chapter 3 nitrogen nuclear magnetic resonance

C H A P T E R 3

N I T R O G E N N U C L E A R M A G N E T I C R E S O N A N C E t

E. W. RANDALL

Department of Chemistry, Queen Mary College, University of London

and

D. G. GILLIES

Department of Chemistry, Royal Holioway College, University of London

C O N T E N T S

1. Introduction 1.1. Historical Development 1.2. Scope 1.3. Basic Nuclear Parameters 1.4. General Spectral Characteristics of N- -H Systcrns

1.4.1. Nitrogen spectra 1.4.2. Proton spectra

2. Experimental Techniques 2.1. 14N Single Resonance 2.2. lSN Single Resonance 2.3. ~4N Double Resonance 2.4. 15N Double Resonance

3. Results for Nitrogen 3.1. Chemical Shifts

3.1.1. Standards 3.1.2. Isotopic effects 3.1.3. Diamagnetic compounds

3.1.3.1. Intramolecular effects 3.1.3.2. Intermolecular effects

3.1.4. Paramagnetic compounds 3.2. Coupling Constants

3.2.1. Signs of N coupling constants 3.2.2. One-bond N- -H coupling constants 3.2.3. Two-bond N - - H coupling constants 3.2.4. Other N - - H coupling constants 3.2.5. Other one-bond nitrogen coupling constants 3.2.6. Exchange, solvent and pH effects on nitrogen coupling constants

3.2.6.1. One-bond coupling constants 3.2.6.2. Longer range ~SN--H coupling constants

• ~Initial survey of the literature was concluded December 1968.

119

120 120 122 122 123 123 125

128 128 129 129 132

134 134 134 134 136 136 142 145 146 146 148 154 157 158 158 158 160

120 E . W . RANDALL AND D. G. GILLIES

"3.3. Line Widths 3.3.1. Nitrogen-15 compounds 3.3.2. Nitrogen-14 compounds 3.3,3. Exchange effects

161 161 161 162

4. Results for Hydrogen 163 4.1. Chemical Shifts 163

4.1.1. Isotopic effects 163 4.1.2. Other effects 163

4.2. Line Shapes and Exchange 164 4.2.1. H l l S N 164 4.2.2. H--t4N 164

5. Conclusions 167

References 169

I. INTRODUCTION

1. I. Historical Development

Nuclear magnetic resonance spectroscopy was taken up enthusiastically by chemists as a structural and analytical tool after the discovery in 1950 of the phenomenon of the chemical shift in non-metallic compounds for t*N by Proctor and Yu, ~1~ for 19F by Dickinson, cz~ and for tH by Thomas {~ and Lindstrtm34~ Although some of this early work utilized I*N nuclei which are of special concern here, a variety of reasons led to a concentration of work on 19F and particularly 1H nuclei: the sensitivity of these nuclei to the method; the advent of commercially available instrumentation to allow exploitation of this sensitivity; the abundance of IH compounds; and unfavourable spectral characteristics for ~*N.

The first attempts ~6-8~ to enlarge on the range of ~*N chemical shifts did not come until several years after Proctor and Yu's initial work. Subsequently the more extensive compilations of t*N shifts by Schmldt, Brown and Williams ~-m came after a shorter interval. This early work highlighted some of the difficulties which would face a chemist seeking to use X*N magnetic resonance spectroscopy as an analytical tool. For example, it became apparent that he would be faced with varying line widths due to the effects of electric quadrupole induced relaxation of 1,N.CS-m

This relative importance of the line width parameter for t*N compared with many other nuclei proved less of an additional aid to structural analysis, since intramolecular as well as intermolecular interactions governed the effect, and more of an experimental nuisance adversely affecting the sensitivity of the experiment and the resolution of spin-spin couplings.

N I T R O G E N N U C L E A R M A G N E T I C RESONANCE 121

Moreover, NMR studies of protons attached to ~*N were complicated by the same agency and in many cases line broadening was accentuated by the lability of the N--H bond which permitted rapid proton exchange. (e. 12. is) Hydrogen bonding too (which renders proton shifts very sensitive to conditions of temperature, concentration, and solvent) initially limited the useful- ness of proton magnetic resonance for structural analytical studies of nitrogen compounds. Consequently we find that in the period 1959-63 very little work was done on '*N resonance spectroscopy. Similarly there was a dearth of studies employing the low abundance 15 N isotope, no doubt due to pessimistic individual judgements that extensive studies on enriched compounds would be not only expensive but would prove as unspectacular as the '*N studies. Other nuclei were, however, receiving attention in addition to the commonly- studied 1H and 'gF nuclei. For example, '3C resonance spectroscopy was investigated primarily because of the potential application in organic chemistry; 31p work blossomed essentially because observation was relatively easy, and ~ ~B studies, although difficult, acquired momentum because of the widespread interest in the boron hydrides, a~) This situation was consequently reflected in the early review articles (reference 14 has only one page on nitrogen) and even in the latest and most comprehensive text on high resolution studies.aS)

The year 1964 witnessed a considerable revival of interest on the part of NMR spectroscopists in nitrogen systems which was rendered inevitable by the importance of nitrogen compounds to the preparative inorganic and organic chemist as well as to the biochemist, and by the challenge to the physical and theoretical chemist to break the conspiracy of factors which complicate nitrogen spectra. Several laboratories invested considerable effort in the nitrogen area. Professor Robert's group at the California Institute of Technology, with its dual potential in preparative and spectroscopic areas, undertook extensive studies of 15N compounds. (le-2a) Professor Richard's group at Oxford with interests in I*N chemical shifts (2s) and quadrupole broadening effects (~4) produced the most comprehensive compilation of X*N results to date, (~5) and the group at Queen Mary College, London, used single and double resonance techniques on both I*N and ~SN compounds for accurate shift and coupling constant measurements including relative signs.C2e-36) Other groups too began to use enrichment with ~ 5 N because of its favourable spectral characteristics in their proton magnetic resonance studies.CST-39) The utility and power of this approach for the study of tauto- meric systems was demonstrated by the elegant work at the National Institutes of Health, U.S.A., on cytosine ~a°) and by the Dudeks at Harvard on Sehiff's bases.(4L 4.o) The last few years have seen the usual "dramatic" increase in the number of publications in this area, coming from an impressive array of groups using the full panoply of NMR techniques.~"

I" A brief review of nitrogen magnetic resonance has recently appeared, osa)

E

122 E. W. R A N D A L L AND D. G. GILLIES

1.2. Scope

Attention will be limited to high resolution studies and solid phase work will be omitted. Both the 14N and ~SN isotopes will be covered as studied by single and by double resonance techniques. Since one of the important spectral parameters of nitrogen, its spin-spin coupling constant to a second nucleus, may sometimes be obtained from the resonance spectrum of that second nucleus, some attempt will be made to cover those cases particularly when tH is concerned. A brief discussion of ~H shifts and line widths in N - - H groups will therefore also be given. No exhaustive compilation of spectral data will be made, nor is the bibliography guaranteed to be complete.t

1.3. Basic Nuclear Parameters

There are two naturally occurring isotopes of nitrogen, 14N and lSN. ~4N has a natural abundance of 99.635~. It possesses a spin quantum number I of 1 and consequently is endowed with an electric quadrupole moment, the value of which is 2 × ex 10 -26 cm 2. The magnetic moment for the bare nucleus has recently been calculated to be +0.403562 +0-000(310 nuclear magnetons. (4s)

For ~SN the abundance is only 0.365 9/0 and since I = ½, there is no quadrupole moment. The magnetic moment was shown by Proctor arid Yu (x' 44) to be negative by NMR studies, and the value for fine bare nucleus has been calculated to be -0.283049 + 0"000007 nuclear magnetons, c4s}

These calculations require reliable estimates of the effects of electronic screening of the nucleus from the applied magnetic field, because the basic experiments involve measurements of the resonance frequencies of screened ~4N and x 5 N (and other) nuclei in bound atoms.

It is possible to obtain the ratio ~5), to t4), to a high degree of precision by observation of the ratio of the resonance frequencies 1% and ~Sv for t4N and 15N respectively in say 14NH~ and ~SNH+ at constant field strength. Neglecting coupling between the nitrogens and the protons, these two frequencies may be given by:

and 1"v = 1"~, H ~ ( I - l'*a) ( 2 n ) - t

~s~ = ~s~,/-/2(1 - l s a ) ( 2 n ) - ' ,

where 14a and 15a are the nitrogen screening constants, and/-/1 and/-/2 are the applied fields. The conditions HI -- Hz can be imposed fairly exactly by utilizing the double resonance technique. Here the proton resonance spectrum

t A large number of references has been added at proof stage (April 1970). Where important and possible they are linked to the text by footnotes.

NITROGEN NUCLEAR MAGNETIC RESONANCE 123

is observed and the effects of irradiation of the sample at a second radiofrequency in the nitrogen region noted. The proton spectrum is effectively used to ensure that H~ =/-/2, since the chemical shifts of the protons in 14NH~ and 15NH~ are nearly equal. In this way Baldeschwieler found the ratio lSv to lay to be 1.4027548 + 2 × 10 -7~45~ for separate solutions of XaNH~ and :SNH4 + and this ratio was taken to be x5~/~47.'~ This approach assumes that the solutions are identical in concentration and pH and that the isotope effects both on the proton and nitrogen screening constants are negligible, i.e. H~ = / / 2 exactly, and 14a = x~cr. These complications are examined in section 3.1.2.

1.4. General Spectral Characteristics of N--H Systems 1.4.1. Nitrogen spectra

The magnetogyric ratios for ~4N and 15N are quite close so that the reso- nant frequencies at a given field strength are similar: 3.076 MHz and 4-315 MHz respectively in a field of 10,000 gauss (1 tesla). The spin-spin coupling constants also are not very different: a coupling J(14N--H) of 50 Hz is changed to approximately 70 Hz upon isotopic substitution by aSN.

The most important single difference for NMR purposes, besides their relative abundance, between :4N and :SN is the electri.e quadrupole moment of X4N which can render line widths large for ~4N resonances. Thus whereas ~SN lines can be narrower than 1 Hz, ~4N signals are commonly 100 Hz or wider.CU~ In select instances narrow 14 N lines are obtained. The condition for this is that the fluctuating electric field gradient at the nitrogen atom should be small. This may occur as a consequence of the molecular symmetry. For example, in the ammonium ion, apart from induced effects, one anticipates a small electric field gradient at the nitrogen atom and consequently narrow ~4N lines. The same is true for tetramethyl and other substituted ammonium ions where the substituents are identical or similar, e.g. methyl and benzyl, cv) In these cases the X4N spectra should resemble the XSN spectra. This is illustrated by the single resonance spectra in Fig. 1 for :aNH4+ and :SNH +.

With lower molecular symmetries electric field gradients at the nucleus are usually obtained. These change direction with respect to the axis of quantiza- tion of the nuclear spins as the molecule rotates, and help to limit the lifetime of the nuclear spin states so that the resonance lines are broadened. Ammonia is a good example: it can be seen from Fig. 2 that the :aN lines are broadened relative to the ammonium ion.

Occasionally small field gradients are obtained even with low molecular symmetry, for example in EtNC c4e) or the pyridinium ion. t~7~ At present these cases cannot be predicted and, in general, line widths cannot be forecast. Some generalizations, however, are possible: for a given compound with

t See p. 135 for a more accurate value.


