
Response

Togetthemeasurement,we
collectadetectorresponseasa
functionoftime
time

Lotsofdifferentfrequenciespresentfromthesample
Theirvoltagesbeatagainsteachothermakinginterferencepattern
(interferogram)
Interferenceisperiodic,becausethefrequenciesareconstantw.r.teachother

AnOscillatingvoltageisinterpretedasaFrequency
The process is similar
to the way a sound
wave is digitized to
make e.g. a music CD

Keytothisis
samplingat
exactlyequaltime
intervals
This is a Frequency
Axis. Think Hz!

InterferingSinusoidsare
Representedinadecayingtrace
Spaceisfrequency1

Spaceisbeatingoffrequency2vs1(12)

Ahumanbeing
couldcompute
thisFT,
countingbeats
pertimeunit

Keytotheprocessisaveryprecisely
definedtimebase(thexaxis)thattheFT
algorithmusestocount

InterferencepatternsAlmost
abletoTransformbyHand
Added together

Damped Sines of 2.77, 28, 34 Hz

2.5

2
1.5

0.5

1
0.5

0
-0.5

-0.5

-1
-1.5

-1
0

200

400

600

800

1000

200

400

600

800

Time(ms)
Time(ms)
ButitsreallytheFastFourierTransformsandfastcomputersthatmakethis

practical!

1000

Sincethetimeacquisitionisfastand
efficientitiseasytoSignalAverage
Addingaccumulatingscansfromthedetectorintomemoryof
computer
Signalsarecoherentandaddingthescanscausessignalto
growlinearlywithnumberofscans.
Noisebeingrandomandincoherentgrowswithno.ofscans
Fromthis,theSignaltoNoiseratio(S/N)grows
proportionallytothesquarerootofnumberofscans
E.g.,aspectrumacquiredwith100scanswillbe10xbetter
thanonewith1scanonly.

SomeFeaturescommontoall
Spectra
Linewidth.Usuallymeasuredat
0.5Imax
Canbelimitedbythe
instrumentation,orbelimitedby
nature.
Nature,hereexertsherselfas
uncertaintytotoslight
chemicalvariation,orinability
tomeasureenergyprecisely.

Usingcomputerized
Datasystemsaddsan
additionallimitation
onourresolution
problem
Moredatapointsare
betterbutusuallyata
costtoexpt
efficiency

Unitsoflinewidtharesameas
axis,e.g.Hz,cm1

Seehere2identical
peaks,digitized
differently

Resolution(abilitytodistinguish
linefromcloselyspaced
neighboringlineisrelatedto
linewidth

Bearsdirectlyonour
abilitytodetermine
thepositionofImax

Noise,thecurseofScience
Allmeasurements,especiallythosewecarryoutwith
instruments,generateNoise.
Detectorsofallsortsgenerateelectricalnoise
Noiseisbad.Itisrandomandincoherentanddoesnot
possessinformation.Wegototremendousexpenseandeffort
toeliminate,suppress,andfinesseourwaypastnoise.
Signalsaregood.Theygiveusinformation.
Noiselimitsourabilitytoevenobserveveryweaksignalsor
toquantifysomewhatweaksignals.TheSignaltoNoise
Ratioisanimportantparameterisassessingourabilityto
interpretdata.
Noiseissuperimposedontopofpeaks

SignaltoNoise
(S/N)ratios

Typicalruleofthumb:

Measure
height

Limitofdetection,S/N=3
LimitofQuantitation,S/N=10
Noise(rms)is
S/N=6.3/2*0.707
0.707xpeakto
=4.45
peak
Sothispeakisreliably
detectable,butnot
reliablyquantitatable

Chemistry421Structure
Determination
InterpretableConnectionbetweenStructural
FeaturesandSpectroscopicsignals
Wewillinterpretspectratolearnabout
structures.
TheInterpretationparadigmconsistsof
charting:
Observation
IRshowsaC=Oat1730cm1

Inference

Mymoleculecontainsaketoneor
aldehyde
NMRshowsa3protonsingletat Imayhaveamethylgroup
adjacenttoC=O
2.2

Mayneed
more
experiments
ortolook
furtherinthe
data!

