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NMR studies of N-nitrosamines
JOURNAL
OF MOLECULAR
SPECTROSCOPY
NMR
30,
77-95
(1969)
Studies
of N-Nitrosamines
III. Saturated
Dinitrosaminesl
R. K. HARRIS AND R. A. SPRAGG’ School of Chemical Sciences, University of East Anglia, Norwich, NOR 88C, England The predominant conformations of the five isomeric 1,4-dinitroso-2,3,5,6tetramethylpiperazines were established from measurements of proton chemical shifts and proton-proton coupling constants. Three of the isomers exist as mixtures of forms with cisoid and transoid orientations of the two nitroso groups; the remaining two isomers are almost exclusively transoid. It is suggested that the transoid y and transoid e isomers prefer to be in twist-boat conformations, while the 01 isomer has a chair conformation with all four methyl groups axial. The conformation of N, N’-dinitrosopiperazine itself is also discussed. The N ,N’-dinitroso derivative of N, N’-dimethylethylenediamine was used as a model compound to establish additivity of chemical shift effects from the two nitroso groups in the absence of conformational differences between isomers. The configurations of the y and 6 isomers of 2,3,5,6-tetramethylpiperazine were established by an NMR study of the 1-methyl+nitroso derivative of the y isomer.
In a previous paper (1) the NMR spectra of saturated cyclic mono-nitrossamines were discussed in relation to the molecular conformations. It was shown that in these compounds a six-membered ring exists in a chair conformation, and that a-methyl groups cis to a nitroso group (i.e. to the oxygen atom of the N=O group) show a strong preference to adopt the axial position. The form of the long-range shielding by the nitroso group was evaluated by measuring chemical shift differences between protons cis and tram to the nitroso oxygen atom. We consider here the spectra of a number of 1,4-dinitrosopiperazines. These compounds are of interest since, with two sp2 hybridized nitrogen atoms in the ring, they are likely to adopt a twist-boat ring conformation (2). In addition to 1,4-dinitrosopiperazine itself, the dinitroso derivatives of the five isomeric 2,3,5,6-tetramethylpiperazines were studied. The configurations of three of these isomers have been established from chemical evidence (3)) and confirmed 1Part II is J. Mol. Spectry. 23, 153 (1967). 2 Present address: Universidade de Site Paulo, Departamento de Quimica FFCL, C. P. 8105, SIto Paulo, Brazil. 77
75
HARRIS
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SPRAGG
by the XRIR spectra of the dihydrochlorides (4). The configurations of the remaining two isomers have been tentatively assigned from chemical evidence (5), and these assignments are confirmed here from the N&MR spectrum of the mononitroso derivative of r-2,3,4,5,6-pentamethylpiperazine. The configurations of the five isomers are shown diagrammatically below:
U IV:
y
v:
6
The atoms of a nitroso group and the carbon atoms directly bonded to it are considered to be planar (6). In dinitroso compounds there is the possibility of isomerism arising from different relative orientations of the two nitroso groups (although these will not, in general, be in the same plane). There may be two, three, or four different isomers of a dinitroso compound, depending on the symmetry of the parent amine. 1,4-Dinitrosopiperazine, for example, has been shown to exist as a mixture of two isomers, cisoid and trunsoid (7) :
VI:
cisoid
VII:
transoid
The chemical shifts in a dinitroso compound are dependent on the orientations of both nitroso groups, and it is therefore necessary to determine whether the long-range shielding effects of the two groups are additive. To investigate this, an acyclic compound, N, N’-dinitroso-N, N’-dimethylethylenediamine, was studied. In this molecule the molecular conformation is expected to be independent of the relative orientation of the two nitroso groups.
NMR
STUDIES
OF NITROSAMINES.
III.
