Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0295 335

of their basic NMR characteristics as well as those of the 13C isotope of the carbon atom, which is invariably one of the atoms normally attached to nitrogen in the compounds discussed in this book.

The main NMR interactions in solution of interest to chemists are the chemical shift relative to some stated standard υ , the indirect coupling constant J and the relaxation times: T1 (spin lattice); T2 (spin spin: related to the line width); and T1 , the relaxation time in the rotating frame. In the case of solids and oriented samples both the direct dipole dipole and the electric quadrupole interactions assume greater importance. We shall confine our attention in this chapter to diamagnetic compounds so that we may neglect nuclear interactions with electron spins.

The spin half nuclei 1H, 13C and 15N, in the absence of chemical exchange and in diamagnetic molecules, give spectra with very narrow lines which are easy to resolve especially at high magnetic fields at least for small molecules, but the low abundances of 13C and especially 15N lead to weak signals. This inherent low sensitivity can be overcome by pulse FT techniques and accumulation, or in some cases by indirect detection (the inverse mode) most commonly with 1H as the observed nucleide. In solution this requires

the presence of a J 1H 15N coupling.

Of the nuclei with I > 1/2, namely 2H I D 1 , 14N I D 1 and 17O I D 5/2 , the latter two give very large line widths, which can be hundreds or thousands of Hz, except in

TABLE 1. Magnetic properties of some nuclei

a Multiples of the nuclear magneton. bMultiples of barns (10 24 cm2).

cases of very high symmetry such as 14NH4C and 14NO3 , and C17O in metalocarbonyls (which are of no concern here). The exception is 2H, which because it has a relatively small quadrupole moment normally gives very narrow lines even though the local symmetry at the deuterium atom is invariably low.

There have been numerous books and reviews1 10 of the NMR behaviour for each of the nucleides of interest in his chapter. The work of Witanowski and coworkers1a is particularly useful since it has a relatively up-to-date compilation of data for the nitrogen isotopes, which are of prime concern here.

Also referenced are several books11 14 which deal with the phenomenon of NMR in general at a variety of levels.

A. Previous Volume

There was no special chapter devoted to NMR in the last edition in 1982, but such is the utility of the technique that many references were made to NMR studies in other chapters. Our main concern here will be work published after that date. Although commercial FT pulse spectrometers had been available for ten or more years, the techniques of spectroscopy in two frequency dimensions, 2D-NMR, were in their infancy11, whereas now they are almost commonplace.

Similarly, instruments operating at 11.7 T (500 MHz for protons) were then only just being introduced whereas now 14.1 T spectrometers (600 MHz) are widespread, those at 17.6 T (750 MHz) are available and the development of spectrometers operating at even higher frequencies is underway.

All these advances have resulted not only in increases in resolution but have also alleviated the detection problems to a considerable extent. As a result, the last decade has seen a dramatic growth in 15N- and 17O-NMR spectroscopy as a versatile method for studying molecular structure, both in isotropic (liquid) and anisotropic (solid) phases. Studies at a natural abundance level of the nucleides are now commonplace. The scope of chemical applications extends from inorganic, organometallic and organic chemistry to biochemistry and molecular biology, and includes the study of reactive intermediates, biopolymers and enzyme-inhibitor complexes.

B. Chemical Shifts

It is not our concern here to delve into the theory of chemical shifts, since most studies mentioned are essentially empirical in their approach and have aimed to correlate the measured shifts with electronic factors. The main fact, however, is that unlike proton shifts, the shifts for other nuclei are governed by the Van Vleck second-order paramagnetic term, which is not easy to handle since its magnitude depends not only on the ground electronic state but also on the manifold of excited states.

It is worth noting in passing that isotope effects on the shielding constants are negligible. The importance of this is that for each of the isotope pairs 1H, 2H and 14N, 15N the chemical shifts are the same. On the other hand, isotopic replacement of the atom bound to the centre being investigated, such as 15N in the isotopomeric pairs, R15N1H2 and R15N2H2, leads to small shifts in the 15N resonance. Normally the shift is linearly dependent on the number n of groups replaced, such as in the series [15N 1H n 2H 4 n]C for which the incremental shift is 0.30 š 0.01 ppm. A summary of shift ranges for the nitrogen shifts in the compounds of interest here is given in Table 2.