AwayofThinking
????????
Knowncompounds

TotalUnknowns

(verifystructure)

Isolatednaturalproducts

Allpredictedsignalspresent?

Unrelatedimpurities,
contaminants

Agreementwithliterature?

PartialUnknowns
Newcompound?

Impuritiespresent?

Singlecomponent,vs
mixture?

Sidereactionproduct

Fingerprint?

Wrongstartingmaterial,carry
throughknownsyntheticsteps
Canwetrackknowncompounds?
Peaksfromprecursorcompounds
mayhavedescendents

AStrategyforHandling
UnknownStructures

Complementary1HNMR,13CNMR,MassSpec,UVanyfeaturesstandout?
GettheMolecuarWeightfromMS
HeavyAtoms?(ratioofMtoM+1,M+2)
Ifheavyatomsareidentified,subtractfromMW
ConsultvariousmolecularformulaDBs(Merck,CRCetc).WriteoutMolecular
Formula
UsetheDBE(sitesofunsaturation)rule
InfraredFunctionalgroupspresent?Identifyaspossiblysubtractfromformula
(retaintheneedtoincorporateatend)
Inventory13CNMRandclassifytheC,Hgroupspresent.Tabulatefragmentsof
structure.ReconcileMSfragments.
Assemblepossiblestructures

MolecularWeightandMolecular
Formulas
AbsolutelycriticaltoStucturedetermination
CentralityofMassSpectrometrytomodernChemistry
Molecularweightmustagreewiththestructure.Notewell,
thatagivennominalMWgenerallyisconsistentwithseveral
possibleformulas.
Thenitrogenrule.Acompoundwithanevennumbered
molecularweighthas0,2oranevennumberofnitrogens.
VeryImportant:Learntheruleforsitesofunsaturation
(doublebondequivalents,DBE)asapredictivetoolfor
multiplebondsand/orrings.Thesearebasedonthestandard
valenciesforordinaryatoms.

DBERules

AimtoreduceaformulatoCNH2N+2

TakeformulaandcrossoffOxygenatoms
Replaceallhalogenatomswithhydrogen
CrossoffallNitrogenatoms,andforeachNremoveoneHatom.
SulfurtreatlikeOxygen(?Usecareiftherearealotofoxygens,
possibleO=S=Otypegroups,similarissueswithPhosphorus)
Subtractyournewlyreducedformula(lookslikeCxHx,from
CxH2x+2numberH(evennumber)
Dividethisanswerby2.ResultisDBE.

Data

SosomeDecisionTree
thinkingispossible TheNMR
branch.

granularityofquestions

Synthetic Product
1H NMR
Could it be what I want?
Quick Inventory of signals
YES
NO
Do I need more information?
What do I need to find out
Carbon Survey
Need Assignments?
Correlations to protons

Information
Contenthigher

Proton coupling pattern

YES

Worth more spectroscopy?

Back to the Lab!
Assess Purity

NO

Noe for stereochemistry

Integrateat
higherlevel
withother
techniques

Separations
methods,Feedback
tosynthesis.

NuclearMagneticResonance
(NMR)

TonightsSubjects
I.

Howdothespectrometerswork?

II.

TheNMRmeasurablequantities

WhatisNMRSpectroscopy?
NuclearMagneticResonance
RadioFrequencyAbsorptionSpectraofatomicnucleiin
substancessubjectedtomagneticfields.
SpectralDispersionisSensitivetothechemical
environmentviacouplingtotheelectronssurrounding
thenuclei.
Interactionscanbeinterpretedintermsofstructure,
bonding,reactivity

TheFundamentalNMR
equations
Spinningnucleiproduceamagneticfieldthatis
proportionaltoitsmagneticmoment.The
proportionalityconstantis;=hI
AnactivenucleusinamagneticfieldB0hasanenergy
w.r.t.zerofieldof:
E(=h=h)=B0whereisthecomponentofthe
magneticmomentcolinearwithB0
ThisgivesforIZ=1/2;E=1/2(hB0)
E=hB0andinangularunits=B0