(a) I4NH~

50 HZ

(b) ~SNH~

F I 50Hz

Fro. 1. Nitrogen resonance spectra for the ammonium ion: (a) I*N spectrum at 3.9 MHz (courtesy of Professor R. E. Richards); (b) accumulated tSN spectrum (553 scans) for a 5 M solution of ammonium-t~N chloride in dilute HC1 (95.4~/. enrichment) at 6.08 MHz (courtesy of Professor

J. D. Roberts).

t 1 I0 HZ

FIG. 2. Nitrogen-14 resonance spectrum of ammoniatT) at 3.0 MHz.


quite narrow lines the width should be proportional to the viscosity and in- versely proportional to the temperature.(24)

XSN resonances are therefore easier to detect with high resolution spectrometers than ~4N at equal abundance. Thus it is reported that S,~4Ns + gave no observable nitrogen signals owing partly to the low solubility of the sample and partly to quadrupole broadening of the fines, whereas S4~sN + gave two detectable signals. These exhibited spin-spin splitting and were interpreted as arising from two kinds of nitrogen in the ratio of 2:1.(4s)

1.4.2. Proton spectra

The electric quadrupole effects of ~*N which limit the lifetimes of the spin states for nitrogen are made manifest in the NMR spectra of nuclei coupled to X*N. The commonest example is the N - - H group. In the absence of exchange and if the relaxation for X4N is slow, three equally intense proton lines are

(a)

~SN

(b)

I00 Hz l T

Fxo. 3. Proton magnetic resonance spectra at 60 MHz of the ammonium ion in aqueous solution (a) ammonium-XSN, Co) ammonium-

14N,

126 E, W. R A N D A L L AND D. G. GILLIES

expected arising from the three magnetic spin states, + 1, 0, and - 1, for the nitrogen (15N in the same circumstance gives two lines arising from the two magnetic spin states +½ and -½). This is illustrated in Fig. 3. For more rapid relaxation, however, the lines broaden and in the limit when the relaxation rate is large compared with J(14N--H) the lines collapse to a single broad line which narrows if the relaxation rate increases further. An example of a single broadened line is illustrated in Fig. 4 for trimethylsilylaniline-~N which is juxtaposed with the spectrum for the XSN isotopomer.t

( b )

I~ N

l i

f _ _ 5 0 H z I

Fro. 4. The N w H region of the proton magnetic resonance spectra(n~) of (a) the t4N and (b) the ~SN isotoporners of N-trimethylsilylaniline at 60 MHz. The small doublet in (b) is attributed

to aniline-~ 5N.

The broadening effects of I'~N may be removed not only by 15N substitution but also by proton-~4N decoupling produced by double resonance techniques(49, ~o~ and this is illustrated in Fig. 5, The information concerning J(N--H) is, however, lost in a decoupling experiment.

t The term isotopomers has been suggested to describe compounds which differ only in isotopic substitution at one position3 sv)

N I T R O G E N N U C L E A R M A G N E T I C R E S O N A N C E 127

(0) //r~ O~C N/CH3 [Zl

14N [ \ H/, -- \H

H{mN}

NH mN (el

- ,I l,l I 50Hz j

I~G. 5. Proton resonance spectra at 60 MHz of N-methylformamide: (a) single resonance spectrum for the 14N isotopomer; Co) double resonance spectrum of the x4N isotopomer with irradiation at the 14N resonance frequency; ~c) single resonance spectrum for the tSN

isotopomer.

Protons directly bonded to nitrogen may exhibit no spin-spin interaction J(N--I-I) if they exchange at a rate r given by

2nr >> J(N~H).

For I~N cases which give single lines for the N - - H proton, it is difncult to decide whether the absence of spin-spin splittings comes from quadrupole or exchange effects, xsN substitution is useful in this regard. In the case of ammonia-14N the spectrum shown in Fig. 6 is quite difficult to obtain since small traces of water effect collapse of the triplet, c51)

128 E. W. RANDALL AND D. G. GILLIES

FtG. 6. Proton magnetic resonance spectrum (s~) at 30 MHz of dry ammonia-l*N, The small doublet is attributed to the I~N isotopomer.

2. EXPERIMENTAL TECHNIQUES~

2.1. ' *N Single Resonance Apart f rom the inherently low sensitivity of this nucleus for the N M R

experiment the situation is complicated by line broadening due to quadrupolar relaxation.

The most convenient method for obtaining spectra is by means of the con- ventional field-sweep technique c52) with calibration by the audio side-band method. Frequency-swept spectra have been obtained by Professor Richard's group. (~-25) The frequency of a modified Varian V4300B wide-line spectrometer was varied by means of motor-driven trimmer capacitors whilst the field was maintained at a reasonably constant value with a flux stabilizer. The spectrum was calibrated by monitoring the radiofrequency with a counter. For narrow lines the frequency was not sufficiently stable. In these cases the field-sweep method was used whilst the frequency was locked to that of a crystal-controlled oscillator.

An improved system has been used by Bothner-By. c53) Frequency-swept spectra were obtained by driving the Varian V4300B wide-line spectrometer with a frequency synthesizer whilst the field was locked to a separate proton sample.

Audio modulation may be employed for base-line stabilization at a frequency and level determined by the nature of the spectrum. Thus modulation at frequenciesless c2~-z5) and greater (54) than the line width have been employed.

The accuracy to which the position of a line may be determined in these experiments is, of course, limited by their generally broad nature but none the less a range of useful data on nitrogen chemical shifts has been accumulated (see section 3.1). Line-width studies yield information on the nature of field gradients at the I*N nucleus and on chemical exchange processes.

t Fourier transform spectrometers are now available and can give sensitivity enhance- ments of greater than ten over continuous wave spectrometers in thesame total time. (194, xg,~

N I T R O G E N N U C L E A R M A G N E T I C RESO N A N CE 129

2.2. aSN Single Resonance

The 15 N nucleus does not suffer from quadrupolar relaxation effects but its low natural abundance and low magnetic moment have, until recently, precluded the detection of signals from unenriched samples under normal conditions. Ray, (55) however, using both high r.f. and high modulation power levels combined with a fast sweep rate, managed to detect the resonance in natural abundance with a signal-to-noise ratio (S/N) of between three and four.

Professor J. D. Roberts' group cIs-22) has pursued the problem by using samples enriched to varying degrees. In their earlier work, the spectra were usually obtained by the fast passage field-sweep method and often employed the Computer of Average Transients (CAT) to improve the S/N ratio. Typi- cally, the spectra displayed narrow lines with an approximate width of 10 Hz although, in favourable cases, under slow passage conditions line widths of about 1 Hz were observed. This enabled line positions to be determined to an accuracy greater than is possible for l 'N, permitting the study of small chemical shift differences and also the measurement of spin-spin coupling constants such as J(15N--lSN),Cle, xT) and J(15N--xsC).Cx~' is) The couplings d(XSNmF) and J(15NmH) are, of course, more readily measured by direct observation of the x 9F and t H resonances.

Recently, the advent of the Digital Frequency Sweep Spectrometer (DFS) together with the use of spectrum accumulation techniques has widened considerably the scope for 15N spectroscopy. (Se, 57) The extreme stability of the system, which results in greatly enhanced reproducibility over long periods of time, is the factor responsible for the improvement. The magnetic field is locked to an internal proton reference, tetramethylsilane (TMS), whose resonance frequency is always accurately related to the tSN resonance frequency. The latter frequency is swept digitally, each point being accurately related to the master crystal in the frequency synthesizer. The system has detected tSN in natural abundance in liquid ammonia, liquid hydrazine and acetonitrile. In the case of liquid ammonia, 4361 scans were employed, the S/N ratio being 0.08 per scan. Acetonitrile is an example where proton coupling, by splitting the available intensity, reduces the effective S/N ratio. Proton decoupling (particularly noise-modulated deeoupling) will dearly be helpful as has been demonstrated already in x3C spectroscopy.(Ss) t

2.3. X*N Double Resonance

If features are observed in the proton (or fluorine) spectrum of a molecule which are attributable to coupling with the I*N nucleus, then they may be

t Reduction in intensity, or even inversion (at different acidity), of 15N signals due to ~5~, being negative have been observed in proton noise decoupling experiments on NI-I, + solutions. (198)

E*


modified or eliminated by simultaneously irradiating at the 14N resonance frequency. The double resonance technique has been reviewed.C4°' 5o~

The nature of the spectrum and precision of the required data are the criteria for the desired power level and frequency stability of the second radiofrcquency. The least precise method simply requires a free-runnlng oscillator and a frequency counter. Baldeschwieler t4b) stabilized such an oscillator by locking to one of the 10 kHz harmonics of a frequency calibrator but this was rather inconvenient in practice. A better method is to employ a stable crystal-controlled radiofrcqucncy which is modulated at an audio- frequency which may be varied. The carrier frequency is suppressed and the upper or lower sideband is used as the variable radiofrequency, c~) A further extension is to suppress either one of the sidebands, cSt' ~2. 59. eo~ This removes the ambiguity as to which sidcband is perturbing the spectrum, although a prior knowledge of the nitrogen line positions would serve equally well for this purpose. The second radiofrcquency may be derived from the proton frequency ~61~ or related to it ~6~) by the use of frequency synthesizers.

By the use of relatively high-power levels the broadening effects of the quadrupole moment may be removed and previously inaccessible proton- proton coupling constants may be measured (see Fig. 5). Hence it is possible by this technique to distinguish unequivocably between quadrupolar and exchange broadening.

The presence of a high radiofrequency field in the probe may cause sample heating so that the decoupled spectrum obtained corresponds to a higher temperature than the probe ambient. Kamei ~u. *~ overcame this problem by controlling the sample temperature by means of a stream of nitrogen gas. He, unlike Piette e t al . , ~ was able to decouple the I"N nuclei completely from the protons in formamide and showed that without sample cooling the spectrum obtained corresponded to a temperature of 55°C. Temperature is an important criterion in this case, since the N - - H proton lines move to a higher field as the temperature is raised on account of decreased amide-amide hydrogen bonding.!"1' 66~

The nitrogen chemical shift may be determined by observation of the optimum decoupling frequency. ~9.s7-72~ In field-sweep double resonance experiments the magnetic field is defined as the value corresponding to the chemical shift of the proton at which decoupling effects are observed and hence for purposes of comparison should be corrected to that field which corresponds to a proton standard, e.g. TMS. c6t~ Field-frequency locked spectrometers facilitate the more convenient frequency sweep mode of operation. The field is held constant and corresponds to the resonance frequency of the lock signal, which is usually that of TMS. The nitrogen resonance frequencies may be compared with that of a reference sample before and after each run. (6s~


A further improvement is allowed when the proton frequency is related to the nitrogen frequency, see section 2.2.

In cases where the proton line widths are narrow and the J(14N--H) spin-spin coupling is observable, the accuracy to which the optimum decoupling frequency may be determined is high, e.g. in I"NH + to within + 0.2 Hz. ~a~ This accuracy is achieved even though the I"N line width is approximately 10 Hz. c9~ By simultaneously counting the proton resonance frequency an accurate value for 714N/~,H in ~4NH: was calculated, ~4~. va~ as

(o)

! !

5OHz

(cJ

Fla. 7. INDOR spectra of (a) : ' N I ~ , Co) 15NI~, (c) CH315NC.

132 E . w . R A N D A L L A N D D. G. G I L L I E S

described in section 1.3. Signs of 14N--H relative to H - - H coupling constants have been obtained. Surprisingly, in ethyl isonitrile, CH3CH2**NC, the field gradient at the nitrogen nucleus is fortuitously small and enabled Manatt *74) to establish the signs of J(14NCH) and JQ4NCCH) relative to the vieinal proton coupling, J(HCCH). The studies have been extended and now include the methyl and t-butyl derivatives. (75~ Similar measurements have been carried out on the following ammonium ions: partially deuterated, (~6. 76) tetraethyl,(76) and trimethyl vinyl.~77~

In other molecules where there is significant broadening of both nitrogen and proton lines, the accuracy to which nitrogen transitions may be located is reduced. However, the accuracy appears to be greater than that previously obtainable by direct observation of the nitrogen spectrum.(es)

The INDOR technique, originally suggested by Baker, (Ts) has been utilized in several of the papers quoted above, e.g. references 68, 36 and 77. The method involves "sitting" on top of one resonance (proton) to which a second nucleus (X4N) is coupled and sweeping through the resonance frequency of the latter. The stability required by the experiment necessitates the use of a field-frequency locked spectrometer. Baker produced a replica of the **N spectrum of X*NH, in acidified NH,NO3. Figure 7(a) shows such a spectrum (7.) which compares favourably with that obtained b3t direct measurement, Fig. 1.