In the normal ‘average E approximation’ E is equated with the lowest energy (highest wavelength, max) transition in the UV region. If E is small, the effect is large and a shift to low field results. This is frequently referred to as a paramagnetic shift (even

TABLE 2. Approximate range of nitrogen chemical shifts in organic molecules with amino, nitro and nitroso groups

though the overall susceptibility is diamagnetic). The nucleus is said to be deshielded. Related terms are ‘diamagnetic shift’ and ‘more shielded nucleus’ and these signify a shift to higher field (lower frequency).

The bond order is also important and reference is frequently made accordingly to the ‘bond order term’. Shifts to low field occur as the bond order increases. The terms are not independent.

There are many instances of correlation between 1/max and the chemical shift for both the nitrogen nucleides and 17O as well as for 13C. It has been used as an aid for assignments.

Authors frequently resort to Valence Bond Theory and its picturesque canonical forms in discussions of results. Readers must make their own judgements on the utility of such approaches. In this chapter we merely report the views of the original authors.

C. Indirect Spin Spin Couplings

The couplings of main interest here are those between protons, 15N and 13C, since the remaining nucleides rarely give resolved couplings because they are quadrupolar.

Normally there is fast relaxation of the quadrupolar nucleus, and this leads to the decoupling of it from other spins.

The one-bond couplings, which are determined almost exclusively by the Fermi contact term, have been treated in some detail, and they have been used to good effect to reveal details of the structural situation particularly at the 15N centre, as discussed in Section V.

D. Effects of Exchange, Hydrogen Bonding and Protonation

The possibility of proton exchange involving the NH2 group is always present. It causes an averaging of both the 1H and 15N shifts, if the exchange is fast enough: otherwise there is line broadening in the slow exchange limit, and possibly a loss of signal, because of such broadening, at intermediate rates. Exchange effects on coupling constants depend upon whether the spins remain correlated during the exchange. If they do then the J values, like the shifts, are averaged over the values for the different sites. Otherwise, the spins become decoupled.

Hydrogen bonding presents a common complication for all the groups under consideration in this chapter. For each of the groups the presence of lone-pairs allows it to function as the donor group, but in addition the hydrogens of the NH2 group can function as acceptors. Consequently the NMR signals of each of the groups depend frequently on such details as the nature of the solvent and the concentration. The solvent pH is also critical. Firstly there is the question of exchange of the hydrogens of the NH2 group, which may be base catalysed. Secondly there is the possibility of protonation. Hydrogen bonding to a solvent may be regarded as incipient protonation as regards its effect on the chemical shift.

In the case of ionic species, which may be represented by the ammonium ion, the nitrogen chemical shift depends upon the nature of the counter ion as well as the concentration. Shifts as large as 6 ppm have been noted.

E. Relaxation Effects

Chemists pay much less attention to the NMR relaxation rates than to the coupling constants and chemical shifts. From the point of view of the NMR spectroscopist, however, the relaxation characteristics are far more basic, and may mean the difference between the observation or not of a signal. For the quadrupolar nucleides such as 14N the relaxation characteristics are dominated by the quadrupole relaxation. This is shown by the absence of any nuclear Overhauser effect for the 14N ammonium ion despite its high symmetry, which ensures that the quadrupole relaxation is minimized. Relaxation properties are governed by motional characteristics normally represented by a correlation time, or several: translational, overall rotational and internal rotational, and thus are very different for solids, liquids and solutions.

Because spectral accumulation is almost invariably used, the choice of the relaxation delay becomes critical. In the case of the quadrupolar nuclei the small relaxation times allow extremely rapid accumulations. This is vital for 17O studies at natural abundance since the receptivity is so small. The 15N nucleus, on the other hand, is frequently characterized by very large values for T1, and since the recommended delay is five times T1, this leads to long accumulation times.

In imaging, faster accumulation by means of the steady-state free procession (SSFP) has been used successfully for 15N, but the method has so far not been reported for spectroscopy, although it should prove useful there also, provided proper attention is paid to phasing problems.

F. Shift Standards

The preferred standard for both the hydrogen nucleides and 13C is tetramethylsilane (TMS). Indeed it is quite feasible to refer all shifts to the proton resonance of TMS, but most spectroscopists prefer a homonuclear reference.

