High-Resolution NMR Techniques in Organic Chemistry

388 Pages·2009·28.935 MB·English

by  Timothy D.W. Claridge (Eds.)

TETRAHEDRON ORGANIC CHEMISTRY SERIES
Series Editors: J.-E. Ba¨ckvall, J.E. Baldwin and R.M. Williams
VOLUME 27
High-Resolution NMR Techniques
in Organic Chemistry
Second Edition
Elsevier
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Preface to Second Edition
It is 9 years since the publication of the first edition of this book and in this period the
discipline of NMR spectroscopy has continued to develop new methodology, improve instru-
mentation and expandin its applications. Thissecond editionaims toreflect thekey develop-
ments in the field that have relevance to the structure elucidation of small to mid-sized
molecules. It encompasses new and enhanced pulse sequences, many of which build on the
sequencespresentedinthefirstedition,offeringthechemistimprovedperformance,enhanced
informationcontentorhigher-qualitydata.ItalsoincludescoverageofrecentadvancesinNMR
hardwarethathaveledtoimprovedinstrumentsensitivityandthusextendedtheboundariesof
application. Many of the additions to the text reflect incremental developments in pulsed
methodsandaretobefoundspreadacrossmanychapters,whereassomeofthemoresubstantial
additionsarebrieflyhighlightedbelow.
Chapters 1 and 2 provide the background to NMR spectroscopy and to the pulse methods
presentedinthefollowingchaptersandthushavebeensubjecttoonlyminormodification.As
withthefirstedition,noattemptismadetointroducethebasicparametersofNMRspectroscopy
and how these may be correlated with chemical structure since these topics are adequately
covered in many other texts. Chapter 3 again provides information on the practical aspects of
NMRspectroscopyandonhowtogetthebestoutofyouravailableinstrumentation.Ithasbeen
extended to reflect the most important hardware developments, notably the array of probe
technologies now available, including cryogenic, microscale, and flow probes and, indeed,
thoseincorporatingcombinationsoftheseconcepts.Thelatestmethodsforinstrumentcalibra-
tions are also described. Chapter 4, describing one-dimensional methods, has been extended a
little to reflect the latest developments in spectrum editing methods and to approaches for the
quantification of NMR spectra using an external reference. Chapter 5 again provides an
introduction to 2D NMR and describes homonuclear correlation methods, and has been
enhancedtoincludeadvancesinmethodologythatleadtoimprovedspectrumquality,suchas
thesuppressionofzero-quantuminterferences.Italsocontainsanextendedsectiononmethods
for establishing carbon–carbon correlations, notably those benefiting from proton detection,
whichgainwiderapplicabilityasinstrumentsensitivityimproves.Chapter6,presentinghetero-
nuclear correlation techniques, has been extended substantially to reflect developments in
methods for establishing long-range proton–carbon correlations in molecules, one of the more
versatile routes to identifying molecular connectivities. These include new approaches to
improved filtering of one-bond responses, to enhanced sampling of long-range proton–carbon
coupling constants, forovercoming spectral crowding, and tomethods fordifferentiating two-
bondfromthree-bondcorrelations.Italsobrieflyconsidersthemeasurementofthemagnitudes
of heteronuclear coupling constants themselves. The section on triple-resonance methods for
exploitingcorrelationsbetweentwoheteronuclides(termedX–Ycorrelations,whereneitherisa
proton) has also been extended to include the more recent methods utilising proton detection.