OriginoftheNMREffect
NucleiwithotherthanA(#protons+neutrons)andZ(#protons)
bothevennumbers,possessnetspinandassociatedangular
momenta
Revealsitselfonlyinmagneticfield.Asusual,suchmomenta
arequantized
Stateshavedifferentenergies,populatedaccordingto
Boltzmanndistribution
Statesare1/2,3/2,5/2forA=oddnumberandintegerifA=
evennumberandZ=oddnumber
Transitionsofindividualnucleibetweenspinstatesispossible
(bothdirections)leadingtoanequilibriumofpopulations
Numberofstatesis2I+1

PictoralViewofSpin
Directionofthe
AppliedMagneticField

Averagesoutinx,yplane;
smallnetresultantvector
alongthezaxis

NucleusMoments
precessaboutmagnetic
field.

Quantizedeitherwithor
oppossedtofield

TheBoltzmannexcessof
lowoverhighenergy
stateisverysmall,1in
106

Precessionofnuclear
magnetUnitsof

Torque

Becauseweareforcedintoobservingthegroupbehavior,wehavethe
mathematicequivalentofthesimplepictureontheright

ResonanceAgeneral
phenomenonforenergypumping

Imagine a kid on a swing

The period (frequency of the swing is determined (g, r(length), ).
Lets say the natural period is 3 seconds, or the frequency is 0.33
If the Daddy gives a push every 3 seconds, the kid will go higher and energy will be absorbed.
Every 2 seconds and the motion will get stalled and interfered with.
Every 1.5 seconds and the energy will get absorbed but not as efficiently. The Daddy will get tired.

This general principal applies in NMR among other kinds of measurement, and holds whether we scan through the applied frequency or multiplex
all at once

NMRWhatisitGoodFor?
(absolutelyeverything!)
Solvingstructuresofcompoundslikesynthetics,impurities,
naturalproducts
Identifyingmetabolites
Stereochemicaldetermination
Followreactions
Validatingelectronictheory;trendswithinseriesofcompds.
Kinetics
Extendedstructure,e.g.proteinnmr
Molecularinteractionse.g.ligandbinding
Acidbasequestions
Purities
Mechanisms,e.g.isotopedistributions,othereffects
Questionsaboutthesolidstate
Imaging

AndBesidesthat
Yougetyoursampleback!
Notsoformassspec
TryrecoveringyourcompoundfromaKBr
pelletornujolmull

ButontheotherHand
NMRisoneoftheleastsensitiveanalyticalmethods
Characterizedbylongrelaxationtimeconstants,
limitingexperimentalefficiencyinrealtime
Sometimestoomuchinformation.Canbe
demandingoninterpretationskill
RelativelyExpensivecomparedwithother
analyticalmethods
AswithothermethodsNMRhasblindspotsand
cannotserveasananalyticalpanacea

WhatDoIHopeyouwillLearn?
Enoughtheorytomakeyouconversantinthearea.
NMRwithrespecttohowtheeffectsariseandcanbepredicted;
connectionwithexperimentsandlimitationsofthese;surveyofhow
theinstrumentswork.
Basisoftheexperiments
Dataprocessingconsiderations,atleveltoappreciatewhatmayhave
beendonetogiveyourresult.
Abasictoolboxofexperiments,whattheydoandhowtousethemin
yourwork
Aworkingknowledgeoforganicchemicalshiftsandinfluenceof
symmetryonsignalcounting
Spincoupling,couplingnetworksandconnectivity,useofJcoupling
constantsinchemistry

WhyNMR?

UnmatchedversatilityasanAnalyticaltechnique
Highonchemicalinformationcontent
Significantinterpretability
Interpretableatseverallevelsofsophistication
Responserelatedtomolarpreponderance
Theseattributesaretrueforsolids,liquids,
mixtures,andtoasmallextent,gasphase
Morethanhalftheperiodictablehasatleastone
NMRactiveisotope

WhataretheMeasurablesin
NMR?
Intensity(analyticalparameter,proportional
tomolarity)
ChemicalShift(theelectronic
surroundings)
Couplings(scalarJanddipolarD;bond
paths,anglesconnectivityanddistances)
Relaxationparameters(motions,distances)