For the nitrogen nucleides there are several reference substances in use. The latest large compilation of nitrogen shifts uses nitromethane (or tetramethyl ammonium ion) as the standard1a. This compound has the advantage that it is easily employed as an internal standard for organic samples, and the 14N line width is not excessive, so that its use is not confined to the 15N isotope. An alternative, which is restricted to use as an external standard, is ammonium nitrate, which has the advantage of containing two nitrogens only one of which gives an Overhauser effect. It thus may be employed not only for shift referencing, but also for checking of the double resonance parameters and for phasing of the spectra. The pH and concentration should be controlled: the conditions which we use are 5M ammonium nitrate [15N2] in 2N HNO3. In the case of some of the compounds under consideration here, an external standard has the utility that the solution conditions are not modified by the addition of an internal standard however inert it may be. If very accurate shifts are required, then corrections should be made for solution susceptibilities, although it may be said here that these corrections are normally so small that only rarely is the procedure necessary. If it is, then investigators may care to bless Witanowski and his collaborators for listing the relevant details1a.

In the case of 17O, a common reference compound is water. For multinuclear studies involving both 17O and either of the nitrogen nucleides, nitromethane would appear to offer an attractive candidate.

II. EFFECT OF ALKYL GROUPS ON THE FUNCTIONAL GROUPS NH2 AND

NO2 AND NO

Table 2 gives the approximate range of nitrogen chemical shifts in the organic compounds with which this book deals. The 14N and 15N NMR spectra of aminoand nitro-aliphatic compounds have been reviewed1,2,15 and the effects of the alkyl group on the 15N chemical shifts have been investigated.

Aliphatic amines are characterized by nitrogen NMR signals at the high-field (lowfrequency) limit of the normal range of shifts ( 50 to C15 ppm referred to Me4NC ). The increasing alkyl substitution of the nitrogen atom in the series

NH3 ! RNH2 ! R2NH ! R3N

results in a downfield (high-frequency) shift of the nitrogen resonance signal (Table 3). The 15N/13C correlations for aliphatic amines in cyclohexane, with slopes of the cor-

relation lines of 2.06, 1.96 and 1.39 ppm N/ppm C for primary, secondary and tertiary amines respectively, show that substituent parameters may be derived and applied in a manner that has been successful for 13C NMR2.

Similarly a nitro group is shielded by the increasing alkyl substitution of the nitrogenbound carbon atom (in a narrow range of C275 to C365 ppm, Table 3) in the series

RCH2NO2 ! R2CHNO2 ! R3CNO2

and for mono-nitroalkanes a linear relationship exists with Taft constants.

A nitro group is also shielded by conjugation with an adjacent system or by bonding to an electronegative group1c. This may be simply explained in terms of -bond order and charge density changes and the average excitation energy approximation of the theory of chemical shifts.

a Referred to Me4NC , temperature 30 °C.

Conformational effects on 15N shifts in substituted cyclohexanes make an axial NH2 more shielded than an equatorial one. Also, 15N resonances are deshielded by ˇ substitution more extensively than are 13C resonances of cyclic hydrocarbons, but the magnitude of the effect depends on the degree of nitrogen substitution. Carbons in the position shield the nitrogen in a manner analogous to 13C, but to a smaller extent in methanol than in cyclohexane solutions, and less for tertiary amines than for primary and secondary amines. These differences have been attributed in part to possible conformational influences on the stereoelectronic relationships between the lone pair and the C C bonds.

The nitrogen nuclei in C-nitroso moieties are strongly deshielded and the smallest algebraical shieldings are observed for nitrosoalkanes. They are shielded from 603 to590 referred to neat nitromethane. If there is a fluoro substituent (F or CF3) at the ˛-C atom of a nitrosoalkane, the nitrogen shielding increases appreciably ( 485 to 425 ppm referred to neat nitromethane). This is attributed to an increased excitation energy of the n ! Ł transition1b, in accord with some correlations of the nitrogen shieldings in X NDO structures with the corresponding low-wavelength absorption bands in their electronic spectra.

III. EFFECT OF AMINO, NITRO AND NITROSO GROUPS ON THE NMR

SPECTRA OF THE AROMATIC RING

A. 1H Chemical Shifts

The 1H-NMR spectra of amino, nitro and nitroso compounds have been reviewed16,17, and the effects of these substituents on the proton chemical shifts have been investigated16. Table 4 gives these substituent effects for mono-substituted benzenes.

There have been many attempts to relate the substituent shifts in benzenes to the electron densities of the molecule, either total or only -densities. It can be seen that

a Solvent CCl4, ppm relative to benzene.