Chapter7onJ-resolvedmethodshasonlyasingleadditionintheformofanabsorption-mode
variantofthehomonuclearmethodthathaspotentialapplicationforthegenerationof‘proton-
decoupledprotonspectra’andintheseparationofprotonmultiplets.RatherlikeChapter5,that
covering the NOE (Chapter 8) reflects incremental advances in established methods, such as
those for cleaner NOESY data. It also extends methods for the observation of heteronuclear
NOEs,atopicofincreasinginterest.Chapter9presentsacompletelynewchapterdedicatedto
diffusionNMR spectroscopy and 2Ddiffusion-ordered spectroscopy(DOSY), mentioned only
briefly in the first edition. These methods have become routinely available on modern instru-
mentsequippedwithpulsedfieldgradientsandhavefoundincreasingapplicationinmanyareas
of chemistry. The principal techniques are described and their practical implementation dis-
cussed,includingthedetrimentalinfluenceofconvectionandhowthismayberecognisedand
dealtwith.Arangeofapplicationsarepresentedandinthefinalsectionmethodsforeditingor
extendingthebasicsequencesarebrieflyintroduced.Descriptionsofthecomponentsthatmake
upmodernNMRexperimentsaretobefoundinChapter10.Thisalsocontainsthemorerecent
developments in experimental methodologies such as the application of adiabatic frequency
sweeps for pulsing and decoupling and the suppression of unwelcome artefacts through zero-
quantumdephasing.Thechapterconcludesbyconsideringsome‘emergingmethods’,technol-
ogiesthatarepresentlygeneratingsignificantinterestwithintheNMRcommunityandmayhave
significant impact in the future, at least in some branches of chemistry, but remain subject to
future development. These include techniques for acquiring 2D spectra in only a single scan,
potentially offering significant time savings; those for generating highly polarised NMR sam-
ples, thus greatly enhancing detection sensitivity; and those for exploiting residual dipolar
xii PrefacetoSecondEdition
couplings between nuclei in weakly aligned samples as an alternative means of providing
stereochemicalinformation.Thebookagainconcludeswithanextensiveglossaryofthemany
acronymsthatpermeatethelanguageofNMRspectroscopy.
Thepreparationofthesecondeditionhasagainbenefitedfromtheassistanceandgenerosity
of many people in Oxford and elsewhere. I thank my colleagues in the NMR facility of the
Oxford Department of Chemistry for their support and assistance, namely Dr Barbara Odell,
TinaJackson,DrGuo-LiangPingandDrNickRees,andinparticularIacknowledgetheinputof
Barbara and Nick in commenting on draft sections of the text. I also thank Sam Kay for
assistance with theHMBC data fitting routinesused in Chapter 6 and DrJames Keeler of the
UniversityofCambridgeformakingtheseavailabletous.IamgratefultoBrukerBiospinfor
providing information on magnet development and probe performance and to Oxford Instru-
mentsMolecularBiotoolsforprovingthedynamicnuclearpolarisation(DNP)dataforChapter
10. I also thank Deirdre Clark, Suja Narayana and Adrian Shell of Elsevier Science for their
inputandassistanceduringtheproductionofthebook.
Finally,IagainthankmywifeRachaelandmydaughterEmmafortheirpatienceandsupport
duringtherevisionofthisbook.Iapologiseforsacrificingthemanyeveningsandweekendsthat
theprojectdemandedandlooktoavoidthisinthefuture.Until,perhaps,thenexttime.
TimClaridge
Oxford,September2008
[email protected]
Preface to First Edition
From the initial observation of proton magnetic resonance in water and in paraffin, the
disciplineofnuclearmagneticresonance(NMR)hasseenunparalleledgrowthasananalytical
method and now, in numerous different guises, finds application in chemistry, biology,
medicine,materialsscienceandgeology.Despiteitsinceptioninthelaboratoriesofphysicists,
itisinthechemicallaboratorythatNMRspectroscopyhasfoundthegreatestuseand,itmaybe
argued, has provided the foundations on which modern organic chemistry has developed.