It is apparent, then, that double resonance provides a method by which information concerning a nucleus of low sensitivity may be obtained with the sensitivity and convenience conferred by proton spectroscopy. It has been a useful tool in the particular ease of*4N.t

2.4. *5N Double Resonance

The general remarks concerning double resonance in the above section apply equally to the 15N ease. The small linewidths observed in the spectra of 15N compounds mean that accurate nitrogen shifts may be deduced for a wider range of compounds than for *4N. A further practical point is that the radiofrequeney power level required is, in general, much lower for :SN than for X*N compounds. The method is of particular use for amides c29-3s) where the increased accuracy may be used to measure solvent dependent shifts. With the advantage of proton sensitivity one can pursue these shifts to higher dilutions than is possible by direct observation of the 1aN spectrum. The comment is still valid, even in the light of the recent multiple scan experiments with the DFS spectrometer described in section 2.2. Recent experiments have shown that it is possible to use the CAT to perform multiple-scan INDOR experiments when the nitrogen frequency is directly related to the movement of the recorder on the Varian HA60-IL system. ~79)

1" Triple (and multiple) resonance studies are also obviously feasible. ~97)


The signs of nitrogen-proton relative to proton-proton coupling constants can be determined in any system with a sufficient number of suitably coupled nuclei. The technique has been applied to several amides including N-methyl formamide, N,N-dimethyl formamide and formamide.(~9-3s)

In the case of formamide, (~s) spin tickling was used so as to determine the ISN line positions to _+ 0"1 Hz as shown in Fig. 8. The theoretical spectrum is calculated from the parameters determined by computer fitting of the proton spectrum. Double resonance studies on methyl isonitriie have related the signs of nitrogen-proton to carbon-proton coupling constants. ~s°) The group at Queen Mary College have made precise measurements on methyl isonitrile, the ammonium ion and deuterated ammonium ion with a view to investigating isotope effects c~) (see section 3.1.2). Further studies on para-substituted anilines have yielded nitrogen shift data.(Ss' xgs, 199~

(a)

I,,I I 1,1 (b)

r, i if, i, , I I00 Hz

Flo. 8. Nitrogen-15 resonance spectra (n) of formamide-lSN at 9400 gauss (0-94 tesla): (a) computed from couplings determined in the proton spectrum; Co) experimentally determined by proton-tSN

double resonance studies.

The INDOR technique has proved to be very useful in many of the recent studies since all the nitrogen transitions associated with a particular proton transition may be found quickly: INDOR spectra ~) of ammonium -1SN and methyl isonitrile -1SN are shown in Figs. 7(b) and 7(c). It was of particular use in the case of aniline in trifluoroacetic acid where the proton spectrum revealed the presence of t w o doublets arising from coupling to the l SN nucleus. (al) The INDOR spectrum revealed a quartet for one doublet and a triplet for the other, presumably indicating the presence of the species C6HsNH + and some unknown species containing NH2. The fact that the triplet did not arise from aniline itself was recognized by the 17 ppm shift to low field. Olah used INDOR in his study of protonated hydrogen cyanide,t8~) ureas and guanidines. (~°°)

134 E. W . R A N D A L L A N D D. G. G I L L I E S

3. RESULTS FOR N I T R O G E N

3.1. Chemical Shifts 3.1.1. Standards

The reference substance most commonly used has been NH4NO3. Both the NH4 + resonance (in saturated aqueous solution) (9-n) and the NO~ resonance (as 4.5 M solution in 3 ~ aqueous HCI) czs) have been employed/f The Roberts' group has used 8.57 N HNO3 in its lSN work. c~e'~s) These reference samples were all used external to the experimental sample either in concentric or quite separate tubes. Shifts due to susceptibility differences were considered small both in the light of the errors involved in the measurement of line positions and the large shifts observed in nitrogen resonances.

CH3NO2 has occasionally been utilized as a secondary externalreference,(Zs) but recently its suitability for use as an internal reference has been advanced c52) on account of its good solvent properties for organic substances. On dilution with other solvents no shift changes were observed outside the experimental e r r o r .

An internal reference compound should ideally have no preferential attrac- tion for one molecule over another. CH3NO2 is rather too polar to fulfil this requirement especially in the light of the enhanced aceur.aey of ~SN spectroscopy.

Perhaps the best reference is the well-proven tetramethylsilane (TMS). The relation of the nitrogen frequency to this standard either by double resonance experiments (restricted to molecules displaying couplings to protons) or by the use of a spectrometer whose field is locked to the resonance of TMS (see section 2.2) is probably the best modern procedure. Schemes for presentation of data from these experiments have been proposed.(Sa' 7.~)

3.1.2. Isotopic effects

Precision tests of the equality of the nitrogen-14 and nitrogen-15 screening constants using double resonance techniques have been made. (3e) Proctor and Yu in their original studies (x" 44) were able to obtain a precision of only 1 in 104 . Subsequently single resonance work of unspecified accuracy on approximately a dozen compounds has been reported where four compounds (including dimethylformamide) reputedly gave widely different values for x4~ and xs~.(ss) N,N_dimethylformamide_lSN has, however, been investigated also by double resonance techniques. (3~. ~). The 15N shift difference between formamide-:SN and dimethylformamide-XSN was found to be less than 15 parts per million contrary to the earlier report of nearly 200 parts per million.

"t" Price (3s) used the double resonance m e t h o d to show that m e d i u m effects on the n i t rogen shift o f :4NH4+ (but no t on the p ro ton shif t )were negligible so that it is a suitable s tandard . l ~ c k e r (~7o advocates the use o f N M e 4 +.

N I T R O G E N N U C L E A R MAGNETIC RESONANCE 135

The screening constants'for dimethylformamide-~4N and -ISN now agree. Figure 9 shows the correlation between ~4N and :SN shifts for a number of compounds.

Price cse) has investigated the isotopomeric pairs NH~ and MeNC, both chosen to give narrow lines in the proton spectra of the ~4N cases. His results are:

XSv/14vforNH4+ = 1.402757 10+0.00000008 X Sv/14v for CH3NC = 1.402 758 00 + 0-000 00016

This yields a barely significant shift difference of 0.54 + 0.20 ppm.J" The only other study of this kind was that made by Diehl and LeipertC38) who found differences in chemical shifts for hydrogen and deuterium.

"t

6 - z/HzO

5 -- / - ~ trans Ph NN Phleth'er

/ 4 / o Ph NO2/neot

N~H4 Ct. / HaO

0 ) 2 ~ 4 5 6 7

~)N chemical shift

Fx6. 9. Plot of ~*N versus ~SN chemical shifts; x IDO ppm downfie]d from ammonia.

Effects on the nitrogen shift caused by isotopic substitution have been observed in deuterated ammonium 14N ions. t~6. u. as) There is a shift to high field of 0.3 ppm for each deuterium substituted, in contrast to the proton shift of 0-015 ppm to low field. Price (Be) confirmed the results for 14N and made a similar study of the XSN analogues. In the deuterated XSNH3 series the nitrogen shifts are in the same sense (0.6 ppm per deuterium) but the proton shifts are in the opposite sense (0.027 ppm). (2°') Temperature and phase effects have been studied. (~°3)

j" Excellent agreement with Price's figure for NH4 ÷, rather than Baldvschwieler's, (~5) has been obtained for NMe4 +, MeONO~, Me2NNO,, CeI-IsCH2NC. (I°l) The isotope effect may therefore be even smaller.


3.1.3. Diamagnetic compounds

3.1.3.1. Intramolecular effects. The large range of nitrogen chemical shifts (900 ppm) and a general guide to values associated with different functional groups are shown in Fig. 10. For more specific data the reader is referred to the paper of Herbison-Evans and Richards (25) for the most complete compilation of Z4N shifts and to those of Roberts (~6' zs) for ~sN work. Much additional information is of course available from other references quoted in this section. Chemical shift calculations have been reviewed3 se)

Amine

Amide

Nitrile

1"mine

Nitro, nitrate

Azo

Nitr i te

Nitroso Paro mag. cyano- metat

T I T ', r T I 14 t2 10 8 6 4 Z 0

Chemical shift, ppmuX 100 downfield from ammonia

FIG. 10. Nitrogen chemical shifts relative to ammonia for different functional groups.

The screening of nuclei has been considered as the sum of three terms: (8~)

aa = ~r= ~A + croaa + ~ o "AB B ~ A

affa A is the diamagnetic term which is a function of the ground state only and is given by

where <r F i ) is the mean inverse distance of electron i from the nucleus and the summation is over electrons on the atom considered.

aA is the paramagnetic term from second-order perturbation theory. Gp

It was first introduced by Ramsey <Ss) and involves matrix elements between the ground state and all excited states of suitable symmetry. The term is usually negative, and can be computed from a knowledge of the ground state wave functions only by the use of AE, the mean excitation energy, although more


accurate summations are preferred. (8~ The expression introduced by PopleC~. 9a~ has been used to calculate nitrogen shifts. ~92-"5, 2o4)

e 2 h a ar't'4 = 2rn2c2AE <r-3>2~ Y~B QAB (B is neighbour of A)

where <r-3>2r is the mean value of the cube of the inverse radius for the 2p orbitals of nitrogen. The terms Qa~ contain the elements of the charge density- bond order matrix and when averaged over the x, y and z axes, take the form:

4

2 - ~ (P,.,~ e . . ,~ +/'=.:~ P , ~ . +/'=A=~ P,.,~)

2 + g (/ ' ,- . . P:,.~ + P:+_:, P..=~ + f~,~,,. P,.=~)

where P~, = 2 • G~ Gv and G , are the coefficients of the valence shell f

atomic orbitals in the LCAO description of the molecular orbital ~'f, i.e.

/t

A similar expression was deduced by Jameson and Gutowsky (N~ where the parameter P , is equivalent to Y.v Q•v above. The latter approach was used by

(97) van Wazer for a detailed explanation of a ~p shifts. The ~ a An term arises from long-range shielding effects of other atoms in

B # A

the molecule and is usually small. Electric field effects (gs~ have not yet been applied to nitrogen shifts.

Faced with so many parameters, one has to make quite drastic assumptions with respect to the variation in their relative magnitudes with changes in molecular structure in order to rationalize shifts.

It has been realized since the earliest days cg-n' 9~ that the range of shifts observed for nitrogen can be explained only in terms of changes in o# "~. Indeed, in the consideration of a range of nitrogen-oxygen compounds, (~°~ an 80 ppm variation in a~ a was calculated, although the total shift range observed was 570 ppm. It seems reasonable then, to ignore changes in o~ a in a first approximation.-~

AA term and we shall consider how Hence our attention is restricted to the ap nitrogen shifts have been interpreted in terms of the three parameters, AE, <r-a>2v and Zs Qan.

, Allowance for cr,aa as well as ep aa has been made recently in nitroso compounds, c*°b)

138 E. W . R A N D A L L A N D D. G . G I L L I E S

Kent and Wagner ~s) considered the following series of sixteen valence- electron linear triatomic compounds and ions: N~O, C1CN, BrCN, NOz +, N ; , NCS-, and NCO-. The dependence of the term (r-3)2o on n-electron density was included in the manner of Karplus and Pople. ~gx~ The magnitude of (r-~)2o was estimated using Slater atomic 2p orbitals and by choosing the nuclear charge according to Slater's rules. ~°°~ The resulting expression was:

(r-3~2o = (1/24ao ~) [3.90 + 0"35 (2--q~)13

where ao is the Bohr radius, 3.90 is the nuclear charge for a neutral nitrogen atom, 0-35 the screening per 2p electron, and q~ is the zc-electron charge density. Constant values for AE were adopted; 3.5 and 5.5 eV for "end" and "central" nitrogen respectively. Suitable molecular orbitals were set up, using the LCAO approximation. Polarity in the o-bonds to nitrogen was included in the description although, in the final event, the polarity parameters were set to zero. The ZBQ~s term was then evaluated. The shift values, when adjusted to agree with the end nitrogen shift in the azide ion, indicated a positive linear dependence on ~t-electron density, and the overall agreement with experiment was reasonable considering the wide range of shifts.

