Essential Practical NMR for Organic Chemistry - Further Elucidation Techniques – Part 2

and 3.9 ppm. This would be a typical shift for an aromatic O alkyl substituent and is important information. Remember that the compound has been base extracted from D2O/sodium carbonate and for this reason, no exchangeable protons will be visible. The fact that both sets of aromatic protons show enhancements to different alkyl protons means that there must be alkyl substituents on both ends of the ring (as opposed to an -OH at one end and everything else attached at the other). The aromatic ring therefore conveniently splits the molecule into two segments that can be dealt with separately. The 2-D ROESY has certainly proven to be very useful so far but the severely overlapped nature of the alkyl protons makes it difficul to see exactly what is being enhanced. For this reason, specifi 1-D ROESY experiments hold a big advantage as the enhanced multiplet is always reconstructed complete with all couplings. Two signals show enhancement from the aromatic protons at 7.15 ppm and they have the appearance of a pair of coupled triplets. By inspecting the ordinary 1-D proton spectrum, it becomes clear that this must be a -CH2-CH2- system with the triplet at 2.83 ppm more intense in appearance than its coupled partner at 3.57 ppm. This shift looks good for another oxygen and in fact, a -OCH3 as another 1-D ROESY irradiating the singlet at 3.35 ppm establishes the connection between this singlet and the triplet -CH2 at 3.57 ppm. So piecing together what we have so far, we’re looking at something like this: O ? NOE NOE NOE H CO3 NOE Concentrating now on the right hand side of the molecule and re-examining the signals which show enhancement from the aromatic protons at 6.8 ppm, it would seem that the entire multiplet (4.05–3.93 ppm) which integrates for three protons is part of a close-coupled non-firs order spin system. The coupling between these protons is not at all clear from the COSY spectrum because the chemical shifts of the protons are so close. The coupling is more apparent from close scrutiny of the 1-D proton spectrum. The right hand side of this multiplet (3.98–3.93 ppm) consists of heavily roofed eight-line system which is characteristic of the AB part of an ABX system where the shifts of ‘A’ and ‘B’ are extremely close. The A-X and B-X couplings are not obvious from the COSY because the ‘X’ is extremely close to ‘A’ and ‘B’ and in fact is the left hand side of the multiplet (4.05–3.98 ppm)! The complexity of this spectrum does not end there however as two key features of this spectrum must now be addressed. First, the ‘X’ part of the ABX system we have just discussed consists of far more than the normal four lines; and second, the four-line multiplets centred at 2.88 and 2.73 ppm are clearly ‘A’ and ‘B’ parts of a second ABX system! These features are linked in that the COSY spectrum clearly shows that the complex ‘X’ part (4.05–3.98 ppm) is in fact coupled to both the ‘A’ and ‘B’ parts of the second ABX system. Therefore, we can deduce that P1: JYS c15 JWST025-Richards October 2, 2010 19:3 Printer: Yet to come Problems 201 the ‘X’ part is common to both ABX systems. Chemical shifts indicate that a likely arrangement of hetero atoms would give a right hand side for the molecule looking like this: O NOEH CO3 OH NR2 Weak NOE Almost home and dry now! Back to the COSY. The six-proton doublet at 1.1 ppm shows a coupling to something at 2.83 ppm. We know that the triplet at 2.83 ppm is part of the closed spin system on the left hand side of the molecule and therefore cannot in any way be responsible for this correlation. Measuring the integral from 2.91–2.78 ppm reveals the presence of four protons. One of them has already been assigned as part of the second ABX system and the triplet at 2.83 ppm accounts for two protons. Then, the implication must be that one proton is almost completely hidden from view beneath these two signals. In terms of chemical shifts, an isopropyl group attached to the nitrogen would fi perfectly. So f tting it all together, we have: O H CO3 OH N H CH3 CH3 (This is the drug Metoprolol, a beta-blocker). Obviously, a great many deductions have to be made to arrive at a structure from scratch in this way and whilst each one in this example is valid in its own right and they all fi together perfectly well with no obvious conflicts structural verificatio via the HMQC/HMBC route would be advisable! Q8. A quick inspection of the proton spectrum for this compound confirm that a heterocyclic proton is present at 8.0 ppm so C-methylation cannot have taken place. Furthermore, the proton spectrum confirm the presence of three methyl signals at approximately 3.9, 3.4 and 3.2 ppm. There is little more to be gleaned from the proton spectrum except for the fact that the methyl at 3.9 ppm is slightly broader than the other two. This is indicative of a small long-range coupling to the heterocyclic proton though this information is only of limited value. It is clear that another nucleus must be examined. As the parent compound contains four nitrogen atoms, it might be tempting to opt for proton–nitrogen HMBC but the technique would be of limited value in this case. 13C spec- troscopy offers by far the most comprehensive solution. The HSQC spectrum shows that the chemical shifts for the methyls are approximately 33, 29 and 27 ppm. It is immediately clear that the methyl groups must therefore all be attached to the nitrogen atoms and not to any of the oxygens (which would give shifts in the 55–65 ppm range). P1: JYS c15 JWST025-Richards October 2, 2010 19:3 Printer: Yet to come 202 Essential Practical NMR for Organic Chemistry The information required to solve this problem will come from the HMBC experiment. After firs discounting the one-bond couplings that have come through (either by reference to the HSQC experiment or just by observation) it can be seen that the