Modern NMR is now a highly developed, yet still evolving, subject that all organic chemists
need to understand, and appreciate the potential of, if they are to be effective in and able to
progresstheircurrentresearch.AnabilitytokeepabreastofdevelopmentsinNMRtechniques
is,however,adauntingtask,madedifficultnotonlybythesheernumberofavailabletechniques
but also by the way in which these new methods first appear. These are spread across the
chemical literature in both specialised magnetic resonance journals and those dedicated to
specific areas ofchemistry, as wellasthemore general entities.They are often referred toby
esotericacronymsanddescribedinaseeminglycomplexmathematicallanguagethatdoeslittle
toendearthemtotheresearchchemist.Themyriadofsequencescanbewhollybewilderingfor
theuninitiatedandcanleaveonewonderingwheretostartandwhichtechniquetoselectforthe
problemathand.InthisbookIhaveattemptedtogathertogetherthemostvaluabletechniques
fortheresearchchemistandtodescribetheoperationoftheseusingpictorialmodels.Eventhis
level of understanding is perhaps more than some chemists may consider necessary, but only
fromthiscanonefullyappreciatethecapabilitiesand(ofequal ifnotgreaterimportance) the
limitations of these techniques. Throughout, the emphasis is on the more recently developed
methodsthathave,orundoubtedlywill,establishthemselvesastheprincipaltechniquesforthe
elucidationandinvestigationofchemicalstructuresinsolution.
NMRspectroscopyis,aboveall,apracticalsubjectthatismostrewardingwhenonehasan
interestingsampletoinvestigate,aspectrometeratone’sdisposalandtheknowledgetomakethe
mostofthis(sometimesalarmingly!)expensiveinstrumentation.Assuch,thisbookcontainsa
considerable amount of information and guidance on how one implements and executes the
techniquesthataredescribedandthusshouldbeequallyathomeintheNMRlaboratoryasatthe
chemist’sorspectroscopist’sdesk.
ThisbookiswrittenfromtheperspectiveofanNMRfacilitymanagerinanacademicresearch
laboratoryandassuchthetopicsincludedarenaturallyinfluencedbytheareasofchemistryI
encounter. The methods are chosen, however, for their wide applicability and robustness, and
because,inmanycases,theyhavealreadybecomeestablishedtechniquesinNMRlaboratories
in both academic and industrial establishments. This is not intended as a review of all recent
developments in NMR techniques. Not only would this be too immense to fit within a single
volume, but the majority of the methods would have little significance for most research
chemists. Instead, this is a distillation of the very many methods developed over the years,
withonlythemostappropriatefractionsretained.Itshouldfinduseinacademicandindustrial
researchlaboratoriesalike,andcouldprovidethefoundationforgraduatelevelcoursesonNMR
techniquesinchemicalresearch.
Thepreparationofthisbookhasbenefitedfromthecooperation,assistance,patience,under-
standing and knowledge of many people, for which I am deeply grateful. I must thank my
colleagues, both past and present, in the NMR group of the Dyson Perrins Laboratory, in
particular Elizabeth McGuinness and Tina Jackson for their first-class support and assistance,
and Norman Gregory and Dr Guo-Liang Ping for the various repairs, modifications and
improvements they have made to the instruments used to prepare many of the figures in this
book.Mostofthese figureshavebeenrecorded specificallyforthebookandhavebeenmade
possiblebythegenerosityofvariousresearchgroupsandindividualswhohavemadetheirdata
and samples available to me. For this, I would like to express my gratitude to Dr Harry
Anderson, Prof. Jack Baldwin, Dr Paul Burn, Dr John Brown, Dr Duncan Carmichael,
DrAntonyFairbanks,Prof.GeorgeFleet,DrDavidHodgson,DrMarkMoloney,DrJoPeach
andProf.ChrisSchofield, andtothemembersoftheirgroups,toonumeroustomention, who
kindlypreparedthesamples;theywillknowwhotheyareandIamindebtedtoeachofthem.
I am similarly grateful to Prof. Jack Baldwin for allowing me to use the department’s instru-
mentationforthecollectionoftheseillustrativespectra.