79
EXPERIMENTAL
N, N’-Dinitroso-N, N’-dimethylethylenediamine was prepared by nitrosation of N, N’dimethylethylenediamine; the melting point, 61-62”C, was in agreement with the literature value (8). The dinitroso derivatives of the 2,3,5,6tetramethylpiperazines originated from the work of the late Dr. I?. B. Ripping: Their preparation has been described in a series of papers (3). Dinitrosopiperazine itself was purchased from Eastman Organic Chemicals. A CCL solution of l-methyl-4-nitroso-y-2,3,5,6-tetramethylpiperazine was obtained by extraction of a neutralized aqueous solution of the hydrochloride. The spectra were obtained at ambient probe temperatures using three spectrometers: (a) Perkin Elmer 40 MHz instrument, (b) Perkin Elmer RlO at 60 MHz, and (c) Varian Associates HA-100 at 100 MHz. Both (b) and (c) are equipped with homonuclear double resonance facilities. The dinitroso compounds were studied in solution in deuterochloroform, with tetramethylsilane as internal reference. No attempt was made to standardize concentrations since in some cases there were limitations due to sample solubility and availability; in certain instances there was evidence of variation of chemical shifts with concentration but such effects are not expected to be of sufficient importance to alter the conforma-
40 c/see
: (iii)
IIV)
A r=5.00
I p t J&d@ I
7:
T = 5.00
FIG. 1. 40 MHz proton spectra of the methine region for chloroform solutions of (i) or-DNTMP, (ii) &DNTMP, (iii) r-DNTMP, and (iv) E-DNTMP. In (iv) the resonances of the transoid isomer are indicated by asterisks and those of the trans-trans protons of the cisoid isomer are marked by arrows.
80
HARRIS
AND
SPRAGG
FIG. 2.1OOMHz proton spectrum of the methine region for a CDCls solution of p DNTMP. The chemical shifts of the protons of the cisoid (C) and trunsoid (T) isomers are indicated using the numbering of schemes XI and XIII, respectively. TABLE
I
CHEMICALSHIFTS (T-VALUES)FOR DINITROSOCOMPOUNDS(CDC13 SOLUTIONS) Compound N,N’-dimethyl-N,N’-dinitroso ethylenediamine” 1,4-Dinitrosopiperazined (YDNTMP” p DNTMPe
y DNTMPe 6 DNTMPd E DNTMP
Signala,b CH, CH2’ CH, CH, CH Z-CHa 2-CH 3-CH, 3-CH 5-CH3 5-CH 6-CH3 6-CH CHI CH CHs CH CHad CHe
Position relative to both nitroso groups cis-cis 6.940 6.260 6.19 8.897 5.085
Cis-trans Trans-cis Tram-tram 6.917 6.066 6.01 8.765 4.972
6.212 5.596 5.54 8.527 5.087 8.304 5.725
8.930 4.769 8.998 5.014 8.949 4.626
9.05 4.654
6.183 5.411 5.45 8.419 4.952 8.202 5.372 8.597 4.793
8.671 5.155 8.746 4.548 8.858 5.395 8.97 4.50 8.78 5.437
8.269 5.367 8.36 5.91 8.20 5.893
8.13 5.987
a For the B isomer the lone equatorial methyl group is taken to be at position 2 (see schemes XI and XIII). b In certain cases it is assumed that the methyl signal at highest field is for cis or-CHp protons. c 60 MC/S data. d 40 MC/S data. e 100 MHz data. f Analysis of the AA’BB’ spectrum of isomer IX gives 3JHH= 5.45 and 6.75 Hz, together with the chemical shifts listed.
NMR
STUDIES
OF NITROSAMINES. TABLE
I-ICINAL
COUPLING CONSTANTS (Hz)
II
IN I,~-DINITR~~~-~,~,~,~-TETR.~METHYLPIPERA~INE~
Isomer
Compound
Positions8
Cisoid
Couplingb
J e* J .3e J 6e J ae J
Cis-cis
Trans-tram Transoid Cisoid
2-3 5-6 2-3 5-6
Transoid
the
b Between e Twist-boat
fi isomer XI
2.7 2.5 4.25 SO.5 4.6 1.5 3.8 4.0
J:: Je, J OB J ec J (Ia J Arms
Cis-cis Tram-tram
TransoS a For
-1.9
JCiS
Transoi& Transoid Cisoid
2 (see schemes
Sl
III.
the
lone
equatorial
methyl
group
is taken
$1.0
10.2 10.8 to
be
at
position
and XIII).
methine
protons.