HowdoweGenerate,andRecord
NMRSpectra?
Pulser
Frequency generation
Power Amplifier
Oscillator

Acquisition
computer

Timing control signals

Network

Host Workstation
User interface
Expt. Setup, control
Data processing, plotting

Free Induction Decay

signal

Probe in
Magnet

receiver
FID with 90deg phase shift

Data file storage

RF pulse

Phase locked loop

NMR Acquisition commands

transmitter

signal

PreAmp

Superheterodyne (beat-down to AF)

Phase sensitive detection
A/D convertor

Block Diagram for Spectrometer

RadioFrequencyTransmit
Receivesystem
FinelycontrolledRFpulses
Microsecondcontrol
Precisecontroloftiming,e.gpulses
anddelays
OtherpreciselydeliveredRFfor
decoupling,selectiveexcitation
Gradientampandgenerator,
shieldedinprobetoavoideddy
currents

ModernSuperconductingNMRMagnets
Older Magnets (1970s)
had opposed pole faces.
High voltages and
currents demanded heroic
temperature control. Field
ran side to side through
sample

Note: Special
superconducting
alloys NiobiumTantalum. Search
goes on for higher
temperature
superconductors.

Supercon magnets have

much larger fields, better
homogeneity. Field runs up
the axis of the sample.

New technology! Built in

auxilliary magnet with
reversed current acts as
active shield, partly
eliminating the projection
into the room.

Lines of force project several feet into the room. They concentrate at the top and
bottom. Magnets can grab iron objects and accelerate them.

Whatstheroleofthemagnet?

energy

Biggerthefieldstrength,thebetter.Thisisboth
fromasensitivityanddispersionofsignalspoint
ofview.
ExpressedinHz,permitseasisermathandtrigas
needed.Gausswouldgenerateenergiesinergs.

E=hH0Iz

Rememberthe
energydifference
givesthepopulation
excess.Roughly
H7/4increase

Fieldstrength,H
0

TheNMRProbe
MatchingtoTxnetwork

Samplegoesinsidehere
Coil
Tuned
Circuit

Usuallythereisadouble
tunedresponsefor
Deuteriumlock
Asecondcoilprovidesa
decoupling,gradientor
otherRF

HowSensitiveisNMR?
N 2h2 I ( I 1)
H0 0H0

3 IkT

N=#spins

TheRidersite,referencedbelowgivesreceptivityvs.13Cwith
clickableentries.Thesereflectnaturalabundance,,etc.

http://arrhenius.rider.edu/nmr/NMR_tutor/periodic_table/nmr_pt_frameset.html

Anothergoodsiteishttp://nmr.magnet.fsu.edu/resources/nuclei/table.htm

Theanswertothatquestionis
NotallthatSensitive!
AtanygiventimeMassspecisatleasta
104timesmoresensitive
ComparewithUV,IRatleast102x
sensitive
ThisistiedtothefactthatNMRdetects

onlythetinyBoltzmannexcess.Anyold
moleculecanfragmentinMSorabsorba
IRphoton.LotsofresearchinNMR
aimedatthesensitivityproblem

E
N
= e kT
N

kisBoltzmannconstant
1.38x1023J/moleculeK
BecausetheEisso
small,theexcess(which
iswhatwedetect)is
miniscule

, aretheshortnames
fortheupper,lowerspin
quantumstatesofa
spin=1/2nucleus

MostImportantNucleiinNMR
1H, (also 2H, 3H)
13C
31P
15N especially when labeled into proteins
19F
29Si
Some isotopes of Sn, Cd. Pb, Ag, Pt
No coincidence that these are the I=1/2 nuclei. Spin numbers
higher possess nuclear quadrupole moment as well. This couples
to, broadens and complicates the nuclear spin angular momentum.
For the most part these are niche nuclei. Exception is 11B

QuadrupolarNuclei
Spin1
Electricfieldatnucleusnonsymmetrical
Effectiverelaxationmechanism,promoteslossof
NMRfinestructure
decouplefromattachedspins.Canevenwipe
outattachedspin1/2signals.
Linesarebroad,verychallengingNMR
35Cl,11B,17O,14N,7Li,etc.
Someredeemthemselves,deuterium,6Li