Witanowski, both in his earlier consideration of nitriles and isonitriles c94~ and in his later work on sp 2 hybridized nitrogen compounds, ~gs~ assumed both the AE and the (r-~)2~ terms to be constant within related groups of com-

A~ appear to be pounds. The grounds for dismissing the (r-3)2p term in a o erroneous. Following Karplus and Pople ~91~ for cry, increasing electron density at A leads to an increase in shielding giving a shift to high field. The contribution from orbital expansion (decrease in (r 7 ~)) leads to a contribution in the opposite sense but is normally thought to be lower in magnitude. The net effect then is a shift to high field for o'~ A. The (r-3)2p term, like ~r 71), will decrease with increasing electron density at A. This will result in a decrease in o~o A leading to an increase in the overall shielding and a conse- quent shift to high field. ~°x~ (The dependence on q~, the zc-electron density at the nitrogen was given earlier.)

Summarizing then, increasing electron density at A (decreasing electronegativity of substituents) leads to high field contribution to the shiR from cz¢ ~ and from the (r-3):p term incorporated in ~A.

Witanowski, then, seeks to explain nitrogen shifts purely in terms of variations in ~;B Q~B. His calculations on the RNO2 system indicated that I;B QAB decreased with increasing q~, the z~-electron density at the nitrogen atom, and it was concluded that this would lead to a shiR to high field. The contributions from the (r-3)2o and EB Qan terms lead to contributions in the same sense so it is informative to compare their relative magnitudes. Taking Witanowski's calculations on the RNO2 system, as E~ Q ~ increases from


2.54 to 2.63 (increase 3.5 ~o) q~ decreases from 1-50 to 1.00. The corresponding change in (r-3)zp according to Kent and Wagner would be an increase of 13~o. In the case of NO~, for the same change in q~ (13~o increase in (r-3)2p), ZB QAs increases from 2.32 to 2.67, an increase of 15 ~ . It seems that the contribution for <r-3)2p can be of comparable or greater magnitude than that from Za QAa, as was indicated by Karp]us and Pople for 13C shifts in conjugated systems.

If decreasing electronegativity of a substituent on nitrogen leads to an increase in q~ then a shift to high field for nitrogen is expected. The observed data for nitro compounds, nitramines, covalent nitrates, isocyanates, thioiso- cyanates and azidcs, indicate a shift to high field as the eleotronegativity of the substituent R is increased, and are clearly contrary to expectations. If, however, one compares the shift to low field for nitrogen attached to oxygen in RNOz (Za QAs = 2.5-2.6) relative to nitrogen attached to carbon in RNC (ZB Q~B = 2.3) and RCN (Za QA~ = 2.2) one finds that the decrease in electronegativity in going from oxygen to carbon is associated with a shift to high field. It appears that increasing electronegativity can produce shifts to either low or high fields.

An increasing shift to low field has been associated with increasing electronegativity of substituents for some time a6. ss~ although, as above, closer inspection of groups of more closely related compounds often reveals a reversal of the relationship. Thus there is a progressive shift to low field in the series NH +, NMe +, NEt +c25) and in the series NMe4_,.Et~ + as n increases from 0 to 4. (~)

In other situations, variation in AE has been postulated. Thus, Baldeschwieler and Randall c49, eT~ suggested that in the case of pyridine important terms arose from 7r* ~ n transitions. On protonation of pyridine, a nitrogen shift of approximately 120 ppm to high field was observed. It was argued that the AE was increased by the use of the lone pair electrons in bond formation. Later calculations by Gil and Murre11 ~9~) did indeed include AE and ~B QAB as variables but held (r-S>zo constant. Witanowski c95) has argued purely in terms of Y-B QAB for this situation. Qualitatively, protoantion was considered as akin to replacing a strongly electron-donating "substituent", i.e. the lone-pair electron, with a more electronegative hydrogen atom as in going from NOi to R~NOz. The shift is certainly in the expected direction and of the right order of magnitude but these arguments we think to be dangerous especially when there are dramatic changes in the ultraviolet spectra which indicate that there may be a substantial change in AE.

In recent studies of the protonation of hydrogen cyanide and acetonitrile, enriched with ~SN,(S~) shifts to high field of 135 and 102 ppm were observed but no theoretical explanation was advanced.t

In diprotonated urea the remaining free unprotonated Nil, is 53.7 ppm downfleld from the free base whereas the NHs + group is 19-3 ppm upfield. <~°°~

140 E . W . RANDALL AND D. G. GILLIES

Explanations in terms of AE variations have been advanced for high field shifts of 140 p p m and 150 ppm on protonation of diphenylketamine and trans.azobenzene.tX6, zs~ These data should be compared with the cases of ammonia and methylamine which, on protonation, show a downfield shift of approximately 25 ppm. cz6~ Approximate correlations between chemical shifts and AE values derived f rom electronic spectra have been made. ~°, 25, 205-207~ Lack of an exact correlation is not hard to understand on accountof theditti- culty of assignment of the electronic spectra, the variation in the matrix elements involved (EB QaB), and the inaccuracies in the use of a mean AE. It was demonstrated that r~* ~--n transitions on the oxygen atoms in nitrate compounds contributed to the nitrogen chemical shift. ¢z°~ The effect of n*~-- n transitions on nitrogen was suggested as a contribution to the ring proton shifts observed on protonation of pyridine, t~9. e7, 9~

The nitrogen shifts in primary and secondary amides have been qualitatively related to the extent of delocalization of the nitrogen lone pair. c6a~ Amides are normally considered to be a resonance structure involving the two forms:

R,\ /R= R,\ .a, O//pC--N~R3 _o/C"~N+~R,

I II Increased contributions f rom H (delocalized lone pair) were associated with" shifts to low field by analogy with the shift to low field on protonation. Thus substituents that favoured form I I lead to shifts to low field. These arguments have been extended to thioamides ~7°, ~08~ and to ureas. ~1°~

Empirical additivity rules have been found for a series of aliphatic nitro compounds, R1RzR3CNO2, where RI = Me, R2 = RCH2 and R3 = C1. tx°a~ An accuracy of approximately 1 ppm was achieved over a range of 70 ppm. Other aliphatic nitro compounds have been studied. Iz°a~

In nitrobenzenes the nitrogen shift was almost identical for ortho-, para- and recta-isomers indicating that n-electron conjugation has no effect. ~x°4~ Electron-withdrawing groups such as formyl and nitro produced a shift to high field whereas no effect was observed for methyl, hydroxy and methoxy groups. Repetition ~1°5~ of some early ~SN results ~22~ has provisionally confirmed the results of Witanowski et al. ~°4~ for l*N. t

In recent studies of acetone solutions of para-substituted ~ N anilines ~5~ the nitrogen shift proved more sensitive to the nature of the substituent than in the case of nitrobenzene. A shift to low field was observed, increasing in the order CH3, H, Br, I, NO2, the total range being approximately 16 ppm. clas,xa9~

An interesting study of N203 has recently been made, tx°a~ which has con- ~" Perfluoronitrobenzene derivatives have now been studied as well as nitrobenzene

interactions with boron halides. ~*-t°, ~tx)


firmed the ON--NO2 structure. The deep blue liquid, pure only near its freezing point, dissociates at higher temperatures thus:

N203 ~ NO+NO2 2NO2 ~ N204

The pure compound, N203, displays two 14N resonances, the nitro one at 165 ppm and the nitroso at - 7 0 ppm (relative to NOT). N20~ displayed one line at +243 ppm. The nitroso shift in N203 was more akin to C- rather than N-nitroso compounds. The coincidence of their deep blue colours and their comparable shifts was explained in terms of a small value of AE.

An early study ce) of N205 revealed a single 14N resonance in CC14 solution, indicating a symmetric structure. In HNO3 dissociation into the species NO2 + and NO~ was known to take place but only one line was observed at a position which corresponded to the mean for the species NO~, NO~ and HNO3. Fast exchange was postulated to explain this result but further studies with more modern equipment would seem to be justified. (See alsoCS~).

Tautomerism is an important subject in the chemistry of heterocyclic compounds of nitrogen. The nitrogen shift in ~- and y-hydroxypyridines was found to be approximately 100 ppm to high field of that in the fl-hydroxy compound and indeed of pyridine compounds in general.~ TM The shifts of the • and 7 compounds were rationalized in terms of the predominance of the amido tautomer. The shift to high field seems analogous to that found on protonation of pyridine. Later studies by double resonance methods ~Tx~ on 2-hydroxyquinoline, in which the proton spectrum has a very broad NH feature, indicated that the material existed predominantly in the amido form with a characteristic nitrogen shift value. In the case of 8-hydroxyquinoline no such broad feature was observed and the nitrogen chemical shift, determined by decoupling effects on the • proton resonance, was in the normal range for a pyridine-type situation. Similar studies were made on some benzthiazoles: 69)

Double resonance studies on N2F2 proved that the two forms were each 1,2 isomers. Cx°7~ The trans isomer has a shift 62 ppm to low field of that of the cis. This dependence on stereochemistry has been observed in amides, c35~ The proton spectra of N-methylformamide-15N (NMF) and N-isopropylformamide -~ 5N (NIF) indicate the presence of cis and trans isomers where the stereochemistry is defined by reference to the formyl and NH protons. Double resonance studies of solutions in CDC13 showed that the cis isomer resonated at lower field than the trans, 2.23 + 0.06 ppm for NMF and 1.60 _+ 0.8 ppm for NIF. These differences are small, but when more data are collected, the technique may be a useful diagnostic tool.

Nitrogen chemical shifts in systems of biological interest may prove ex- tremely useful. Roberts in his study of pyrimidines ~x~ was able only to observe the ~sN resonance of 2,4-dichloropyrimidine on account of solubility prob-

142 E. W . R A N D A L L AND D. G. GILLIES

I e'ms. Much coupling constant information was gained from the proton spectra (see section 2.2). Nitrogen shifts could have been obtained by double resonance, although with the latest DFS spectrometer (see section 2.2) the direct nitrogen spectra may be observable. The 15 N spectrum of adenosine triphosphate (ATP) enriched in 15N to 70~o at all nitrogen positions has been observed using the CAT technique. (l°s~ Five well-separated nitrogen resonances were observed and assigned. Intermolecular effects in biological systems are discussed in section 3.1.3.2.

The application of nitrogen shifts in inorganic chemistry is rather sparse but further applications should be very fruitful. In thiocyanate complexes it was observed that there was no appreciable nitrogen shift relative to thiocyanate ion if the complex was bonded through the sulphur? 1°9J Bonding through nitrogen, however, produced a significant shift to high field.t

3.1.3.2. Intermolecular effects. Shifts to low feld of the proton resonance in chloroform in solutions of nitrogen bases have been observed. (m~ These were ascribed to hydrogen bond formation. One might expect a simultaneous nitrogen shift and indeed this has been observed in the pyridine/methanol system where an apparent shift of 9+ 3 ppm shift to high field was reported, nm The situation occurred at 0.5 molar concentration and coincided with the maximum shift to low field of the hydroxyl proton. Later work, using .an internal reference technique, indicated that I#N shifts of pyddine in organic solvents capable of hydrogen bonding were hardly outside the experimental error.(~5) The referencing technique was not specified in the earlier paper.

Loewenstein and Margalit m2~ studied the positions and line widths of 1H, t3C and ~*N resonances in CH3NC and CH3CN. The study of all the nuclei involved in intermolecular interactions provides useful additional information. Thus the nitrogen shift in the isonitrile and the carbon shift in the nitrile were found to be insensitive to dilution with polar or non- polar solvents. The shift of the terminal atom, whether carbon or nitrogen, was solvent sensitive. In the nitrite the presence of hydrogen bonding solvents produced a shift to high field, water the largest at ,--,6 ppm. Shifts to low field in CC1, and C~H6 were ascribed to solvent effects not related to hydrogen bonding. Similar shifts to high field were observed for the 13C resonance in CH3N~3C. Enthalpy data was obtained for the interaction of CH3OH with CH3NC and CH2CN from the OH shift data. Unfortunately the lack of sensitivity precluded the use of ~3C shift data and the small shift range the use of ~*N data. An external reference was employed for the t*N work and no susceptibility corrections were made.

Witanowski, (m) however, in his consideration of nitromethane as an internal reference (see section 3.1.1) found no shift change in CH3CN under several conditions which included the addition of water.