conformation
stable.
tional conclusions of this paper. The coupling constants and chemical shifts are summarised in Tables I and II; Figs. 1 and 2 show representative spectra. NMR
N, N’-Dinitroso-N,
SPECTRA
N’-Dimethylethylenediamine
There are three possible isomers of this compound, shown in the “extended” conformation below: \
B N-N
4 \
\
N--N\,
0
0
a
N-N
N-N
/p
/-/ \
NO4
In isomers VIII and X the two methyl groups are equivalent, as are also the methylene protons, so that the spectrum of each isomer consists of two single peaks (long-range coupling between CH2 and CH, protons being negligible). In isomer IX the methyl groups are not equivalent, being respectively cis and trans to the adjacent nitroso group. The two methylene groups are also not equivalent, and form an AA’BB’ spin system. The spectrum is easily recognized as being that of a mixture of all three isomers, and the assignment of the signals to the different isomers is straightforward on the basis of the chemical shifts
82
HARRIS
AND SPRAGG
and intensity ratios. Integration shows that in CDCh solution the relative isomer populations for VIII, IX and X are 1.00: 0.85:0.17. The N , N’-Dinitroso-2 ,S ,5,6-Tetramethylpiperazlines,
General Comments
In the spectra of the dinitrosotetramethylpiperazine (abbreviated to DNTMP) isomers the resonances of the methyl protons occur at 8.0-9.0 T, and those of the methine protons between 4.5 and 6.0 r. The separation between these is much greater than the coupling constants, thus simplifying analysis of the spectra. The two CH&HCHCH3 groups of each isomer may be treated separately, since any cross-ring coupling will be small, so that the spectrum of each molecule may be regarded as the superposition of two subspectra. These subspectra are of two kinds; if the two methyl groups (and the methine protons) are chemically equivalent, an XZAA’X~’ spin system is formed, if they are not equivalent the spin system is X3ABM3 . Since the LY,y, 6, and e-tetramethyl isomers have (on a time-average over the conformations) either a plane of symmetry or a two-fold rotation axis through the two nitrogen atoms, the only possible isomerism arises from the relative orientation of the two nitroso groups. Thus there may be cisoid or transoid isomers of each dinitroso derivative, as with 1,4-dinitroso-piperazine (7). Each cisoid isomer gives two XsAA’Xa’ subspectra; one from the protons cis to both nitroso groups, the other from the truns protons. Each transoid isomer gives a single X3ABM3 spectrum, as the two CH&JHCHCHs groups are equivalent, being related by an axis of rotation. In these cases it is simple to identify the subspectra arising from the cisoid and trunsoid isomers. The P-tetramethyl isomer is more complicated, since there are four possible isomers, two cisoid and two transoid, each of which gives two XJBM, subspectra. Exact isomer cisoid: transoid isomer ratios are not usually obtained for the DNTMP compounds because the closeness of peaks precludes accurate integration and the presence of second-order fine structure for both XdA’X3’ and X,ABM, spin systems means that methyl doublet peak-heights are unreliable measures of relative intensities. ar-DNTMP The methyl region appears as four doublets, showing that both cisoid and transoid isomers are present; the intensities show that the isomers occur in roughly equal amounts. Two of the doublets show additional structure characteristic of X&A’X,’ spectra (9), and are therefore assigned to the cisoid isomer. Values of the vicinal coupling constants between the methine protons, J,,,r , between methine and methyl protons, J,*o, , and of the long range coupling, J Hf,CH3, are obtained from these methyl resonances. Less information is obtained from the methyl resonances of the transoid isomer. The methine region is very complex (Fig. 1) because of the small shift differences between the protons, but considerable simplification is obtained by
SMR
STUDIES
OF NITltOSAMINES.
III.
SY
decoupling the methyl groups. Irradiating one methyl signal from the cisoirl isomer reduces the corresponding methine resonance to a singlet, from which the chemical shift is obtained. Irradiating one methyl signal of the transoid isomer reduces the spin system to X&S ( withJBX very small), the B resonance of which approximates to a doublet of separation JAB ; this gives the chemical shift of B.