IwouldliketothankDrsCarolynCarrandNickReesfortheirassistanceinproofreadingthe
manuscriptandforbeingabletospotthoseannoyinglittlemistakesthatIoverlookedtimeand
timeagainbutthatstilldidnotregister.NaturallyIacceptresponsibilityforthosethatremain
and would be grateful to hear of these, whether factual or typographical. I also thank Eileen
xiv PrefacetoFirstEdition
MorrellandSharonWardofElsevierSciencefortheirpatienceinwaitingforthisprojecttobe
completedandfortheirrelaxedattitudeasvariousdeadlinesfailedtobemet.
Iimagineeveryoneventuringintoacareerinsciencehasatsometimebeeninfluencedoreven
inspiredbyoneorafewindividual(s)whomayhaveactedasteacher,mentororperhapsrole
model.Personally, Iamindebted toDrJeremyEverett andto JohnTyler, bothformerly from
(whatwasthen)BeechamPharmaceuticals,foracceptingintotheirNMRlaboratoryforayeara
‘‘sandwich’’ student who was initially supposed to gain industrial experience elsewhere as a
chromatographeranalysinghorseurine!Myfortuitousescapefromthisandthesubsequenttime
atBeechamPharmaceuticalsprovedtobeaseminalyearformeandIthankJeremyandJohnfor
theirearlyencouragementthatignitedmyinterestinNMR.Myunderstandingofwhatthiscould
reallydocamefromgraduatestudieswiththelateAndyDerome,andI,likemanyothers,remain
eternallygratefulfortheinsightandinspirationheprovided.
Finally, I thank my wife Rachael for her undying patience, understanding and support
throughoutthislongandsometimestortuousproject,onethatI’msureshethought,onoccasions,
she would never see the end of. I can only apologise for the neglect she has endured but not
deserved.
TimClaridge
Oxford,May1999
Chapter 1
Introduction
From the initial observation of proton magnetic resonance in water [1] and in paraffin
[2],thedisciplineofnuclearmagneticresonance(NMR)hasseenunparalleledgrowthasan
analytical method and now, in numerous different guises, finds application in chemistry,
biology, medicine, materials science and geology. The founding pioneers of the subject,
Felix Bloch and Edward Purcell, were recognised with a Nobel Prize in 1952 ‘for their
developmentofnewmethodsfornuclearmagneticprecisionmeasurementsanddiscoveries
inconnectiontherewith’.Thematurityofthedisciplinehassincebeenrecognisedthrough
the awarding of Nobel prizes to two of the pioneers of modern NMR methods and their
application, Richard Ernst (1991, ‘for his contributions to the development of the metho-
dology of high-resolution NMR spectroscopy’) and Kurt Wu¨thrich (2002, ‘for his devel-
opmentofNMRspectroscopyfordeterminingthethree-dimensionalstructureofbiological
macromoleculesinsolution’).Despiteitsinceptioninthelaboratoriesofphysicists,itisin
thechemicalandbiochemicallaboratoriesthatNMRspectroscopyhasfoundgreatestuse.
Toputintocontexttherangeoftechniquesnowavailableinthemodernorganiclaboratory,
includingthosedescribedinthisbook,webeginwithashortoverviewoftheevolutionof
high-resolution (solution-state) NMR spectroscopy and some of the landmark develop-
mentsthathaveshapedthesubject.