I" For other ligands, NH3, NO2- , -NO + and CN, see Bram/ey et al. (2m For pyridine and boron halides see Mooney et al. (2~)


Recently Price {s6) has found a shift of 2 ppm to high field of the nitrogen shift in CH~NC on dilution with TMS. The double resonance technique enabled the use of TMS as the internal reference. In the light of these dis- crepancies it is felt that the use of an internal proton reference for the study of nitrogen spectra will greatly facilitate the measurement of small solvent dependent shifts.

The nitrogen shift in N-methyl acetamide was observed to move 2 ppm to high field on dilution in CDCI3 over a 6-35 ~o w/v range, (6s) but this was only of the order of the error in the experiment. No significant change was observed with other amides and it was concluded that amide shifts were largely indepen- dent of concentration and solvent. This view was supported by other work on dimethylformamide.(~5' m)

However, a shift to low field was observed in the N-methylformamide- ~SN/water system as the water concentration was increased. (St) The shift is 2.6 ppm between the neat amide and a 25 ~ by weight solution in water. A stabilization of the planar resonance structure (III)

- O \ +/CH,(~,) . ~N .

H(1) / \H(3) III

had been postulated previously to explain the increase in the proton coupling Jla on dilution with water, m4) The shift to low field of 8 ppm on protonation of N,N-dimethylformamide {~5) which yields IV

HO\ +/CH, /C.-----N\

H CH3 IV

lends added support to the increased importance of structure HI as the dilution in water is increased.J"

15N spectroscopy has been used to study the interaction of 15N-labelled adenosine triphosphate (ATP) with Mg 2+ and Zn 2+ ions. (l°s) The ions were added in amounts necessary to produce equal metal ion and ATP concentrations and the pH adjusted to approximately 9"5. Chemical shifts did not change noticeably over the pH range 7.0 to 9.6 nor on addition of Mg 2+. Addition of Zn 2+, however, did produce effects, the largest of which was a 5.5 ppm shift to low field. The conclusion was that Mg 2+ does not interact with ATP whereas Zn 2+ does. This argument is perhaps a little facile, especially

t An interesting study of solvent and concentration effects on the N shift in 15NHa has been made. (21°


as Mg 2+ is important to the functioning of ATP. For instance, the strong charge transfer interaction between pyridine and iodine appears to produce no change in the nitrogen shift. (m)

Hunter (m) has studied the nitrogen spectrum of ethylenediaminetetraacetic acid -15N (EDTA) (V) as a function

HO2CCH2 CH2CO2H "",,s NCH,CH ,SN(

HO=CCH/ \CH,CO2H V

of complexing with metal ions. First, the pH dependence of the shift was measured since complexing with EDTA is very pH dependent. A shift to low field of approximately 17 ppm was observed on reducing the pH from 14 to 4. Metal ions were then added to solutions of EDTA with N(CH3)~ whose pH was I 1 "8.

Shifts both to high and low fields were observed, e.g. addition of Ba 2+ at concentration of 1.0 M produced a shift of ,~10 ppm to low field whereas similar addition of Li + produced a shift of ~4.5 ppm to high fields. Mg z+ and Cs + produced only very small shifts (0.0 and 0.1 ppm respectively). This could indicate no complexing for Mg 2+ and Cs + (cf. reference 108); this was thought to be surprising for Mg z+ but reasonable for Cs +. It was observed, however, that addition of metal ions may alter the pH of the solution. In particular addition of 1 M Mg 2÷ changed the pH from 11.8 to 9.5 whereas addition of Cs + changed the pH to I 1.3. Thus the inherent effect of the Mg 2+ addition happens to be equal and opposite to the pH effect, i.e. a shift to high field of 1.6 ppm. In the case of Cs +, there being little pH change, the nitrogen shift is unaffected and the implication that there is no complexing does not seem unreasonable.

An interesting technique which may become of particular importance in biochemical studies is the use of I~N as a "tracer". This technique has been used in the study of the possibility of isotope rearrangement (Via = VIb) during the generation or reactions of phenyldiazonium ion.(X~e)

(C6H,~N---- N)+ ~ (C6HgN------" N)+ Via VIb

Thus phenyldiazonium chloride was prepared from aniline - t SN by diazotiza- tion with unlabelled sodium nitrite. Various reactions were carried out by which the fragment VIIa or VIIb might be produced depending on the occurrence of rearrangement.

C e l l s ' s N H - - N - ~ - ~ C , H s N H - - ~ N - ~ ~

VlIa VIIb


By examination and integration of the proton spectra the abundance of tsN in the products were compared with the original abundance in aniline-~SN. It was found that there was no change in abundance indicating no randomization. Some earlier work on hydrolysis of diazonium fiuoroborate Itx7) was repeated and again no randomization was found, disagreeing with the figure reported earlier of 2-3 ~ randomization.l"

The nitrogen shift of disodium tetrathiocyanatocadmium in water differs by 42 ppm from that in methanol, a fact which was attributed to the presence of both N- and S-bonded species in kinetic equilibrium3 a°9) Similarly averag- ing of N shifts in the ~SNHz, 15NH+4 system is reported. (~m

3.1.4. Paramagnetic compounds

Loewenstein et aL (xzs-xzl} have studied the 14N and laC resonances in both paramaguetic and diamagnetic cyanometal complexes. In the case of potassium ferrieyanide, K3Fe(CN)6 (paramagnetic), the a4N resonance is shifted 724 ppm to lower field and the x3C resonance 3492 ppm to higher field relative to the diamagnetic potassium ferrocyanide K4Fe(CN)6. These shifts arise either from the presence of electron spin density at the nuclei or because of g-tensor anisotropy.CX2~) The former mechanism was preferred and the signs and magnitudes of the hyperfine coupling constants were deduced. The shifts showed the expected linear dependence on the inverse of the absolute temperature. By consideration of data from other cyano-metal complexes a correlation between the a4N contact shift and the inverse of the lowest optical t2a ~ e 0 transitions was found.

Solutions containing both ferri- and ferrocyanide ions display a single peak, intermediate in position between the resonances of each constituent indicating the presence of a fast exchange process. This enabled data on the kinetics of the exchange to be measured.

The absence of a contact shift for the cyano resonance in Cr(CN)sNO 2- indicated that the odd electron was located to a greater extent on the NO than on the CN group,C2s) a fact confirmed by the ESR spectrum.(X2s)

In their study of the sodium-ammonia system Acrivos and Pitzer (u) observed Knight shifts of both the 23Na and the ~ aN resonances. The electron density at the sodium atom was 9 ~ of the free atom value at high sodium concentrations but fell, on dilution, to 0.13 Yo. There was a parallel increase in the electron density at the ~'~N nucleus. These results dearly indicated that withincreasing dilution the electrons increasingly occupied expanded orbitals in the dielectric medium. A theoretical model involving the Na- 6NH3 species yielded electron densities too high by an order of magnitude. Other models produced more plausible values but it was felt that more refined wavefunctions

The earlier work is proving hardier than expected, however, since application of the new technique by old hands supports the idea of a small randomization. (sin

146 E.W. RANDALL AND D. G. GILLIES

were required to determine the extension of the expanded orbitals in the dielectric medium. Studies over the temperature range - 3 3 ° to +22°C furnished kinetic data.

Recent studies (xu~ of solutions containing tetrabutyl-ammonium ion and paramagnetic ions such as Fe(CN)~- revealed a shift to low field for the nitrogen resonance which decreased on dilution. Again an explanation in terms of a contact shift mechanism was preferred rather than one involving g tensor anisotropy. The decreasing shift on dilution was ascribed to decreasing association.

3.2. Coupling Constants

3.2.1. Signs of N coupling constants

The usual convention for signs of couplings is that a positive sign denotes a stabilization of antiparallel spin states. The consequence of this definition is that isotopic substitution of tSN for I*N changes the sign of the coupling simply because 15 7, being negative, is opposite in sign to 14~. This consideration may be eliminated by the use of the reduced coupling constant, K~m, defined by

Yam- K ~ 27t

Pople and Sax~try have calculated that the reduced couplings for N--H, N--B, N - - N should all be positive whereas K(N--F) should be negative.tsg)J "

Several investigations of the relative signs of coupling constants in tSN substituted formamides have been performed using analytical single resonance, proton-proton, and proton-' sN double resonance techniques. (2e-Ss' 114) The results are shown in Fig. l l in which the one-bond reduced coupling K(N--H) has been given a positive sign as required by theory. The two-bond N - - C - - H coupling through the sp a hybridized carbon is negative in contrast to the positive coupling through the formyl (sp 2) carbon., With the above sign convention the vicinal H - - H coupling is found to be positive as for H- -C- - -C~H systems.(~s)

The signs of couplings relative to an assumed positive one-bond 13C--H reduced coupling, tK(t3C--H), in methyl-, ethyl- and t-butyl isocyanide and tetraethylammonium ion are now known. (T4' ~, 1~5) The combined results are shown in Fig. 12.

By heteronuclear double resonance experiments on the trimethylvinyl- ammonium ion cTv~ it has been shown that all three N ~ H couplings (one two-bond, two three-bond) have the same sign which was the same as for all the H ~ H couplings except the geminal H - - H coupling which is negative, c218)

J" See also reference 217. ~. A positive coupling through the sp 2 carbon of vinyl isocyanide has also been

reported, m.)


0 H(2)

c- '~N / \

H(I) H(3)

0 Me (2)

\ H(I) H,31

0 Me (2) ~ c %/ \

HU) Me(3)

K N[ + K t2 +

KN2+ KI3 +

KN3 "F K23 +

KNt + K Jz --

KN2 -- "Kt3 +

KN~' + K23 +

I KN I -J- K m -- [

KN2 -- Ki3

KN3 Kz3 0

° " / I ~C.. K Ni 4-

~H(3) KN3 + H{I)

cis

0% .,, ,5 S,2, \ ] C KNt +

\ .L K NZ + trans

FIG. 11. The signs of reduced coupling constants in various substituted formamides.

1 K ( N - - z a C ) 2 K ( N - - H )

C H s N C + - C H s C H 2 N C - + ( C H s ) s C N C + ( C H s C H 2 ) 4 N + O H - +

Fro. 12. Signs of reduced couplings deduced from double resonance experiments on several ~4N-containing molecules.

3 K ( N - - H )

One mos t in teres t ing resul t is the oppos i te signs for the two N - - H coupl ings in f o r m a l d o x i m e and the p r o t o n a t e d derivat ive. (12e)

1" Now also related by heteronuclcar double resonance to the gcminal H- -H coupling. (==)

148 E. W. R A N D A L L A N D D. G. G I L L I E S

For quinoline-XSN the assumed and deduced relative signs azT) have been confirmed by heteronuclear tickling experiments :(3e) the reduced ~ 5N--H and H--H couplings all have the same sign.'~ The same relations have been established for pyridineJSN and the pyridinium-~SN ion by analogy. ~86)

3.2.2. One-bond N - - - H coupling constants

In recent years many investigators have used or tested the hypothesis that a one-bond coupling between two nuclei depends upon the structure at each atom (usually expressed in a hybridization approach). The theory of nuclear spin-spin coupling as developed by Ramsey and others azs-az) evaluates the coupling constant as the sum of three terms: (i) the Fermi contact term, (ii) the electron dipole-nuclear dipole interaction and (iii) the interaction between the nuclear spin and electron orbital motions. It is recognized that the Fermi contact term usually dominates. The contribution of this term to the coupling, J12, is proportional to the product of the s-electron densities ($1 and $2) at the respective nuclei (1 and 2) of the orbitals forming the bond:

$1 $2 J l z oc A E

where AE is the mean excitation energy. Most investigations have been concerned with 1H because for this case the

usual assumption that the hybridization at the hydrogen atom remains constant, i.e. there is no change in the angular portion of the hydrogen wave function from one case to another, makes the task easier. Furthermore, it is usuaUy implicitly assumed that the radial part of the wave function does not change either. In these circumstances attention is focused on the hybridization at the second nuclear centre, X. The general approach is to measure X--H couplings in a variety of molecules, to ascribe s characters to the hybrid orbitals of X which are involved in the bonding. A plot of the coupling against the s characters is expected to be linear in this approach if (i) the angular portion of the wave function for X is known reasonably, (ii) the excitation energy AE does not change appreciably, (iii) the radial portion of the hydrogen ls wave function does not alter, (iv) the radial portion of the wave function for the hybrid orbital X is unchanged.