The methyl region of the spectrum consists of four doublets, one of which shows additional structure typical of an S&A’Xs system. Both cisoicl and transoid isomers are present in this case too, in roughly equal amounts. The methine region (Fig. 1) shows a quartet at low field, arising from an XSAA’S,’ spin system (cisoicl isomer) in which J,,, is less than the linewidth, about 1 Hz. Double resonance experiments show that this is associated with the methyl signal at highest field. In the rest of the methine region the AB part of an S,iZBdI, spectrum (transoicl isomer) is readily picked out, giving JAB and the =1 and B chemical shifts. As JAs = JeM, this part of the spectrum is symmetrical, but the A and B signals can be related to the X and M signals by partial decoupling. The remaining cisoicl peaks in the methine region are overlapped by lines from the transoid isomer, but can be assigned to an S3AA’S,’ system with J,,r = 10.2 Hz.
y and &DNTMP Both compounds have relatively simple spectra which may be interpreted as arising from XdBMs spin systems i.e. only the transoid isomers are present. In both cases the methyl region consists of two doublets with slightly different splittings. The methine regions differ markedly (Fig. I), the chemical shift differences between the two methine protons being 0.03 ppm for the y isomer and 1.41 ppm for the 6 isomer. In both cases double resonance experiments showed which methyl and methine resonances arose from the same CH,CH group. In the case of the 6 isomer, this assignment was confirmed by measurement of the methylmethine coupling constants (the two values differ by ,-0.4 Hz). The spectrum of the y isomer is of some interest because the methyl resonances are not simple doublets; in very dilute solution in CDC13 there are additional weak bands at the centers of the doublets (see Fig. 3) and also slight shoulders on the doublet lines. Similar features are shon-n by the methyl resonances of the transoid CYisomer. It can be shown that t,hese second order effects may be expected for the SaABd~a spin system even when Ja, s JBs :Z 0. In particular the absorption at ca. v.+~ occurs n-hen / v,* & SiJAX - vg 1w Jg.w. Th is condition does not give such bands for the SABX system. In more concenttrated solutions in CDCl, than that of Fig. 3, 1vA - vB / increases and the second-order features disappear from the S and .11 resonances. Bands at vx are not present for the X,AA’X3’ system with values of coupling constants typical for the present cases.
84
HARRIS AND SPRAGG
FIG. 3.100 MHz proton spectrum of the methyl region for &dilute solution of y DNTMP in CDCls, showing the second-order effects for the XaABMs spin system. &DN TMP In this case there are four possible isomers, each of which would give two XglBM3 subspectra. The methyl region of the spectrum is readily assigned as consisting of eight doublets, some of which overlap so that only thirteen peaks are observed at 100 MHz. This shows that only two isomers are present in significant amounts, since each isomer will give four methyl doublets. The methine region is much more complex (Fig. 2), but the eight different methine resonances can be recognized. The vicinal couplings between the methine protons are all sufficiently different to enable the pairs of protons which are coupled together to be identified. The methine signals can be assigned to the corresponding methyl signals by double resonance. By irradiating at a series of positions in the methine region, while observing the collapse of the methyl double splittings, most, of the methine and methyl signals can be related. The remaining ambiguities are removed by irradiating the methyl region and observing the methine signals. It is not possible to tell directly which pairs of XABIM3 subspectra arise from the same isomer, as the two isomers are present in almost equal amounts. ASSIGNMENT OF CONFORMATIONS General Discussion In a mononitxosamine the chemical shift differences between protons cis and trans to the nitroso group may be used to determine the positions of the protons relative to that group (1) . These results may be applied to dinitroso compounds if the shielding effects of the two nitroso groups can be considered separately. Chemical shift, differences within a single isomer result from the effects of both nitroso groups; in order to separate the effects of the two nitroso groups it is necessary to consider the shift differences between the different, isomers. In this way one can obtain chemical shift differences between protons whose environment,s differ only in their positions relative to one nitroso group, provided that the molecular conformation is the same in the two isomers. In general, if the chemical shift effects of the two nitroso groups in a dinitroso compound are not additive, the conformations of the different. isomers are highly unlikely to be identical. For the cyclic compounds considered here, such differences in conformation between cisoid and transoid isomers can in principle arise in at least three ways, namely (a) from differences in chair-chair ring-inversion equilibria, (b) by
NMR
STUDIES
OF NITROSAMINES.