1.1. THEDEVELOPMENTOFHIGH-RESOLUTIONNMR
Itisnowover16yearssincethefirstobservationsofNMRweremadeinbothsolidand
liquid samples, from which the subject has evolved to become the principal structural
technique of the research chemist, alongside mass spectrometry. During this time, there
have been a number of key advances in high-resolution NMR that have guided the
development of the subject [3–5] (Table 1.1) and consequently the work of organic
chemists and their approaches to structure elucidation. The seminal step occurred during
theearly1950swhenitwasrealisedthattheresonantfrequencyofanucleusisinfluenced
byitschemicalenvironmentandthatonenucleuscouldfurtherinfluencetheresonanceof
Table1.1.Asummaryofsomekeydevelopmentsthathavehadamajorinfluenceonthepracticeandapplication
ofhigh-resolutionNMRspectroscopyinchemicalresearch
Decade Notableadvances
1940s FirstobservationofNMRinsolidsandliquids(1945)
1950s Developmentofchemicalshiftsandspin–spincouplingconstantsasstructuraltools
1960s Useofsignalaveragingforimprovingsensitivity
Applicationofthepulse-FTapproach
TheNOEemployedinstructuralinvestigations
1970s UseofsuperconductingmagnetsandtheircombinationwiththeFTapproach
Computercontrolledinstrumentation
1980s Developmentofmultipulseandtwo-dimensionalNMRtechniques
Automatedspectroscopy
1990s Routineapplicationofpulsedfieldgradientsforsignalselection
Developmentofcoupledanalyticalmethods,e.g.LC-NMR
2000– Useofhigh-sensitivitycryogenicprobes
Routineavailabilityofactivelyshieldedmagnetsforreducedstrayfields
Developmentofmicroscaletubeandflowprobes
2010+ Adoptionoffastandparalleldataacquisitionmethods...?
FT,Fouriertransformation;LC-NMR,liquidchromatographyandnuclearmagneticresonance.
2 High-ResolutionNMRTechniquesinOrganicChemistry
another through intervening chemical bonds. Although these observations were seen as
unwelcome chemical complications by the investigating physicists, a few pioneering
chemists immediately realised the significance of these chemical shifts and spin–spin
couplings within the context of structural chemistry. The first high-resolution proton
NMR spectrum (Fig.1.1) clearly demonstrated how the features of anNMR spectrum, in
thiscasechemicalshifts,couldbedirectlyrelatedtochemicalstructure,anditisfromthis
thatNMRhasevolvedtoattainthesignificanceitholdstoday.
Figure1.1.Thefirst‘high- The 1950s also saw a variety of instrumental developments that were to provide the
resolution’protonNMRspectrum,
chemistwithevengreaterchemicalinsight.Theseincludedtheuseofsamplespinningfor
recordedat30MHz,displayingthe
averaging to zero field inhomogeneities, which provided a substantial increase in resolu-
protonchemicalshiftsinethanol
tion,sorevealingfinesplittingsfromspin–spincoupling.Later,spindecouplingwasableto
(reprintedwithpermissionfrom[6],
Copyright1951,AmericanInstitute provide more specific information by helping the chemists understand these interactions.
ofPhysics). Withtheseimprovements,sophisticatedrelationshipscouldbedevelopedbetweenchemi-
calstructureandmeasurableparameters,leadingtorealisationssuchasthedependenceof
vicinal coupling constants on dihedral angles (the now well-known Karplus relationship).
Theinclusionofcomputersduringthe1960swasalsotoplayamajorroleinenhancingthe
influence of NMR on the chemical community. The practice of collecting the same
continuous wave spectrum repeatedly and combining them with a CAT (computer of
average transients) led to significant gains in sensitivity and made the observation of
smaller sample quantities a practical realisation. When the idea of stimulating all spins
simultaneouslywithasinglepulseofradiofrequency,collectingthetime-domainresponse
and converting this to the required frequency-domain spectrum by a process known as
Fouriertransformation(FT),wasintroduced,morerapidsignalaveragingbecamepossible.
This approach provided an enormous increase in signal-to-noise ratio and was to change
completelythedevelopmentofNMRspectroscopy.Themid-1960salsosawtheapplication
of the nuclear Overhauser effect (NOE) to conformational studies. Although described
duringthe1950sasameansofenhancingthesensitivityofnucleithroughthesimultaneous
irradiation of electrons, the Overhauser effect has since found widest application in
sensitivityenhancementbetweennuclei,orinthestudyofthespatialproximityofnuclei,
andremainsoneofthemostimportanttoolsofmodernNMR.Bytheendofthe1960s,the
firstcommercialFTspectrometerwasavailable,operatingat90MHzforprotons.Thenext
great advance in field strengths was provided by the introduction of superconducting
magnets duringthe 1970s, which were able toprovide significantlyhigher fields than the
electromagnets previously employed. These, combined with the FT approach, made the
observationofcarbon-13routineandprovidedtheorganicchemistswithanotherprobeof
molecularstructure.Thisalsopavedthewayfortheroutineobservationofawholevariety
of previously inaccessible nuclei of low natural abundance and low magnetic moment. It
wasalsointheearly1970sthattheconceptofspreadingtheinformationcontainedwithin
the NMR spectrum into two separate frequency dimensions was proposed in a lecture.