The nucleus most extensively investigated in this way has been 13C bonded to ~H. The compounds originally studied differed markedly in hybridization from the so-called sp 3 to sp 2 and sp. a32-3)

It was found that ~ j(13C__H) could be approximately expressed by

iJ(z3C__H) = a2Jo

I" Also studied by D. Crepaux et al. (22°)

N I T R O G E N N U C L E A R M A G N E T I C RESO N A N CE 149

where Jo is 500 Hz, and a is the coefficient of the carbon 2s wave function (~/~) in the LCAO description of the hybrid orbital:

and ~,p is the wave function for a carbon 2p orbital. Here the s characters in each sp hybrid are considered to be the same irrespective of the non-equiva- lence of the groups attached to the carbon. This factor has been discussed in connection with substiment effects on lY(lsC--H). For methanes this substituent effect has been evaluated empirically by Malinowski, cls~ who propounded an additivity relation, which was rationalized by Juan and Gutowsky c135-e) in terms of the Fermi contact term by allowing uneven distribution of s character in the four bonds of tetrahedraliy bound carbon. This approach has been adopted for other pairs of nuclei also, for example 119Sn--H'XST-8~ and 31P--H.C~89} The validity of the additivity relationship has not gone unchallenged. {~4°-~ The discussion was extended to the sp 2

hybridized cases of substituted formamides, both by Muller {14z~ and by Malinowski, {~4"~ and to substituted benzenes, pyridines, and pyrimidines and other heterocyclic molecules.'~44~

The possibility of using coupling constant measurements to determine structure is so attractive that many of the difficulties in the approacl~ have been brushed aside. Thus inconsistencies between this approach and the s characters deduced by hybridization theory from structural data have been attributed to the assumption that inter-orbital and internuclear angles are equal, rather than to the approximations in the treatment of the coupling constant.

Recently the importance of the radial portion of the wave function ~145) has been restated by Grant and Litchman who have calculated considerable changes in ~ J (13C_H) for tetrahedral carbon as the effective nuclear charge on carbon changes, cx4e) Certainly there would appear to be no other explanation for the increased coupling for substituted benzenes with a large amount of electron withdrawal. Thus 1,3,5-trinitrobenzene gives the large value of 179.5Hz for J(13C--H),C147~ and benzene chromium triearbonyl gives 173 _+ 1 Hz ~l~s) compared to the value of 159 Hz for benzene, cxss)

The situation for the important case of the one-bond N - - H coupling in terms of the structure at the nitrogen atom has been considered by two groups. It should be stressed that although discussion of the problem has been in terms of the concept of hybridization, the basic search for the relation of J (N--H) to structure does not depend on the validity of that concept, hybridization theory provides merely the language and is dispensible. An alternative approach is to describe the structural situation in terms of the number of groups bonded to nitrogen and the spatial situation of the lone pair.


The two groups each set up a hypothetical relation between s character and tJ(N--H).txT.2m They chose slightly different compounds and there were minor differences in the assumptions used. Other compounds were then tested against this relation. Professor Roberts' group used N H + for the sp a

system and ( C 6 H s ) 2 ~ N + H 2 for the sp 2 system. They deduced that the percentage s character is given by

100a 2 = 0.431 j(1SN__H) _ 6. Cl)

The British group used the origin of the plot of J against a 2 as a fixed point in addition to the obvious sp 3 case of NH~. NH3 was included since it had the merit that all three groups bonded to nitrogen were the same, so that the problem of unequal distribution of s character between the hybrid orbitals engaged in a-bonding did not arise. This approach, however, meant accepting the calculations of a S in terms of the known bond angles of ammonia. ~x3m It should be mentioned here that the inversion of ammonia is anticipated not to affect the coupling because the minima in the potential energy function correspond to the two pyramidal forms characterized by the above angles and all other configurations are presumably at best activated transition states. The resultant expression

s = 0.34 tJ(~SN--H) (2)

differs very little from equation (1). If the pyridinium ion is planar with bond angles at nitrogen of 120 °, i.e. if

the s characters in each of the two N - - C bonds are equal to the s character in the N - - H bond, then a 2 is expected to be 0-33 (s = 33 70). The measured value of 1J(I+N--H) for this ion is approximately 70 Hz, ~47> from which xJ(~SN--H) is calculated to be 99 Hz. Use of either equations (1) or (2) gives a 2 ~ 0.33.

For formamide the framework has been shown to be almost planar and the three nitrogen bond angles are nearly equal, Its9> hence a 2 should be slightly less than 0.33. A large number of values for ~J(15N--H) in the formamide series is known: formamide, (2s. ~6> the cis- and t rans - i somers of N-phenylformamide,~7> N_methylformamide~S. am and N-isopropylformamide <~ and N-n-butylformamide.C15°~ They correspond to a range

a 2 = 0"300-2_ 0"015 (3)

in reasonable accord with the hypothesis. The substituent effect upon t J (N- - H) in these compounds appears to be less than 2 Hz. A more important consideration is the orientation of the N - - H bond. Invariably the bond cis to


the carbonyl group has the smaller coupling constant. For formamide this is the longer of the two N--H bonds and hence presumably has the smaller s character.Ces) A similar situation occurs in acetamide for the two N--H bonds: the higher coupling occurs for the NH t rans to the carbonyl group.(~)

J Other cases involving the grouping ~ C - - N H - - o r the thio analogue

have been reported; phthalimide, C~HsNHCOCH3, CH3CONHCHzCO~H, NH2CONHCONH2 (terminal hydrogens), NH2CONH~, (iv) and C~HsNHCONHC~Hs and C6HsNHCSNHC~Hs. clsl) In each case the a j(1SN__H) value falls in the range 88----94 Hz.

The important and striking case of the nitrilium ions has been reported recently. (82) These ions arc expected to be linear (a 2 ~ 0"5) and to have large one-bond couplings. For protonated HCN, 1J(~SN--H) was 134 Hz and the value deduced from equation (1) for a t is 0.52. The figures for protonated methyl cyanide arc 136 Hz and 0.53. These are the largest ~SN--H couplings known. Protonated propionitrile has also been reported, c~55)

Two apparently anomalous cases have been reported for which the s characters are deduced to be unacceptably low. For pyrrole the early coupling data obtained by a high temperature study in the ~4N compound gives s ,~ 25 ~o czS' x52) whereas the structural data ~asS-4) lead to a deduced value of nearly 50 ~o. The latest results, however, obtained by spectrum accumulation give a revised coupling of about 100 Hz for the ~SN~H satellites in natural abundance, c~°~) so that the anomaly is thus largelyremoved.'~ The second case involves diphenylketimine [IJ~5(N~H) = 51.2Hz] with an expected valueof 33% and a deduced value of 16%. (m One suggestion for the discrepancy involves consideration of an orbital contribution to the coupling.(~7) A second possibility, not discussed so far, is that the coupling is averaged over two sites (see section 3.2.6) as for the Schiffs' bases. ~ ' 4~) This would require a mechanism additional to that used to explain the collapse of the spin multiplet.Cx~)

There is a third anomalous case which this time involves a high coupling value. The reported value of J(~SN~H) for cyanamide is 89-4+ 1.0Hz c~) which would indicate a nearly planar molecule. The most recent microwave spectroscopic work, however, indicates a pyramidal situation at nitrogen c~) of about the same extent as in aniline in contrast with the first reports. (z~v~ The enhanced non-planarity of nitramide compared with formamide and cyanamide makes it a strong candidate for ~SN substitution and for a proton resonance study.

Attempts to argue from the magnitudes of observed N ~ H couplings to hybridizations and structures have been, or can here be, made in a number of other interesting cases. In uracil-~N~ (VIII) the two NH couplings were

~" A number of other groups have now reported values in excess of 90 Hz for ~ JQSN~H) in pyrroles. ( ~ - ~ )

154 e.w. RANDALL AND D. G. GILLIES

coupling, including N--H, should prove of considerable importance. The method is a finite perturbation variant of the molecular orbital approach. In the case of the 13C--H coupling not only is the observed trend reproduced as the number of groups bonded to carbon changes from four to two, but the theory also correctly predicts the substituent effect for a fixed number of bound groups. In thecaseof N--H the relation of coupling to geometryusing simple hybridization theory is verified by calculations on ammonia with various bond angles: a value of 42.7 Hz for a pyramidal situation is increased to 99.4 Hz for a hypothetical planar form. Additionally, the substantial difficulty on the simple hybridization scheme, for the ketimine situation is resolved. Calculations give lower couplings than for ammonia in agreement with experiment. The sequence NH +, NH2CHO, H---C-------N+--H is also verified and the methyl substituent increase of 2 Hz for j(1SN__H) in the latter reproduced. Similar treatment of I J(~ 3C--H) is reported: ~')

3.2.3. Two-bond N--H coupling constants

The most frequently reported fragment is N--C--H. Although a considerable number of magnitudes for such couplings, 2J(N--H), are known the scarcity of information on signs renders even empirical correlation difficult except for closely related groupings.

For the case of an sp 3 hybridized carbon (four-bonded groups) linked to a nitrogen with two, three or four atoms, the known couplings are all small, the largest value being 3-3 Hz in 13CH3XsNCS.(IT)

Published examples include the methyl cases: Me~6NH2, MeXSNH3CI, CeHsCH~SNMe, <tT~ XIV, XVI, XVII at low temperature, c~) Me2xSNCHO, (") MelsNHCHO <",aS~ and MeNC: 75> The sign of the reduced coupling in the last three cases is negative (section 3.2.1, and Figs. II and 12). A most interesting observation on the stereospecificity of the coupling has been made for the tetrahydro-l,3-oxazines. ~"x~ The ISN at position 3 is coupled to the equatorial proton at position 4 (1-5 Hz) but not to the axial protons at either 4 or 2. The coupling to the N-methyl protons was I- I Hz.

Enhanced values may occur if the carbon atom is attached to three groups. Thus the value of ~ 15 Hz is observed in substituted formamides-~SN("-")1 " and the value in pyridineJSN is 10-6Hz. <s4~ Similarly 2,4-dichloro- pyr/midine -~ SN 2 (XVIII) and 2,4-dimethoxypyrimidine -t SN 2 gave couplings between H(6) and XSN(x) of 12"5 and 12.2 Hz respectively:") It should be noted that the reduced coupling in formamides-XSN is positive (see section 3.2. I and Fig. 1 I). An interesting possibility is the use of these couplings to diagnose ~r-character in the C--N bond. One could on this basis contrast the small values of 3.6 Hz and 3-6 or 1-8 Hz for the H(e)--N<I) couplings in

3" The early values of 19 Hz or more<") for formamide-:SN are believed to be in error.(., , - )

NITROGEN NUCLEAR MAGNETIC RESONANCE

XIV

XV

O~-~N/CH3

155

xv, , XVII ~NCTCH~

Ct

uracil-lSN2 and l-methyl-4-methoxy-2-pyrimidine-15N2 respectively (=I) with those noted above, as evidence for the unimportance of canonical forms such as XIX. Similarly the absence c4z) of two-bond NmH coupling (except that involving the methyl group) in the spectra of N-methyl-2-hydroxy- l-naphthaidehydeimine-15N (XX and XXI) favours structure XX over XXI in agreement with the arguments based on the direct NmH coupling.

Some caution must be applied in using this approach, however, notably in the case where nitrogen has two neighbours and one lone pair. It has now been shown that small couplings for the syn system (XXII) may be obtained. Thus the value of 3.9 Hz for the A coupling in C6HsCHANCHs czv~ is very close to the 4-5 Hz measured for the syn configuration of XXIII. (ze=) These contrast

F*

156 E. W . R A N D A L L A N D D . G . G I L L I E S

XIX

XX

XXI

-0

o"

C.H3

0

0

XXI 1

XXtll CH\c= N

/ \ H ?--CH2 CH3

H

with the value of 14.5 Hz for the anti-form. (162~ Lehn and co-workers tles~ independently have pointed out the different behaviour of syn- and anti-form- in the case of lSN substituted oximes. Using ring compounds like 5-phenys- thiazole as models for the anti-forms they have demonstrated that the couplings are high. They have also shown most interestingly that the low and high couplings in formaldoxime are opposite in sign. ~1s4,218~

It is of interest to note that the small reduced couplings for the bonding situations XXIVA and XXIYB

XXIVA XXIVB


are of the same absolute sign (negative), and that the absolute signs of the (large) couplings for the situations XXIVC and XXIVD

S - \ / = % XXlVc XXlVo

are each positive. (~as) Only two cases involving higher C- -N bond orders are known, namely

hydrogen cyanide-~SN (1~) and its protonated derivative (s~) where the values are 8.7 Hz and 19.0 Hz respectively.