heterocyclic CH shows two, three-bond correlations to carbons at 148 and 106 ppm. Since the carbon shifts of the methyl groups indicates that O-methylation is not an option, it is safe to assume that the oxygen atoms will still be in the form of conjugated amidic or urea carbonyl functions. The chemical shift of such carbonyls will always be in the 150–160 ppm range. We know the shift of the carbon bearing the solitary heterocyclic proton (142 ppm) and of the two remaining quaternary carbons, the one flan ed by two nitrogens is likely to be far more de-shielded than the other so even without using 13C prediction software, this problem should be relatively straightforward. The salient features of the HMBC could be summarised as follows: 1. There is a common correlation from the methyl protons at 3.9 ppm and the heterocyclic proton (8.0 ppm) to a quaternary carbon at 106 ppm. 2. This proton also correlates to another quaternary carbon at 148 ppm. 3. The methyl protons at 3.2 ppm correlate to two quaternary (carbonyl) signals at 154.5 and 152.0 ppm. 4. The methyl protons at 3.4 ppm correlate to one of the carbonyls at 152 ppm and also to the quaternary carbon at 148 ppm (see item 2, above). Putting all this information together we have: caffeine. N N O O N N H C3 CH3 CH3 H 34 142 29.5 27 152 154.5 106 148 This summarizes the proton–carbon correlations and shows all the 13C chemical shifts. Note that no other arrangement of the methyl groups would satisfy the observations made. For example, had one of the methyl groups been attached to the other nitrogen in the fi e-membered ring, then the correlation to a carbon anywhere near 106 ppm would have been replaced by one to a carbon nearer to 150 ppm. Note also that though the methyl protons at 3.9 ppm correlate to the carbon at 142 ppm, there is no guarantee that the corresponding proton at 8.0 ppm will show a correlation to the carbon of this methyl group (34 ppm). In fact this correlation does exist but it is a lot weaker than the others and does not show up in the plot without turning up the gain to the point where the rest of the spectrum becomes difficul to understand. The apparent intensities of the observed correlations reflec the size of the proton–carbon couplings concerned. The (methyl) proton–heterocyclic carbon coupling must be significantl different from the CH-methyl (carbon) coupling. Q9. At firs glance, the proton spectrum for this compound looks excellent. The protons are, with the exception of two aromatic protons, well separated and this is always a bonus! The alkene protons draw immediate attention as they sit on either side of the aromatic protons and the doublet at about 8.4 ppm is definitel the alkene closest to the aromatic ring. Its coupling partner, closest to P1: JYS c15 JWST025-Richards October 2, 2010 19:3 Printer: Yet to come Problems 203 the t-butyl ester is the doublet at approximately 6.32 ppm. The coupling between these two alkene protons looks large and measurement indicates that it is in fact 16 Hz. This is too large to support the proposed cis alkene and is far more in keeping with trans geometry! As an interesting footnote to this question of alkene configuration a trans alkene on an aromatic ring will generally show NOEs between both alkene protons and the aromatic proton(s) ortho to the point of substitution, whilst the corresponding cis alkene can only show an NOE from one of the alkene protons and the ortho protons on the aromatic ring. This could provide useful back up information if the observed coupling was in any way doubtful. Furthermore, scrutiny of the aromatic region shows coupling patterns that are not consistent with 1,3 substitution. Given that the aromatic protons are relatively well spread out – and this is an important point as little or nothing could be deduced about the substitution pattern if the substituents were such that all the aromatic protons were heavily overlapped – we should be looking to see two doublet of doublets, one with two small (meta) couplings and one with two larger (ortho) couplings. What we do observe is a pair of broad triplet structures, a broad doublet with one ortho coupling and a doublet of doublets dominated by an ortho coupling. This pattern can only occur in 1,2 disubstituted aromatic rings. Thus a far more plausible structure would be: N H H C3 CH3 O O O O CH3 H C3 CH3 O O H C3 CH3 The ethyl ester protons are worthy of note in this molecule. Though there is no chiral centre present, these are non-equivalent by virtue of being diastereotopic (remember the ‘Z test?’). In order to be as fully confiden as possible with this compound, given the two errors already apparent, it would be advisable to check it out thoroughly with HSQC, HMBC and a ROESY. This would establish the relative positions of the ethyl ester and methyl groups. A mass spectrum might be a good idea as well! Q10. Flippancy aside, there is at least a semiserious aspect to this tongue in cheek question. Without wishing to cause offence to any mass spectroscopist or devotee of any other form of spectroscopy, we hope that we’ve demonstrated (to some extent at least) the unrivalled power and fl xibility of the NMR technique for elucidating chemical structures. The quality and depth of the information available is remarkable and the range of associated techniques gives the method huge versatility. If an organic compound can be dissolved then it will give NMR signals – no question about it. NMR may be used in a quantitative as well as qualitative manner and given the right hardware, can be applied to several key nuclei. Spend the money wisely – on the best NMR system you can get your hands on – and don’t forget to keep your camera handy at next year’s offic party – you might fancy an upgrade. P1: JYS c15 JWST025-Richards October 2, 2010 19:3 Printer: Yet to come 204 Essential Practical NMR for Organic Chemistry Pr ep ar e th e sa m pl e 2 3, 4 7, 8, 9, 10 8, 9 7, 8, 9, 