However,becauseofinstrumentallimitations,thequalityofthefirsttwo-dimensional(2D)
spectra was considered too poor to be published, and not until the mid-1970s, when
instrument stability had improved and developments in computers made the necessary
complex calculations feasible, did the development of 2D methods begin in earnest.
These methods, together with the various multipulse one-dimensional (1D) methods that
also became possible with the FT approach, did not have significant impact on the wider
chemicalcommunityuntilthe1980s,fromwhichpointtheirdevelopmentwasnothingless
than explosive. This period saw an enormous number of new pulse techniques presented
thatwerecapableofperformingavarietyof‘spingymnastics’,thusprovidingthechemist
withevermorestructuraldata,onsmallersamplequantitiesandinlesstime.Nolongerwas
itnecessarytorelyonempiricalcorrelationsofchemicalshiftsandcouplingconstantswith
structural features to identify molecules, but instead a collection of spin interactions
(through-bond, through-space and chemical exchange) could be mapped and used to
determinestructuresmorereliablyandmorerapidly.Theevolutionofnewpulsemethods
continued throughout the 1990s, alongside which has emerged a fundamentally different
way of extracting the desired information from molecular systems. Pulsed field gradient
selected experiments have now become routine structural tools, providing better quality
spectra, often in shorter times, thanwas previously possible.These came into widespread
use not so much from a theoretical breakthrough (their use for signal selection was first
demonstrated in 1980) but again as a result of progressive technological developments
defeating practical difficulties. Similarly, the emergence of coupled analytical methods,
such as liquid chromatography and NMR (LC-NMR), has come about after the experi-
mentalcomplexitiesofinterfacingtheseverydifferenttechniqueshavebeenovercome,and
thesemethodshaveestablishedthemselvesfortheanalysisofcomplexmixtures.Develop-
ments in probe technologies over the last decade have led to the wider adoption of
cryogenically cooled coils in probe heads that reduce significantly system noise and so
Chapter1: Introduction 3
enhance signal-to-noise ratios. Probe coil miniaturisation has also provided a boost in
signal-to-noiseformass-limitedsamples,andthemarryingofthiswithcryogenictechnol-
ogy nowadays offers one of the most effective routes to higher detection sensitivity.
Instrument miniaturisation has been a constant theme in recent years leading to smaller
and more compact consoles driven by developments in solid-state electronics. Likewise,
new generations of actively shielded superconducting magnets with significantly reduced
strayfieldsarenowcommonplace,makingthesitingofinstrumentsconsiderablyeasierand
farlessdemandingonspace.Forexample,thefirstgenerationunshieldedmagnetsoperat-
ingat500MHzpossessedstrayfieldsthatwouldextendtoover3mhorizontallyfromthe
magnet centre when measured at the 0.5mT (5 gauss) level, the point beyond which
disturbances to the magnetic field are not considered problematic. Nowadays, the latest
generationshieldedmagnetshavethislinesitedatsomewhatlessthan1mfromthecentre
and only a little beyond the magnet cryostat itself. This is achieved through the use of
compensatingmagnetcoilsthatseek tocounteractthe strayfieldgeneratedoutsideofthe
magnetassembly.Otherdevelopmentsareseekingtorecycletheliquidcryogensneededto
maintainthesuperconductingstateofthemagnetthroughthereliquificationofheliumand
nitrogen.Recyclingofheliuminthismannerisalreadyestablishedforimagingmagnetsbut
posesconsiderablechallengesinthecontextofhigh-resolutionNMRmeasurements.