3.2.4. Other N - - H coupling constantst

Couplings through threa bonds, N - - C - - C - - H , have bean reported for a number of cases, the first being the isonitriles, t-butyl and isopropyl. The long-range coupling for I"N was found to be greater (2"6 versus 1.8 Hz) and of opposite sign to the short-range coupling. (4e.v4.75) For the tetraethylammonium ion the value was 1.7 Hz compared with a two-bond coupling which could not be.resolved. T M As the ethyl groups are successively replaced .by methyl groups thethrea-bond couplingincreases, c~7°--~) a behaviour which may be rationalized in terms of the Fermi contact mechanism and the subsfituent effect on the s character in the nitrogen orbitals, ar~)

An extensive study of the N - - C - - C ~ H coupling in acyclic and cyclic quaternary ammonium iodides has been made by Gassmann and Heckert. (2~°)

Presence of some double bond character in the N---C bond has little effect on the coupling which remains small. Thus in acctamide-~SN the fragment XXV gives a coupling of 1 "3 Hz ¢I~' ~) and in acctanilide-lSN either 0"7 Hz (~)

X'XV c4C.-~.N

or 1.3 Hz. (~) Not very different values are obtained in ~mLroa~ne-l-~SN and other p-substituted anflines-~SN for the ortho protons ;(~) methyl cyanide, CH3ClSN;¢Iv, 1as) in XVIII and related compounds; (m) and in the syn form of XXIII. For the anti-form of XXHI the coupling is increased to 5.1 Hz, (les) whereas in pyridine-lSN it is 1.6 Hz: ~) Two interesting tauto- meric pairs (XXVI and XXVII) where R is phenyl and isopropyl are reported. (z~s) The couplings increase from 2.18 and 2-77 Hz for the keto forms to 3.91 and 4.27 Hz for the enols, respectively.

? New references in this area are 220 and 22~-229.


Even if the C ~ N bond is formally of the triple type the coupling remains small: the values reported for methyl cyanide - t SN and its protonated derivative are 1.8 Hz and 2.8 Hz respectively. ~s2)

XXVI ( ; H ~ - - R XXVl I H

0 H..,.O..y,.:C __ R

The system N ~ N ~ C ~ H also gives couplings in the range 2--4 Hz. (xe=) The case of dimethylnitramine is interesting: the long-range nature of the 1.7 Hz coupling was demonstrated by a double resonance decoupling experiment which not only confirmed that the coupling was due to t*N, but identi- fied the particular t a n as the nitro one from the shift. (72)

3.2.5. Other one-bond nitrogen coupling constants

A number of directly bonded t aC t 5 N couplings have been observed, and have been discussed in terms of the product of the s-characters of the carbon and nitrogen orbitals forming the tr-bond. (17) The correlation is not so appro- priate as for the tSN--~H case. It was noted that the exceptions (C6HsCHlSNIaCHa, C6HstaCHNCHa, CHataCISN)were typified by low tSN shifts, which was taken to indicate large orbital contributions. So far no attempt to employ Frei and Bernstein's modified s characters (which utilized ~aC--H couplings to gauge s characters in C--C bonds in xaC--laC--H systems) has been made. ~aTa)

The ~sN---tSN coupling in trans-azoxybenzene-tSN is 13.7+0.8 Hz. (xT} One ~gsPt--t*N coupling of 4.30Hz is reported. ~a09) One-bond ~*N--F couplings of 328, ,-~232,155, 145 and 136 Hzare reported

respectively for N2F +, NF, +, NFa, trans-N2F2 and cis-N2F2. (I°~, 2a6-~ss) For the last pair the two-bond t*N--N--F couplings are 37 and 73 Hz respectively and of opposite sign to the one-bond coupling. (*°7~

3.2.6. Exchange, solvent and pH effects on nitrogen coupling constantst

3.2.6.1. One.bond coupling constants. In the very interesting studies of ~SN-substituted Schiff's bases ~J(tSN--H) is apparently smaU, and the explanation offered is that the coupling is averaged over two sites: one for which 1J(I~N--H) is approximately 90Hz and a second for which ~J(tSN--H) is zero. t41.4~) Thus for N-methyl-l-hydroxy-2-acetonaphthone imineJSN (XIV) 1J ( lSN- -H)= 79.1Hz at 30 ° in deuterochloroform

t A n u m b e r of studies of tau tomer ic exchange in var ious sys tems has now appeared, (~3°-~34) as well as studies o f pro tonat ion . (xsS, 2,o. 2as)


solution, and the presence of 10~o of the tautomer (XV) was suggested. (~) For the N-phenyl case in deuterochloroform the value is down to 33 Hz, and is even lower (12 Hz) in carbon tetrachloride. (42) Similarly for N-methyl- and N-phenyl-2-hydroxyl-l-naphthaldehydeimine-lSN (XX and XXI) values of 64.5 t-Iz and 27.5 Hz have been reported. (41" 4z) Other Schiff's bases exhibit higher couplings: the adduct of methylamine-lSN and 2-acetyldimedone (XVI) gives J ( lSN- -H)= 88"1 Hz and 2-(N-methylamino-)-5,5-dimethyl- 2-cyclohexene-l-one-lSN (XVII) gives 94-3 Hz. (~) All these values as well as some zero couplings (~a) are rationalized according to the balance of a keto- enol tautomerism, and the results have been correlated with ultraviolet spectral data.t

The explanations require that the exchange is intramolecular with preserva- tion of spin correlation between the nitrogen and proton during the motion. A much more onerous (and implicit) assumption is that the coupling through the hydrogen bond between nitrogen and hydrogen is zero. This would seem to be substantiated by the observation of zero coupling for cases where the enol form is strongly favoured, and for which hydrogen bonding occurs. This then constitutes a most important, but so far unmarked, deduction for the theory of the hydrogen bond. The argument requires no spin correlation through the bond--hence the bond is not covalent in character.

A pronounced solvent effect upon the 1SN--H coupling in aniline -x 5N was discovered by Becker: ¢1~4) the values varied from 78.0 Hz in deuterochioroform, eyclohexane-d12 or carbon tetrachioride to 81-4Hz in pyridine, 82.1 Hz in acetone and to 82.3 Hz in either dimethylformamide or dimethyl- sulphoxide.

For the two solvents deuterochioroform and acetone this effect has been generalized by Bramwell (s~) to include some substituted anilines (see Fig. 13). The difference in coupling for p-nitroaniline-l-:SN between the two solvents is approximately 10 Hz.~: If the structure-coupling relation is applied to these eases, one deduces that large structural changes in the NH2 group are caused by the solvent for acceptor substituents. The sign of the coupling change can be rationalized from the Lewis acid character of deuterochioroform. Inter- action with this solvent should cause a decrease in the coupling for the substituted aniline towards the small value (ss) for the anilinium ion which has been found to be 75 Hz.

One may then rationalize the small change in the case of donor substituents in terms of the substituent effect, which ensures an approximately sp s

situation at nitrogen even in basic solvents. So far studies of the concentration dependence of the solvent effect and

discussions of the longer range couplings have not been reported. These would

"~ Some similarly elegant work on the N - - H . - . N system has been reported. (z~-~x) Perhaps only 3 Hz. (~99) The discrepancy is being investigated.


I, 3 , 5 - t r i b r o m o - ~ . ~ ' I " ~" 5 , 5 - d i b r o m o , _ . ~ - - !

. -- p-bromo / 1 =. I \ . z I

X

70 -- o in acetone

÷ CDCL 3

! I I t I 1 -0 .6 -0 .4 -0,?. 0.2 0.4 0"6

O"

FIO. 13. Graph showing the relationship betw~n the directly boilded coupling JssNs in anilines-tSN and the Hammett factor

for changes in solvent and substituent.Os, tgs)

obviously be valuable for determining the nature of the solvatcd species and the various equilibria which may be present in the solution. One difficulty is that the obvious experiment for determining the relation between 1J(t 5N--H) and pH is not possible because spin correlation is not conserved. This difficulty should be absent for 2j(t 5N__H) ' however, as shown below for other systems.

Price (as) has found that 1J ( t*N--H) for NH + depends slightly upon pH in the range - 1.2 to + 1 "6 varying from 53.4 ( _+ 0.2) to 52.4 ( + 0.2) Hz.

3.2.6.2. Longer range z ~N--H coupling constants. In cases other than aniline the effects of solvent upon longer range couplings for nitrogen are known. These cases are the heterocyclic ring systems. The situation is exemplified by quinolinv-tSN and some of its derivatives. It has been shown that in acidic solvents 2 j ( lSN--H) is small (2.0 Hz in D2SO4) in contrast to values in more basic or aprotic solvents (1 l ' l Hz (1~7' 17~)) and that, moreover, inD20/dioxane the coupling varies from 3.0 Hz to 10.4 Hz as DC1 is added to increase the pH.(127)I" A decrease in 2J( tSN--H) for 5-phenylisothiazole from 14.2 Hz in deuterochloroform to 4-2 Hz in sulphuric acid has also been noted. (175)

fFor pyridine the change is from -10.6 Hz in the free base to -2.2 Hz in the pyridinium ion. (m


Presumably one is dealing in each of these cases with an equilibrium between free and complexed species having different J values but for which spin correlation is conserved during the forward and reverse reactions.

Quaternization or formation of the N-oxide similarly produces small values for 2J(15N--H). Involvement of the nitrogen lone pair in a-bonding thus appears to be of prime importance for 2j(15N__H): the nature of the bonded group and ~z-effects (which should be very different in the protonated species and the N-oxide) appear to be secondary.

It is interesting that these changes in coupling are probably not associated with structural changes in the c-framework (in hybridization language the angular parts of the nitrogen wave function are unchanged). One would therefore rationalize the changes in terms of the Fermi interaction by radial effects or by invoking an increase in AE.

The magnitude of the coupling 3 j(15N__H) has been shown to increase with protonation at nitrogen from: - 1.6 Hz to -4-3 Hz for pyridine; (Be) - 1.4 Hz to - 4 " 5 H z for quinoline; (1~7,1vs) and from - 5 - 0 H z t o - 6 . 0 H z for quinoline-l-oxidc. The coupling in the ethiodide is invariant to acid concentration. (12~)

3.3. Line Widths 3.3.1. Nitrogen-15 compounds

The relaxation time for 15N (like 13C) is apparently long so that the natural line width should be very small ( < 1 Hz) and may not in faetyet have been reached.

This fact coupled with the large spread of nitrogen shifts compared with those of hydrogen should render all nitrogen shift differences resolvable. Complications and larger line widths would obviously occur in a situation involving exchange of a nucleus coupled to 15N. No studies in this important area have been reported except for line widths of protons coupled to ~N.

3.3.2. Nitrogen-14 compounds Nitrogen-14 line widths are larger than those of nitrogen-15 because of the

contributions of electric quadrupole effects to the relaxation of the former. Compared with heavier quadrupolar nuclei, however, the quadrupole relaxation rates are small. This is not only because of the smaller quadrupole moment of 14N (7.1 x 10 -26 e xcm~), compared with say ~SAs (0.3x 10 -24 e xcm 2) or 121Sb ( - -0"53 X 10 -24 e xcm 2) from the same periodic group, but is doubtless partially due to the smaller Sternheimer factor.~e)

The relaxation characteristics of ~*N in a variety of diamagnetic compounds in the liquid phase have been measured by pulse methods which yield the spin-lattice relaxation time/'1 (~vv) and by measurements of 14N linewidths. ~u) The relaxation time T2 may be defined as the inverse of the width at half-height of the I'~N resonance.