10 7, 8, 9, 10 1, 2, 3. .. R el ev a n t c ha pt er s 7, 8, 9, 10 7, 8, 9, 10 5, 6 Ac qu ire 1 D Pr ot on S pe ct ru m Pu rif y G ive u p – m ov e o n ! Tr e a t a s to ta l u n kn ow n 1 Tr e a t a s to ta l u n kn ow n 1 A “ fe a si bl e” st ru ct ur e is o ne th at is a r e a so n a bl e po ss ib ilit y fro m th e re a ct io n. O fte n th is ca n be re gi oi so m er s wh er e th e re ag en ts ha ve a tta ch ed in a d iff e re n t w ay fro m th at e xp ec te d. 1 Tr ea t a s un kn ow n In th e ca se o f a to ta l u nk no w n it is a c as e of th e m or e da ta , t he b et te r. So lvi ng th is s or t o f p ro bl em is li ke d oi ng a jig sa w p uz zle . Yo u p ie ce to ge th er in fo rm a tio n fro m a v a rie ty o f s ou rc es to c om e up w ith a fe a si bl e st ru ct ur e. Yo u th en te st th at s tru ct ur e w ith m or e ex pe rim en ts to e ns ur e yo u g et a c on sis te nt a ns w e r. As a m in im u m y o u s ho ul d co ns id er C O SY , H SQ C, H M BC , 1D 1 3C . D on ’t fo rg et – N M R is n ot th e on ly te ch ni qu e so lo ok a t m as s sp ec tro m et ry (a cc ura te m as s in pa rti cu la r) an d I R to he lp. 2 Pl an n ew e x pe rim en ts If yo u h av e tw o o r m o re p os sib le s tru ct ur es th at fi t t he d at a, y o u w ill ne ed to lo ok fo r di ffe re n ce s th at c an b e id en tif ie d by N M R. O fte n th is is HM BC a nd /o r N O E (to id en tify ke y co nn ec tiv itie s). Ev e ry p ro bl em is d iff e re n t s o yo u n e e d to u se a ll yo u r sk ills to lo ok fo r to ol s th at c an h el p di st in gu ish th e pu ta tiv e st ru ct ur es . As in th e ca se o f t ot al u nk no w n s, do n’ t u se N M R to th e ex cl us io n of o th er te ch ni qu es a s th ey m ay b e ab le to m ak e th e ch oi ce m u ch e as ie r. D oe s sp ec tru m m a tc h th e st ru ct ur e? Is it a m ix tu re ? Y Y Y Y Y Y Y Y Y N N M R In te rp re ta tio n Fl ow C ha rt D on ’t fo rg et ! N M R on it s ow n c a n n o t p ro ve a s tru ct ur e. N N N N N N N N N M R h as a pr op os ed st ru ct ur e N M R h as a pr op os ed st ru ct ur e Co ul d ot he r f e a si bl e st ru ct ur es m at ch th e sp ec tru m ? D oe s it ha ve th e rig ht m as s? Is fe a si bl e st ru ct ur e a re gi oi so m er ? D oe s H M BC o r N O E co nf irm st ru ct ur e? Tr e a t a s to ta l u n kn ow n 1 Tr e a t a s to ta l u n kn ow n 1 Pl an n ew ex pe rim en ts 2 D o yo u n e e d to kn ow w ha t i t i s? D oe s it ha ve th e rig ht m as s? Ar e th er e ot he r fe a si bl e st ru ct ur es A pp en di x A .1 U se fu lt ho ug ht pr oc es se s fo r ta ck lin g N M R pr ob le m s. P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come Glossary Note – This glossary is by no means exhaustive but it hopefully contains most of the more important terms you will come across in a typical ‘NMR environment.’ Some of the entries may not even have featured in the text itself. Whilst every effort has been made to make the entries scientificall valid, please note that it is sometimes difficul to condense a highly complex topic into a pithy three-line explanation, so some of the definition are sketchy to say the least! Acquisition Process of collection of NMR data. Adiabatic pulse A type of pulse employing a frequency sweep during the pulse. This type of pulse is particularly efficien for broadband decoupling over large sweep widths. Aliased signals Signals that fall outside the spectral window (i.e., those that fail to meet the Nyquist condition). Such signals still appear in the spectrum but at the wrong frequency because they become ‘folded’ back into the spectrum and are characterised by being out of phase with respect to the other signals. Anisotropy Non-uniform distribution of electrons about a group which can lead to non-uniform lo- calised magnetic field within a molecule. The phenomenon leads to unexpected chemical shifts – particularly in 1H NMR – in molecules where steric constraints are present. Apodization The use of various mathematical functions which when applied to an FID, yield improve- ments in the resultant spectrum. These include exponential multiplication and Gaussian multiplication. Bloch-Siegert shift A shift in resonant frequency of a signal which is in close proximity to a sec- ondary applied r.f. The effect forces signals away from the applied r.f. and is only ever noticeable in homonuclear decoupling experiments where the applied r.f. and the observed signal can be very close. Boltzmann Distribution The ratio of nuclei which exist in the ground state to those in the excited state for a sample introduced into a magnetic fiel - prior to any r.f. pulsing. This varies with probe temperature but primarily with magnet fiel strength. Broadband decoupling Decoupling applied across a wide range of frequencies, e.g., the decoupling of all proton signals during the acquisition of 1-D 13C spectra. CAMELSPIN Cross-relaxation appropriate for minimolecules emulated by locked spins. Now known as ROESY. Chemical shift Position of resonance in an NMR spectrum for any signal relative to a reference standard. Chiral centre An atom in a molecule (usually but not exclusively carbon) which is bound to four different atoms or groups such that the mirror image of the whole molecule is not super-imposable on the molecule itself. A chiral centre in a molecule implies the possibility of the isolation of two distinct forms of the compound which are known as enantiomers. Chirality Properties conferred by the presence of one or more chiral centres. Essential Practical NMR for Organic Chemistry S. A. Richards and J. C. Hollerton © 2011 John Wiley & Sons, Ltd. ISBN: 978-0-470-71092-0 P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come 206 Glossary Composite pulses Use of a series of pulses of varying duration and phase in place of a single pulse. Such systems, when used in the pulse sequences of many modern NMR techniques, give improved performance as they are more tolerant to