NO2, which is a strongly electron-withdrawing group, deshields all the protons but the effect is largest at the ortho and para positions. The converse is true for NH2, a strongly electron-donating group. In fact the effect of amino, nitro and nitroso groups on the 1H chemical shifts of benzene is a combination of inductive, resonance and magnetic anisotropy effects, and there is a very approximate rule that there is an upfield shift of about 10 ppm at the CH proton for a unit increase in the -electron density at the attached carbon atom. Also in the case of the NH2 group (in RNH2), which is capable of forming intermolecular hydrogen bonds with solvent molecules, the observed proton chemical shift depends critically on solute concentration, the nature of the solvent, temperature and other effects.

B. 13C Chemical Shifts

The 13C-NMR spectra of amino, nitro and nitroso compounds have been investigated extensively16,18 21. Table 5 gives these substituent effects for mono-substituted benzenes for each of these groups.

a Parts per million relative to benzene. Data obtained relative to internal TMS and converted using υC D 128.5 for benzene. Solute concentration ca 10% in CDCl3.

Shifts for meta carbon atoms remain almost unaffected by all kinds of substituents, unlike shifts for ortho and para carbons. Electron-releasing substituents (electron donors) increase electron densities in ortho and para positions and thereby induce a shielding relative to benzene (υC o,p < 128.5 ppm)22. Electron-withdrawing groups (electron acceptors), on the other hand, decrease the ortho and para electron densities and lead to a deshielding relative to benzene (υC o,p > 128.5 ppm).

In the ortho positions, the substituent chemical shifts are between those for a double and a single bond, as would be expected on the basis of an aromatic bond. For these positions proximate interactions such as electric field effects assume an increased importance.

In nitrobenzene, for example, the intramolecular electric field of the nitro group increases the electron densities at the ortho carbon nuclei, so reducing the electron density at the attached protons. This effect, in fact, overcompensates the effect of electron withdrawal by the nitro group, and a net shielding is observed (Table 5).

Para carbon shieldings, however, clearly follow the pattern described by the canonical formulae. They may be correlated well with the total charge densities22 and with the Hammett constants.

IV. EFFECT OF ARYL GROUPS ON THE FUNCTIONAL GROUPS

NH2, NO2 AND NO

Over the last two decades, NMR chemical shifts have been used extensively as probes of electronic substituent effects24,25. Although 1H chemical shifts show small but systematic changes with molecular substitution, the larger chemical shift ranges of 13C and 19F nuclei make them more useful probes, as has been demonstrated in studies of substituent effects in substituted aromatic derivatives23,25 28. The utility of NMR chemical shifts as probes of substituent electronic effects relies on there being a linear relationship between measured substituent chemical shifts (SCS) and calculated electron densities. Although there is a good theoretical basis for these terms, complicating influences from a number of other factors contribute to chemical shifts, so that precise correlations are not usually obtained, except in compounds with closely related structures. The utilization of chemical shifts as electronic probes therefore depends mainly on empirical SCS correlations with electron density in substituted aromatics or similar systems.

A. Anilines and their Derivatives

1. Substituent effects on 15N chemical shifts

The problem of substituent effects in aromatic systems, particularly in benzene derivatives, has long been a subject of interest29. Nitrogen resonance positions of para- substituted anilines are known to be influenced by the extent of nitrogen lone-pair delocalization30. As shown in Table 6, the resonance position of aniline is shifted to higher shielding when an electron-donating substituent is present in the para position31. Conversely, electron-withdrawing para substituents shift the resonance position to lower shielding.

N-methylation of aniline results in shifts of the aniline nitrogen resonance to higher shielding (Table 6), and this has been discussed in terms of perturbation of the lone-pair

-delocalization by the methyl group37.

The effect of para substituents in N,N-dimethylanilines is similar to that observed for N-unsubstituted anilines, but the range is slightly larger.

In the case of 2,6-dimethylanilines (Table 7), although the chemical shifts for corresponding para substituents are at somewhat higher shielding than those of para substituents of aniline, owing to the shielding effect of the ortho methyl groups, the

TABLE 7. 15N chemical shifts for para-substituted 2,6-dimethyl-anilines (I) and para-substituted 2,6- N,N-tetramethylanilines (II)

a Resonance positions to lower shielding relative to anhydrous ammonia. Samples were run as ca 2M solutions in DMSO

b υN D υNX υNH. Positive values denote shifts to lower shielding.