162 ~. w . R A N D A L L AND D. G. GILLIES

For the case of extreme narrowing :( ~*s

1 1 = 3 i+~- re (4) T, T2 8

where, is the asymmetry factor of the field tensor, eqQ/h is the quadrupole coupling constant for I*N, and z¢ is the correlation time for the molecule.

An approximate expression for zc, derived from the Stokes' formula aTg~ is

V~ (5) ~ = k"~

where Vis the volume of the molecule assumed to be a sphere, r/is the viscosity of the solution, k is Bol~maml's constant, Tis the absolute temperature.

For a given quadrupole coupling, therefore, l*N lines may be narrowed (T2 increased) by lowering 1/and raising T.

Moniz and Gutowsky aTn employed microwave and pure quadrupole measurements in conjunction with 7"1 measurements to measure zc. For each of a number of these compounds Herbison-Evans and Richards obtained T2 and found it to be equal to/ '1 as expected, tz4~ The correlation times calculated from equation (5) were too long compared with the experimental results. Fiowever, linear plots of T~ t against viscosity were obtained. While this is an important empiricism, the use of the concept of viscosity, a bulk property, in explanations at the micromoleeular level is obviously intellec- tually unsatisfactory.

In their NMR studies of cyano-metal complexes, both diamagnetic and paramagnetic, Loewenstein, Shporer and Navon deduce that the line widths for t*N are governed mainly by the quadrupolar relaxation, even in the paramagneties where contributions due to electron-spin relaxation are possible.mS-2x~

3.3.3. Exchange effects'(

The analysis of line shapes for nitrogen coupled to an exchanging nucleus should prove to be a fascinating study. From the ~SN spectra the kinetics of the exchange at various temperatures could be calculated. Utilization of the X*N case under the same conditions would then allow the exchange effects to be factored out leaving the quadrupole effects alone. It might then be possible to determine whether the quadrupole relaxation is dependent upon the exchange. Although one would anticipate that this should be the case since the electric field gradient must change during the exchange, ~s°~ the effect has so far not been recognized.

t" The effect of exchange upon t4N line widths in nickel-ammine complexes in both pure liquid and aqueous ammonia has been studied, tm~


4. RESULTS FOR HYDROGEN

4.1. Chemical Shifts

4.1.1. Isotopic effects

The small effect of isotopic substitution of 15N for X4N upon an attached proton has not been studied extensively. Accurate measurements require a mixture of the isotopic species in the one solution so that as many conditions as possible, e.g. concentration, and temperature, are common to both species. Price ~3eJ has found that the effect in the ~4~r~+/,s~-T.T+ . . . . a J . . . . 4 s y s t e m i s l e s s than 0.1 Hz (one-bond effect). This may be contrasted with the two-bond isotope effect on the 59Co shift in K3Co(CN)6. A shift of 1.18+0-04ppm was produced by substitution of all six nitrogens-14, exs~

No effects on nuclei two bonds removed from nitrogen have been reported for other systems so far, although a two-bond deuterium effect on hydrogen has been reported for the series NH~, NH3D +, NH~D~ and NHD~ both in the ease of nitrogen-14 cve~ and nitrogen-15, c3e~

4.1.2. Other effects

The chemical shifts of protons bonded to nitrogen are very sensitive to conditions primarily because these protons are labile and readily undergo exchange and hy.drogen bonding. Ammonia and aniline, for example, are diffleult to dry to the extent that the 15N--H coupling may be discovered, and the ammonium and pyridinium ions each exchange protons readily, a process that is slowed down by large excess of acid. If exchange is rapid then the signal obtained is at the weighted mean of the characteristic shifts for the exchanging species. A change in the relative amounts of these species is reflected in the shift, provided of course that the characteristic shifts are different.

Hydrogen bonding can be regarded as a particular case of very rapid exchange, the equilibrium being between free and hydrogen-bound species. The mean shift, studied as a function of the relative concentrations of the two species, can give both the shift difference between the species (the association shift) and the equilibrium constant3 ls~ Association shifts may be large: for ethyl and diethylamine in carbon tetrachloride values of nearly 1 ppm were found as for ammonia and the association constants were found to be 2.5 x 10 -3 and 2.5 × 10 4 respectively, cls2> In order to make the analysis tract- able it is usually assumed that only one associated species is present. The nature of this species may then be determined; in the ethylamines it was tetrameric.

le, IiI

164 E . w . RANDALL AND D. G. GILLIES

• The case of self-association of pyrrole in cyclohexane was studied with the aid of H--{X*N} double resonance to sharpen the N--H signals. A cyclic dimer was favoured as the associated form. ¢a83~

Complex behaviour may cause difficulty in interpretation. Thus formamide even when isotopically substituted with tSN to give narrow proton lines is complicated since it can undergo both solute-solute and solute-solvent hydrogen bonding, proton exchange, rotation around the CwN bond, and inversion at the nitrogen atom. ~ee~ For N-monosubstituted formamides, e.g. phenylformamide, two rotamers are sometimes obtained which have different hydrogen-bonding potential. (~.st) Characteristic dilution curves in CDCIs are obtained depending on the orientation of the N--H bond with respect to the rest of the amide framework both for the cis- and trans-phenylformamide- tSNt~) as well as for formamideJ 5N, tat) and N-methylformamide-t 5Ntm and acetamideJ SN.~as)

4.2. Line Shapes and Exchange

4.2.1• H--tSN

The main agency governing proton line shapes for diamagnetic .ISN--H systems is exchange. Thus commercially produced aniline--lSN gives a single N--H line at 35°C about the same width as for aniline--t*N. If the sample is dried and cooled to - 77°C a doublet of line width 3 Hz is produced.

Other substituted anilines behave similarly (sS) although their susceptibility to exchange depends upon the substituent, p-Nitroaniline-1--1 SN, for example, gives a resolved doublet even with sufficient water present to give an observable NMR line. The main hindrance in these cases to definitive kinetic studies lies in the irreversibility of some of the effects and ageing of the samples, both presumably attributable to decomposition coupled with sensitivity to decomposition products.

An interesting study of diphenylketimineJSN (xg~ has shown that the exchange is bimolecular and between equivalent species--the collapsed line was apparently centred on the t SN--H doublet.

4.2.2. H--t*N

The line shapes for a proton attached to t*N as a function of the electric quadrupole relaxation of the latter have been considered in some detail. (xs4-5) The results are shown in Fig. 14. As the quadrupole relaxation rate increases, the outer components of the triplet broaden more than the central component.

Slow relaxation is attained by the use of solvents of low viscosity and by using high temperatures. (15~) Thus Roberts studied a variety of t4N---H


systems which gave unresolved lines at room temperature but which yielded approximate z 4 N _ H couplings at elevated temperatures.(X6~) t

The temperature behaviour in the region - 7 0 ° to + 35 ° of the proton spectrum of "super dry" Z*NH3 has been shown to quantitatively obey Pople's equation. (z84) Moreover, the coupling was shown to be temperature invariant. (is° Behaviour in acids has been studied: 16°

FIG. 14. Calculated line shapes (t") for a nucleus of spin quantum number of a half coupled to I*N as a function of

electric quadrupole relaxation.

For a compound containing two kinds of hydrogen each differently coupled to nitrogen, the proton line widths depend upon the couplings J(I*N--H). The larger this coupling the more likely it is to be fully resolved if the relaxation rate is slow. Conversely in the limit of quite fast relaxation the proton

1" See also references 226, 243 and 244.

166 E . w . RANDALL AND D. G. GILLIES

lin~ characterized by the larger coupling to nitrogen has the larger line width. This is illustrated in Fig. 15 for eis- and t rans- formani l ide- t*N. The

broad lines are associated with the protons directly bonded to nitrogen which arc characterized by large couplings as determined in the tSN isotopomers: 91.0 Hz for cis, 88-3 Hz for trans. I~7) The CH proton lines are narrower and

NH,r=ns NHcit ~ C Htra~¢ CHcls

cls 0% .,'/~

C~r~ / \ H(i) H(31

÷

H (z)

C ~ N / \ Hill

irons

B "

J,z =t1"0 Hz J,3=2'0 HZ I I J iz=l f 'OHz J13 = ?_.'0 Hz

FIG. 15. Proton magnetic resonance spectra at 60 MHz of the CH and NH regions of eis- and trans-formanilides.

have smaller couplings to nitrogen (approximately 15 Hz for each tSN isomer). A similar situation was found in N-methylformamide for which the proton line widths decrease in the sequence NH, CH, methyl for the t*N compound/TM and the corresponding ~SN--H couplings are roughly 93, lfi and 1 Hz. c28)

Similar differential effects between one- and two-bond couplings occur in CH3NH +.(m The nitrogen heterocycles provide examples for two and three bonds. The ~-protons (two bonds removed from ~4N) in pyridine, thiazole,(Z~, zs~-~) isothiazole<t~5, t91) and isoxazole ~5) are broadened relative to the 8- and other protons at about 30°C in the neat liquids or in aprotic low viscosity solvents.


The broadening agency was shown to be the 14N nucleus in the case of pyridine by a heteronuclear decoupling experiment which produced narrow lines for the ~-protons. (67) More recently it has been established from the proton spectrum for pyridine-XSN that JCSN--H~) is larger than the p- or 7- couplings. (34) The values are -I0.6, -1.6 and 0.13 Hz respectively. ~s°

The line narrowing may bc accomplished also by lowering the temperature to -40 °, (~Ts) by use of the viscous solvent triethyleneglycol, (z~5) and in aqueous solution.(192)

Similar line narrowing by one or all of these agencies has been demonstrated for thiazole, isothiazole and isoxazole for which details of the proton linewidths have been discussed in terms of the measured nitrogen-14 linewidths, and the relaxation times for the H~ protons. (z~s) The general conclusion is that the broadening of the proton lines is not caused by a shortening of the proton relaxation time through an ~H--~4N dipole-dipole interaction, but is owing to the incomplete "washing out" of the J(N--H) coupling for nitrogen relaxation rates obtained, as discussed above and illustrated in Fig. 15.

The solvent effects on the nitrogen relaxation which may be predicted from viscosity data were verified by measurement of the a4N linewidths. In each case the effect on the protons could then be accounted for.

The case of protonating "solvents" requires a consideration of the appro- priate N--H coupling in the protonated heterocycle. Since J(N--H~) is reduced in the protonated species the broadeni.ng of the ~-protons should be reduced relative to the neutral molecules. However, the nitrogen relaxation is also reduced because of a smaller field gradient which should broaden the ~-proton lines. The actual result derives from competition between these two effects. The correlation time is also important of course.

5. C O N C L U S I O N S

The long-standing interest in work on compounds containing 14N is expected to continue both through development of spectrometers which have increased sensitivity due to the employment of high magnetic fields, and through a more widespread adoption of the hetvronuclear double resonance technique. Care in calibration and an awareness of the importance of temperature and other solution characteristics should go a long way'in removing the stigma of inconsistency which has justifiably been levelled at 14N work. (~4) Investigators contemplating use of ~SN need no longer consider it "an expense of spirit in a waste of shame". Financially expensive it apparently is (XSNH4 + costs approximately U.S. $400 per gram of contained ~SN), but compared with capital investment in machines and manpower, outlay on lSN can be adequately justified provided investigations are carefully planned both

168 E. W. R A N D A L L A N D D. G. G I L L I E S

for synthetic and spectrometric procedures. In synthesis, a number of "dummy" runs on 14N isotopomers under exactly the same conditions of concentration and scale is usually advisable for the evolution of procedures for 15N.

We may confidently expect utilization of the 15 N isotope in high resolution studies on substituted pyridines and pyrroles. Projects on larger systems like the important case of porphyrin are now quite feasible as witnessed by the elegant work on pyrimidines and cytosines. (21. 4o) In the realm of inorganic chemistry, too, extensions of the work on compounds containing a bond between nitrogen-15 and an element in Group IV (~7. 39) will surely be made to include elements in other groups of the Periodic Table including the transition metal series which has proved of considerable interest in the problem of nitrogen fixation.


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chapter 3 nitrogen nuclear magnetic resonance

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