r.f. inhomogeneity. Configuraton The arrangement of atoms and bonds in a molecule. The configuratio of a molecule can be changed by breaking and re-forming bonds to yield different regioisomer. Conformation The shape a molecule adopts by the rotation and deformation (but not the breaking and re-forming) of its bonds. Continuous Wave (CW) Technology used initially in the acquisition of NMR data. The radiofrequency or the magnetic fiel was swept and nuclei of different chemical shift were brought to resonance sequentially. COSY Correlative spectroscopy. Homonuclear (normally 1H) 2-D spectroscopic technique which re- lates nuclei to each other by spin coupling. Coupling The interaction between nuclei in close proximity which results in splitting of the observed signals due to the alignment of the neighbouring nuclei with respect to the magnetic field Also referred to as spin coupling. Coupling constant The separation between lines of a coupled signal measured in Hz. CPMG pulse sequence Carr-Purcell-Meiboom-Gill pulse sequence. A pulse sequence used for remov- ing broad signals from a spectrum by multiple defocusing and refocusing pulses. Cryoprobe Probe offering greatly enhanced sensitivity by the reduction of thermal electronic noise achieved by maintaining probe electronics at or near liquid helium temperature. Cryoshims Rough (superconducting) shim coils that are built into superconducting magnets and ad- justed at installation of the instrument. Decoupling The saturation of a particular signal or signals in order to remove spin coupling from those signals. Also referred to as spin decoupling. DEPT Distortionless enhancement by polarization transfer. A useful one-dimensional technique which differentiates methyl and methine carbons from methylene and quaternary carbons. Diastereoisomers Stereoisomers that are not enantiomers. Diastereoisomers are compounds that always contain at least two centres of chirality. Diastereotopic proton/group A proton (or group) which if replaced by another hypothetical group (not already found in the molecule), would yield a pair of diastereoisomers. Enantiomer A single form of an optically active compound. Optically active compounds usually (but not exclusively) contain one or more chiral centres. Enantiomers are define by their ability to rotate the plane of beam of polarised light one way or the other and these are referred to as either ‘D’ or ‘L’, or alternatively ‘+’ or ‘–’, depending on whether the polarised light is rotated to the right (Dextro) or the left (Levo) . Enantiotopic proton/group A proton (or group) which if replaced by another hypothetical group (not already found in the molecule), would yield a pair of enantiomers. Epimers Diastereoisomers related to each other by the inversion of only one of their chiral centres. Epimerization Process of inter-conversion of one epimer to the other. The process is usually base- mediated as abstraction of a proton is often the firs step in the process. Excited state. Condition where nuclei in a magnetic fiel have their own magnetic field aligned so as to oppose the external magnet, i.e., N-N-S-S. Also known as the high-energy state. Exponential multiplication The application of a mathematical function to an FID which has the effect of smoothing the peak shape. Signal/noise may be improved at the expense of resolution. P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come Glossary 207 First-order spin systems Not very specifi term used to describe spin systems where the difference in chemical shift between coupled signals is very large in comparison to the size of the coupling. In reality, there is no such thing as a completely first-orde system as the chemical shift difference is never infinite See Non-first order spin system. Folded signals See aliased signals. Fourier Transformation. Mathematical process of converting the interference free induction decay into a spectrum. Free Induction Decay (FID) Interference pattern of decaying cosine waves collected by Fourier Transform spectrometers, stored digitally prior to Fourier Transformation. Gated decoupling A method of decoupling in which the decoupling is switched on prior to acquisition and turned off during it. Gradient field A linear magnetic fiel gradient, deliberately imposed on a sample in, for example, the z-axis in order to defocus the magnetisation. This allows other refocusing gradient pulses to be used to selectively observe desired transitions. Only possible with appropriate hardware. Gradient field improve the quality of many 2-D techniques and where used, replace the need for phase cycling. Gradient pulse The application of a gradient field for a discrete period of time. Also referred to as Pulsed field gradients (PFGs). Gaussian multiplication The application of a mathematical function to an FID to improve resolution (sharpen lines) at the expense of signal/noise. GOESY Gradient Overhauser effect spectroscopy. An early version of a 1-D NOESY making use of gradients. Gradient shimming A system of shimming based on mapping the magnetic fiel inhomogeneity using fiel gradients and calculating the required shim coil adjustments required to achieve homogeneity. Ground state Condition where nuclei in a magnetic fiel have their own magnetic field aligned with that of the external magnet, i.e., N-S-N-S. Also known as the low-energy state. Gyromagnetic ratio A measure of how strong the response of a nucleus is. The higher the value, the more inherently sensitive will be the nucleus. 