Modern NMR spectroscopy is now a highly developed and technologically advanced
subject.WithsomanyadvancesinNMRmethodologyinrecentyears,itisunderstandably
an overwhelming task for the research chemist, and even the dedicated spectroscopist, to
appreciatewhatmodernNMRhastooffer.Thistextaimstoassistinthistaskbypresenting
theprincipalmodernNMRtechniquesandexemplifyingtheirapplication.
1.2. MODERNHIGH-RESOLUTIONNMRANDTHISBOOK
TherecanbelittledoubtthatNMRspectroscopynowrepresentsthemostversatileand
informativespectroscopictechniqueemployedinthemodernchemicalresearchlaboratory
andthatanNMRspectrometerrepresentsoneofthelargestsingleinvestmentsinanalytical
instrumentationthelaboratoryislikelytomake.Forboththesereasons,itisimportantthat
the research chemist is able to make the best use of the available spectrometer(s) and to
harnessmoderndevelopmentsinNMRspectroscopyinordertopromotetheirchemicalor
biochemical investigations. Even the most basic modern spectrometer is equipped to per-
formamyriadofpulsetechniquescapableofprovidingthechemistwithavarietyofdata
onmolecularstructureanddynamics.Notalwaysdothesemethodsfindtheirwayintothe
handsofthepractisingchemist,remaininginsteadintherealmsofthespecialist,obscured
behindesotericacronymsorotherwiseunfamiliarNMRjargon.Clearly,thisshouldnotbe
so,andtheaimofthisbookistogatherupthemostusefulofthesemodernNMRmethods
andpresentthemtothewideraudiencewhoshould,afterall,findgreatestbenefitfromtheir
applications.
The approach taken throughout is non-mathematical and is based firmly on using
pictorial descriptions of NMR phenomena and methods wherever possible. In preparing
and updating this work, I have attempted to keep in mind what I perceive to be the
requirementsofthreemajorclassesofpotentialreaders:
1. those who use solution-state NMR as tool in their own research, but have little or no
directinteractionwiththespectrometer,
2. thosewhohaveundertakentrainingindirectlyusingaspectrometertoacquiretheirown
data,butotherwisehavelittletodowiththeupkeepandmaintenanceoftheinstrument,
and
3. thosewhomakeusespectrometersandareresponsiblefortheday-to-dayupkeepofthe
instrument. This may include NMR laboratory managers, although in some cases the
usermaynotconsiderthemselvesdedicatedNMRspectroscopists.
The first of these could well be research chemists and students in an academic or
industrial environment who need to know what modern techniques are available to assist
them in their efforts, but otherwise feel they have little concern for the operation of a
spectrometer. Their data is likely to be collected under fully automated conditions or
provided by a central analytical facility. The second may be a chemist in an academic
environmentwhohashands-onaccesstoaspectrometerandhashisorherownsamplesthat
demand specific studies that are perhaps not available from fully automated instrumenta-
tion. The third class of reader may work in a smaller chemical company or academic
chemistry department who have invested in NMR instrumentation but may not employ a
dedicated NMR spectroscopist for its upkeep, depending instead on, say, an analytical or
synthetic chemist for this. This, it appears (in the UK at least), is often the case for new
4 High-ResolutionNMRTechniquesinOrganicChemistry
start-up chemical companies. NMR laboratory managers may also find the text a useful
referencesource.Withtheseinmind,thebookcontainsafairamountofpracticalguidance
on both the execution of NMR experiments and the operation and upkeep of a modern
spectrometer.Evenifyouseeyourselfinthefirstoftheabovecategories,somerudimen-
taryunderstandingofhowaspectrometercollectsthedataofinterestandhowasequence
produces, say, the 2D correlation spectrum awaiting analysis on your desk can be enor-
mously helpful in correctly extracting the information it contains or in identifying and
eliminatingartefactsthatmayarisefrominstrumentalimperfectionsortheuseoflessthan
optimalconditionsforyoursample.Althoughnotspecificallyaimedatdedicatedspectro-
scopists, the book may still contain new information or may serve as a reminder of what
was once understood but has somehow faded away. The text should be suitable for (UK)
graduate level courses on NMR spectroscopy, and sections of the book may also be
appropriate for use in advanced undergraduate courses. The book does not, however,
contain descriptions of the basic NMR phenomena such as chemical shifts and coupling
constants,andneitherdoesitcontainextensivediscussionsonhowthesemaybecorrelated
withchemicalstructures.Thesetopicsarealreadywelldocumentedinvariousintroductory
texts [7–12], and it is assumed that the reader is already familiar with such matters.