1H has the highest value. Also known as Magnetogyric ratio. Hard pulse A pulse which is equally effective over the whole chemical shift range. See Soft pulse. HETCOR Heteronuclear correlation. Early method of acquiring one-bond 1H-13C data. Not nearly as sensitive as HMQC and HSQC methods which have largely superseded it. HMBC Heteronuclear multiple bond correlation. A proton-detected, two-dimensional technique that correlates protons to carbons that are two and three bonds distant. Essentially, it is an HMQC that is tuned to detect smaller couplings of around 10 Hz. HMQC Heteronuclear multiple quantum coherence. A proton-detected, 2-D technique that correlates protons to the carbons they are directly attached to. HOHAHA Homonuclear Hartmann Hahn spectroscopy. See TOCSY. HSQC Heteronuclear single quantum coherence. As for HMQC but with improved resolution in the carbon dimension. INADEQUATE Incredible natural abundance double quantum transfer experiment. Two-dimensional technique showing 13C-13C coupling. It should be the ‘holy grail’ of NMR methods but is in fact of very limited use due to extreme insensitivity. Indirect detection Method for the observation of an insensitive nucleus (e.g., 13C) by the transfer of magnetisation from an abundant nucleus (e.g., 1H). This method of detection offers great improve- ments in the sensitivity of proton–carbon correlated techniques. P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come 208 Glossary Inverse geometry Term used to describe the construction of a probe that has the 1H receiver coils as close to the sample as possible and the X nucleus coils outside these 1H coils. Such probes tend to give excellent sensitivity for 1H spectra at the expense of X nucleus sensitivity in 1-D techniques. They offer a lot of compensation in terms of sensitivity of indirectly detected experiments. J-resolved spectroscopy Two-dimensional techniques, both homo- and heteronuclear, that aims to sim- plify interpretation by separating chemical shift and coupling into the two dimensions. Unfortunately prone to artifacts in closely coupled systems. Laboratory frame model A means of visualising the processes taking place in an NMR experiment by observing these processes at a distance, i.e., with a static coordinate system. See Rotating frame model. Larmor frequency The exact frequency at which nuclear magnetic resonance occurs. At this frequency, the exciting frequency matches that of the precession of the axis of the spin of the nucleus about the applied magnetic field Larmor precession The motion describing the rotation of the axis of the spin of a nucleus in a magnetic field Linear prediction Method of enhancing resolution by artificiall extending the FID using predicted valued based on existing data from the FID. Longitudinal relaxation (T1) Recovery of magnetisation along the ‘z’ axis. The energy lost manifests itself as an infinitesima rise in temperature of the solution. This used to be called spin-lattice relaxation, a term which originated from solid-state NMR. Magic Angle Spinning (MAS) 54◦ 44′ (from the vertical). Spinning a sample at this, the so-called ‘magic angle’ gives the best possible line shape as the broadening effects of chemical shift anisotropy and dipolar interactions are both minimised at this angle. Used in the study of molecules tethered to solid supports. Meso compound A symmetrical compound containing two chiral centres configure so that the chirality of one of the centres is equal and opposite to the other. Such internal compensation means that these compounds have no overall effect on polarised light (e.g., meso tartaric acid). Normal geometry Term used to describe the construction of a conventional dual/multi channel probe. Since the X nucleus is a far less sensitive nucleus than 1H, a ‘normal geometry’ probe has the X nucleus receiver coils as close to the sample as possible to minimise signal loss and the 1H receiver coils outside the X nucleus coils (i.e., further from the sample). This design of probe is thus optimised for X nucleus sensitivity at the expense of some 1H sensitivity. NOE Nuclear Overhauser effect/nuclear Overhauser enhancement. Enhancement of the intensity of a signal via augmented relaxation of the nucleus to other nearby nuclei that are undergoing saturation. See also: NOE Nuclear Overhauser experiment. Experiment designed to capitalise on the above. Such experi- ments (and related techniques, e.g., NOESY , etc.) are extremely useful for solving stereochemical problems by spatially relating groups or atoms to each other. NOESY Nuclear Overhauser effect spectroscopy. Two-dimensional technique that correlates nuclei to each other if there is any NOE between them. Non-first-order pattern Splitting pattern where the difference in chemical shift between coupled signals is comparable to the size of the coupling between them. These are characterised by heavy distortions of expected peak intensities and even the generation of extra unexpected lines. Nyquist condition Sampling of all signals within an FID such that each is sampled at least twice per wavelength. P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come Glossary 209 Phase The representation of an NMR signal with respect to the distribution of its intensity. We aim to produce a pure absorption spectrum (one where all the signal intensity is positive). Phase cycling The process of repeating a pulse sequence with identical acquisition parameters but with varying r.f. phase. This allows real NMR signals to add coherently whilst artifacts and unwanted NMR transitions cancel. Phasing The process of correcting the phase of a spectrum (either manually or under automation). Probe Region of the spectrometer where the sample is held during the acquisition of a spectrum. It contains the transmitter and receiver coils and gradient coils (if f tted). Pulse A short burst of radio frequency used to bring about some nuclear spin transition. Pulsed field gradients (PFGs) See Gradient pulse. Quadrature detection Preferred system of signal detection using two detection channels with reference signals offset by 90◦. Quadrupolar nuclei Those nuclei, which because of their spin quantum number (which is always >1/2), have asymmetric charge distribution and thus posses an electric quadrupole as well as a magnetic dipole. This feature of the nucleus provides an extremely efficien relaxation mechanism for the nuclei themselves and for their close neighbors. This can give rise to broader than expected signals. Quadrupolar relaxation Rapid relaxation experienced by quadrupolar nuclei. Racemate A 50/50 mixture of enantiomers. Regiochemistry The chemistry of a molecule discussed in terms of the positional arrangement of its groups. Regioisomers Isomeric compounds related to each other by the juxtaposition of functional groups. Relaxation The process of nuclei losing absorbed energy after excitation. See longitudinal relaxation and transverse relaxation. Relaxation time Time taken for relaxation to occur. ROESY Rotating-frame Overhauser effect spectroscopy. A variation (one and two dimensional) on the nuclear Overhauser experiment (NOE). The techniques have the advantage of being applicable for all sizes of molecule. See Laboratory frame model. Rotating frame model A means of visualising the processes taking place in an NMR experiment by observing these processes as if you were riding on a disc describing the movement of the bulk magnetisation vector. Saturation Irradiation of nuclei such that the slight excess of such nuclei naturally found in the ground state when a sample is introduced into a magnet, is equalized. Shim coils Coils built into NMR magnets designed to improve the homogeneity of the magnetic fiel experienced by the sample. Two types of shims are used: cryoshims and room temperature shims. Normal shimming involves the use of the room temperature shims. Shimming The process of adjusting current fl wing through the room temperature shim coils in order to achieve optimal magnetic fiel homogeneity prior to the acquisition of NMR data. The process may be performed manually or under automation. Soft pulse Pulse designed to bring about irradiation of only a selected region of a spectrum. See Hard pulse. Solvent suppression Suppression of a dominant and unwanted signal (usually a solvent) either directly by saturation or by use of a more subtle method such as the WATERGATE sequence. Spectral Window The range of frequencies observable in an NMR experiment. Spin coupling See Coupling. P1: JYS gloss JWST025-Richards October 2, 2010 19:7 Printer: Yet to come 210 Glossary Spin decoupling See Decoupling and Broadband decoupling. Spin quantum number Number indicating the number of allowed orientations of a particular nucleus in a magnetic field For example, 1H has an I value of 1/2, allowing for two possible orientations, whereas 14N has an I of 1, allowing three possible orientations. Spin-lattice relaxation See Longitudinal relaxation. Spin-spin relaxation See Transverse relaxation. Stereochemistry The chemistry of a molecule discussed in terms of its 3-D shape. Stereoisomers Diastereoisomers related to each other by the inversion of any number of chiral centres. Superconduction Conduction of electric current with zero resistance. This phenomenon occurs at liquid helium temperature and has made possible the construction of the very high powered magnets that we see in today’s spectrometers. TOCSY Total correlation spectroscopy. One and two-dimensional techniques that are analogous to COSY but which differ in that it shows couplings within specifi spin systems. Transverse relaxation (T2) Relaxation by transfer of energy from one spin to another (as opposed to loss to the external environment as in longitudinal relaxation). This used to be referred to as spin–spin relaxation. WATERGATE Water suppression through gradient tailored excitation. Zero filling Cosmetic improvement of a spectrum achieved by padding out the FID with zeros. P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come Index 2-D see two dimensional 3-D see three dimensional AA’BB’ systems 54–5, 200 ab initio prediction 171 AB systems 67–9, 75, 96, 200–2 absolute quantificatio 158 absorption signals 36–8 isotopic abundances 13, 127 ABX systems 69–72, 75, 96, 107, 200–2 accidental equivalence 76–8 acidificatio 103 acquisition software 167 adiabatic pulses 26 alcohols 46, 84–5, 102–3, 104–5 aldehydes 47 aliasing 25 alkenes 57, 60–3, 141 alkyl systems 63–5, 142 alkynes 57, 63–4, 141 amides 46–8, 79–81 amines chemical elucidation 104 interpretation of spectra 97–100 15N NMR spectroscopy 153–5 ammonium salts 89–90 anisotropic interactions 67–8, 74–5, 79, 93 anisotropic solvents 104 apodization 34–6 aromatic systems 13C NMR spectroscopy 138, 140 interpretation of spectra 48–57, 59–60, 85–6 auto-correlation 134 axial–axial coupling 92, 95 10B-H couplings 90–1 backward linear prediction 33 baseline correction 38–9 baseline distortions 161 basificatio 103 bicyclic heterocycles 57, 60 bio-flui NMR 143, 145 borohydrides 90–1 13C NMR spectroscopy 125, 127–42 chemical shifts 138–42 distortionless enhancement by polarization transfer 129–30, 131–2, 137, 177, 182, 189, 193 general principles and 1-D 13C 127–30 problems and solutions 175–9, 180–3, 185–7, 189–90, 192–5, 197–204 proton decoupling 128, 130 resolution 136 sensitivity 127–8, 133 software tools 169–70 spectrum referencing 128–9 two dimensional proton–carbon correlated spectroscopy 130–7 13C-H couplings 82–4 carbon tetrachloride 16 carbonyls 139 carboxylic acids 46–8, 85 Carr–Purcell–Meiboom–Gill (CPMG) pulse sequence 147–8 chemical elucidation 101–9 acidification/basificati 103 chiral resolving agents 106–9 deuteration 101–3 lanthanide shift reagents 106 solvents 104, 109 trifluoroacetylatio 101, 104–5 chemical shifts 13C NMR spectroscopy 138–42 confidenc curves 43–4 interpretation of spectra 42 origin 6–7 terminology and conventions 6–7 chiral binaphthol 107–8 chiral centers chemical elucidation 106–9 interpretation of spectra 67–74, 93–6, 99–100, 200–2 Essential Practical NMR for Organic Chemistry S. A. Richards and J. C. Hollerton © 2011 John Wiley & Sons, Ltd. ISBN: 978-0-470-71092-0 P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come 212 Index chiral resolving agents 106–9 confidenc curves 43–4, 57 contamination of