Likewise, the book does not seek to provide a comprehensive physical description of the
processesunderlyingtheNMRtechniquespresented;thebookbyKeeler[13]presentsthis
atanaccessibleyetrigorouslevel.
The emphasis is on techniques in solution-state (high-resolution) spectroscopy, princi-
pally those used throughout organic chemistry as appropriate for this series, although
extensions of the discussions to inorganic systems should be straightforward, relying on
thesameprinciplesandsimilarlogic.Likewise,greateremphasisisplacedonsmalltomid-
sizedmolecules(withmassesuptoafewthousandsay)sinceitisonsuchsystemsthatthe
majority of organic chemistry research is performed. That is not to say that the methods
describedarenotapplicabletomacromolecularsystems,andappropriateconsiderationsare
given when these deserve special comment. Biological macromolecules are not covered
however,butareaddressedinanumberofspecialisedtexts[14–16].
1.2.1. What this book contains
The aim of this text is to present the most important NMR methods used for organic
structure elucidation, to explain the information they provide, how they operate and to
provide some guidance on their practical implementation. The choice of experiments is
naturally a subjective one, partially based on personal experience, but also taking into
account those methods most commonly encountered in the chemical literature and those
recognised within the NMR community as being most informative and of widest applic-
ability. The operation of many of these is described using pictorial models (equations
appearinfrequently andare only included whentheyserve a specific purpose) so that the
chemist can gain some understanding of the methods they are using without recourse to
uninviting mathematical descriptions. The sheer number of available NMR methods may
makethisseemanoverwhelmingtask,butinreality,mostexperimentsarecomposedofa
smaller number of comprehensible building blocks pieced together, and once these have
been mastered, an appreciation of more complex sequences becomes a far less daunting
task. For those readers wishing to pursue a particular topic in greater detail, the original
referencesaregivenbutotherwisealldescriptionsareself-contained.
Followingthisintroductorysection,Chapter2introducesthebasicmodelusedthrough-
outthebookforthedescriptionofNMRmethodsanddescribeshowthisprovidesasimple
picture of the behaviour of chemical shifts and spin–spin couplings during pulse experi-
ments. This model is then used to visualise nuclear spin relaxation, a feature of central
importance for the optimum execution of all NMR experiments (indeed, it seems early
attempts to observe NMR failed most probably because of a lack of understanding at the
timeoftherelaxationbehaviourofthechosensamples).Methodsformeasuringrelaxation
ratesalsoprovideasimpleintroductiontomultipulseNMRsequences.Chapter3describes
thepracticalaspectsofperformingNMRspectroscopy.Thisisachaptertodipintoasand
whennecessaryandisessentiallybrokendownintoself-containedsectionsrelatingtothe
operating principles of the spectrometer and the handling of NMR data, how to correctly
prepare the sample and the spectrometer before attempting experiments, how to calibrate
the instrument and how to monitor and measure its performance, should you have such
responsibilities. It is clearly not possible to describe all aspects of experimental spectro-
scopy in a single chapter, but this (together with some of the descriptions in Chapter 10)
shouldcontainsufficientinformationtoenabletheexecutionofmostmodernexperiments.
Thesedescriptionsarekeptgeneral,andinthese,Ihavedeliberatelyattemptedtoavoidthe
use of a dialect specific to a particular instrument manufacturer. Chapter 4 contains the