samples 20, 89–90 continuous wave (CW) systems 2–3, 4 contour plots 114–15 correlated spectroscopy (COSY) 112–16 nuclear Overhauser effect 118, 122 problems and solutions 176, 181, 185, 192, 198, 201–2 processing 33 spectrum acquisition 28 three dimensional NMR techniques 149 see also two dimensional proton–carbon correlated spectroscopy coupling constants 9 coupling patterns 42 CPMG see Carr–Purcell–Meiboom–Gill cryogens 165–6 cryoshims 28 CW see continuous wave deceptive simplicity 77–8 density functional theory (DFT) 171 DEPT see distortionless enhancement by polarization transfer deshielding substituents 52–3, 55 deuteration 47, 101–3 deutero benzene 16, 104 deutero chloroform 14, 17 deutero dimethyl sulfoxide 14–15, 17 deutero methanol 15, 17, 81 deutero pyridine 104 deutero water 16, 18 DFT see density functional theory 1,4-di-substituted benzene systems 54–5 1,3-di-substituted benzene systems 55 diastereoisomers 70–4 diastereotopic protons 72–4 diffusion ordered spectroscopy (DOSY) 148–9 dihedral angles 64–5, 69, 92–6 dimethyl sulfoxide (DMSO) 103 dispersion signals 36–8 distortionless enhancement by polarization transfer (DEPT) 129–30, 131–2, 137, 177, 182, 189, 193 DOSY see diffusion ordered spectroscopy double bonded systems 57–64 edge effects 18–19 electronic reference to access in vivo concentrations (ERETIC) 159 enantiomers 70–4 enantiotopic protons 72–4 enol ethers 57, 63–4 ERETIC 159 exchangeable protons 44, 46–8, 101–3 exponential multiplication 34 external locks 31 external standards 158–9 19F NMR spectroscopy 124–5, 151–2, 153 19F-H couplings 84–7 falloff 35–7 FID see free induction decay fiel homogeneity 11, 18–20 filtratio 19–21 fin structure 11–12 firs order spectra 9 fli angle 25–6 fl w NMR 144–5 fl wchart for NMR interpretation 174 folding 25 four-bond coupling 133–4 Fourier transform (FT) processes 2, 3–10, 36, 113–14 free bases 96–100, 173, 196–7 free induction decay (FID) 3–4 instrumental elucidation 113, 117 processing 33, 34, 38 frequency domain 4, 36 frequency lock 30–1 FT see Fourier transform furans 57 Gaussian multiplication 34–5 geminal coupling 67–9, 75, 100 gradient enhanced Overhauser effect spectroscopy (GOESY) 116, 124 gyromagnetic ratio 1, 13 health risks 163–6 cryogens 165–6 magnetic field 163–5 sample-related injuries 166 heterocycles 13C NMR spectroscopy 132–3, 138 instrumental elucidation 120–1 interpretation of spectra 49, 56–60, 85–7, 91–6 Karplus curves 91–6 15N NMR spectroscopy 154–5 problems and solutions 173, 196 heteronuclear coupling 82–100 10B-H couplings 90–1 P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come Index 213 13C-H couplings 82–4 19F-H couplings 84–7 heterocyclic protons 85–7, 91–6 Karplus curves 91–6 14N-H couplings 89–90 31P-H couplings 87–9 salts, free bases and zwitterions 96–100 29Si-H couplings 91 117/119Sn-H couplings 91 heteronuclear multiple bond correlation (HMBC) 130, 133–8, 152–3, 155 heteronuclear coupling 84 problems and solutions 178, 183, 190, 194, 198, 200, 202–4 heteronuclear multiple quantum coherence (HMQC) 130–4, 137, 149, 202 heteronuclear single quantum coherence (HSQC) 130–4, 137, 149 problems and solutions 177, 182, 189, 193, 198, 200, 202–4 hierarchically ordered spherical description of environment (HOSE) code 169–70, 171 high performance liquid chromatography (HPLC) 143–4 HMBC see heteronuclear multiple bond correlation HMQC see heteronuclear multiple quantum coherence homonuclear spin decoupling 111–12 HOSE code 169–70, 171 HPLC see high performance liquid chromatography HSQC see heteronuclear single quantum coherence imines 57, 63, 139 impurities 44–6, 84 incredible natural abundance double quantum transfer experiment (INADEQUATE) 147 incremental parameters 171 indirect detection 130 indirect dimension 28 indoles 132–3 instrumental elucidation 111–25 correlated spectroscopy 112–16, 118 nuclear Overhauser effect 116–25 positional isomers 124–5 selective population transfer 119–20, 125 spin decoupling 111–12 total correlation spectroscopy 116 instrumentation 2 chemical shifts 6–7 continuous wave systems 2–3, 4 Fourier transform systems 2, 3–10 integration 9–10 splitting 7–9 superconducting NMR magnets 4–5 integration 9–10 chemical elucidation 108 interpretation of spectra 41–2 processing 39 quantificatio 161 internal locks 30 internal standards 158 interpretation of spectra 41–65 AA’BB’ systems 54–5 AB systems 67–9, 75, 96 ABX systems 69–72, 75, 96 accidental equivalence 76–8 alkyl protons 63–5 anisotropic interactions 67–8, 74–5, 79, 93 aromatic protons 48–57, 59–60, 85–6 chemical shifts 42 chiral centers 67–74, 93–6, 99–100, 200–2 confidenc curves 43–4, 57 coupling patterns 42 deceptive simplicity 77–8 double and triple bonded systems 57–64 enantiotopic and diastereotopic protons 72–4 exchangeable protons 44, 46–8 fl xibility and complacency 42–3 fl wchart 174 heterocyclic protons 49, 56–60, 85–7, 91–6 heteronuclear coupling 82–100 impurities 44–6 integration 41–2 Karplus curves 91–6 magnetic non-equivalence 51, 54–6 nonfirs order spectra 50–4 polycyclic aromatic systems 49, 56–7, 59–60 problems and solutions 173–204 restricted rotation 78–82 salts, free bases and zwitterions 96–100 solvents 44–6, 81 spin coupling 49, 52 substituent effects 48–56 virtual coupling 76–7 see also chemical elucidation; instrumental elucidation inverse geometry 13 isonitriles 139 J-resolved 2-D NMR 147–8 Karplus curves 91–6, 115, 134 keto-enol exchange 103 P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come 214 Index lanthanide shift reagents 106 line broadening 13C NMR spectroscopy 128 exchangeable protons 46–8 filtratio 20 high performance liquid chromatography 143–4 long-range coupling 11 quantities of sample 13 restricted rotation 78–9 solvents 14 substituent effects 50, 54 linear prediction 33 long-range coupling 11–12 magic angle spinning (MAS) 146–7 magnetic field homogeneity 11, 18–20 safety issues 163–5 magnetic non-equivalence 51, 54–6, 78 magnitude mode 37 mandelic acid 108 MAS see magic angle spinning matching 30 metacyclophanes 75 mixed solvents 17 molecular anisotropy 74–5 monosubstituted benzene rings 50–4 morpholines 93–5, 114–15, 129, 131–2, 134–5 multisubstituted benzene rings 54–6 14N-H couplings 89–90 15N NMR spectroscopy 152–5 N-methylation 132–3 naphthalenes 117–20, 121–3, 137 nickel contamination 20 nitriles 139 nitro groups 153, 155 nitrovinyl groups 80–1 NOE see nuclear Overhauser effect nonfirs order spectra 9, 50–4, 76–8 nuclear Overhauser effect (NOE) 13C NMR spectroscopy 128, 133, 137 chemical elucidation 101, 103 instrumental elucidation 116–25 interpretation of spectra 47, 56, 96, 197, 198, 200–1, 204 number of increments 27–8 number of points 24 number of transients 12–13, 23–4 O-methylation 132–3 organotin compounds 91 oximes 63 31P NMR spectroscopy 152 31P-H couplings 87–9 partial double bond character 78–9 Pascal’s triangle 8–9, 69 peak picking 39 phase correction 36–8, 41–2 phase cycling 12–13 phenols 104–5 pivot points 37 polycyclic aromatic systems 49, 56–7, 59–60, 138 population differences 1 positional isomers 124–5, 173, 175, 196–7 power falloff 35–7 prediction software 128–9, 168–71 probe tuning 143–4 problems and solutions 173–204 processing 33–9 apodization 34–6 baseline correction 38–9 Fourier transformation 36 integration 39 linear prediction 33 peak picking 39 phase correction 36–8 software 167–8 spectrum referencing 39 zero f lling 33 prochiral centers 74 proton decoupling 128, 130, 151–2 pseudo enantiomeric behavior 99–100 pulse width/pulse angle 25–7 pyridines 57, 61, 85–7, 120–1 Q-modulation sidebands 31 quantificatio 157–61 absolute 158 baseline distortions 161 electronic reference 159 external standards 158–9 integration 161 internal standards 158 QUANTAS technique 159–60 relative 157–8 relaxation delays 160–1 quantificatio through an artificia signal (QUANTAS) technique 159–60 P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come Index 215 radical scavengers 21 referencing see spectrum referencing relative quantificatio 157–8 relaxation delays 27, 39, 160–1 residual solvent signals 15–16, 18 restricted rotation 78–82 ROESY see rotating frame Overhauser effect spectroscopy roofin 52–3, 55, 67, 95 room temperature (RT) shims 28 rotameric forms 78–82 rotating frame Overhauser effect spectroscopy (ROESY) 116, 123–4, 149, 179, 186–7, 195, 198, 201, 204 RT see room temperature safety issues 163–6 cryogens 165–6 magnetic field 163–5 sample-related injuries 166 salts 96–100, 173, 196–7 sample depth 18–19 sample preparation 11–21 contamination 20 filtratio 19–21 magnetic fiel homogeneity 11, 18–20 mixed solvents 17 number of transients 12–13 quantities of sample 12–13 residual solvent signals 15–16, 18 sample depth 18–19 solvents 13–18 spectrum referencing 17–18 sample-related injuries 166 selective population transfer (SPT) 119–20, 125 semi-empirical prediction 171 sensitivity of NMR technique 1–2, 3 13C NMR spectroscopy 127–8, 133 high performance liquid chromatography 143–4 quantities of sample 12–13 spinning of samples 31 see also signal-to-noise ratio shielding substituents 52–3 shimming high performance liquid chromatography 143–4 interpretation of spectra 83–4, 91 spectrum acquisition 18, 28–30 29Si-H couplings 91–2 signal-to-noise ratio (SNR) 1–2, 3, 10 13C NMR spectroscopy 127–8, 134, 136 instrumental elucidation 115 number of transients 12–13, 23–4 quantities of sample 12–13 sample depth 18 simulation software 171–2 sinc function 25–6 117/119Sn-H couplings 91 SNR see signal-to-noise ratio software tools 167–72 acquisition software 167 13C NMR spectroscopy 169–70 1H NMR spectroscopy 170–1 prediction software 168–71 processing software 167–8 simulation software 171–2 structural elucidation software 172 structural verificatio software 172 solvent suppression 145 solvents chemical elucidation 104, 109 interpretation of spectra 44–6, 81 mixed solvents 17 residual signals 15–16, 18 sample preparation 13–18 spectrum referencing 17–18 spectral interpretation see interpretation of spectra spectral width 25 spectrum acquisition 23–31 acquisition time 25 frequency locks 30–1 number of increments 27–8 number of points 24 number of transients 23–4 pulse width/pulse angle 25–7 relaxation delay 27 shimming 28–30 spectral width 25 spinning 31 tuning and matching 30 spectrum referencing 17–18, 39, 128–9 spin choreography 4 spin decoupling 111–12 spin quantum numbers 1–2 spin–spin coupling 7–9, 49, 52 spinning of samples 31 spinning side bands 83–4 splitting 7–9, 51 SPT see selective population transfer stabilized free radicals 20–1 stack plots 114 structural elucidation software 172 P1: OTA/XYZ P2: ABC ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come 216 Index structural verificatio software 172 substituent effects 48–56 superconducting NMR magnets 4–5 tautomerism 120–1 tetramethyl silane (TMS) 6, 17–18, 39, 91–2 TFAA see trifluoroaceti anhydride TFAE see (–)2,2,2,trifluoro-1-(9-anthryl ethanol thiophenes 57 three dimensional (3-D) NMR 149 three-bond coupling 64–5, 92–6, 133–4, 136, 153 time-domain data 4 TMS see tetramethyl silane total correlation spectroscopy (TOCSY) 116, 123, 149 1,2,4-tri-substituted benzene systems 55–6 trifluoroaceti acid 16 trifluoroaceti anhydride (TFAA) 101, 104–5 (–)2,2,2,trifluoro-1-(9-anthryl ethanol (TFAE) 106–7 3-(trimethylsilyl) propionic-2,2,3,3-D4 acid (TSP) 17–18 triple bonded systems 57–64 TSP see 3-(trimethylsilyl) propionic-2,2,3,3-D4 acid tuning 30 two dimensional (2-D) NMR 111, 112–16 diffusion ordered spectroscopy 148–9 INADEQUATE 147 J-resolved 147–8 problems and solutions 179, 186, 195 processing 33, 37 spectrum acquisition 25, 27–8, 31 two dimensional (2-D) NOESY 116, 122–3 two dimensional (2-D) proton–carbon correlated spectroscopy 130–7 vertical scaling 41–2 vicinal coupling 64–5, 92–6, 133–4, 136, 153 virtual coupling 76–7 WATERGATE pulse sequence 145 WET pulse sequence 145 Z test 72–4 zero fillin 33 zwitterions 96–100