s5
III.
distortion from the ideal chair form for one of the isomers, and (c) from occurrence of twist-boat forms for one isomer. In some of the cases considered here (e.g. (r-DNTMP) (a) has been rejected for steric reasons or because it cannot of itself provide a reasonable explanation of the observed chemical shifts and coupling constants. The ring conformation in the dinitrosotetramethylpiperazines is determined principally by interactions between the nitroso groups and the methyl groups. In mononitrosamines the interaction between a nitroso group and a cis a-methyl group is such that the methyl group adopts an axial position even if this results in a l-3 interaction between two axial methyl groups (1). This effect has been found (10) to be general for 6-membered rings with a substituent at a planar (effectively sp’) ring site and a possible neighbouring equatorial substituent. The conformations in the compounds discussed here can be rationalized just by considering the interaction between both nitroso groups and the cis a-methyl groups. There are two empirical rules which describe the occurrence of cisoid and transoid isomers, and the ring conformation adopted: 1. If an isomer can have a chair conformation in which both cis a-methyl groups are axial, this conformation is found. 2. If there is no chair conformation in which both cis a-methyl groups are axial, either this isomer is not present in significant amounts, or a non-chair ring conformation is adopted.
N , N’-Dinitroso-N, N’-Dimethylethylenediamine The additivity of shift effects due to two nitroso groups may be tested with the chemical shift data for N, N’-dinitroso-N, N’-dimethylethylenediamine. For each group of protons there are four possible positions relative to the two nitroso groups: cis to both, (cis-cis) ; cis to the adjacent nitroso group and trans to the more distant group, (cis-trans); trans to the adjacent group and cis to the more distant group, (transcis) ; and trans to both groups, (trans-trans). There are two ways of calculating the shift difference between protons cis and trans to the adjacent nitroso group (eliminating the effect of the more distant group), namely either from the difference in the chemical shifts for the cis-cis and trans-cis positions or from the difference between the cis-trans and trans-trans resonances. Similarly two values may be obtained for the shift differences between protons cis and trans to the more distant group. The results (in ppm) of applying this approach to N, N’dinitroso-N, N’-dimethylethylenediamine are shown below: Adjacent Distant
nitroso nitroso
group: group:
(cis-cis (cis-tram) (cis-cis) (truns-cis)
-
(trans-cis) (t?ms-t?ms) (CL-tru?zs) (truns-hns)
NCH, 0.728 0.734 0.023 0.029
NCH, 0.664 0.655 0.194 0.185
In each case the shift differences obtained from the two methods differ by less than 0.01 ppm, showing that the chemical shift effects of the two nitroso groups are additive. Most of the above shift differences produced by each nitroso group
86
HARRIS
AND SPRAGG
are similar to those observed in acyclic mononitrosamines (11). However, the effect of the distant nitroso group on the methyl protons is noteworthy as these protons are separated from the nitroso oxygen atom by seven chemical bonds. Such a long-range effect has not been reported before, but it should be observed that certain molecular conformations allow the oxygen and hydrogen atoms in question to approach closely in space. In this molecule the populations of the different conformers produced by rotations about the carbon-carbon and carbonnitrogen bonds are unlikely to be affected by the relative orientation of the nitroso groups. If the conformations were different in the different isomers, the chemical shift effects of the two nitroso groups would not appear to be independent and additive. 1,4-Dinitrosopiperazine The chemical shift difference between protons which are cis and trans relative to the adjacent nitroso group (see VI and VII) is given by (~1 - TV) or (TV - Q) ; and for protons cis and trans to the more distant group by (TV- TV) or (TV -Q). Thus one obtains (Table I, CDC13 solution) for the effect of the a-nitroso group 0.65 or 0.56 ppm, and for the /3-nitroso group 0.18 or 0.09 ppm. In this case there is apparent non-additivity of the chemical shift effects of the two nitroso groups, indicating that the ring conformations of the two isomers are somewhat different. For a chair conformation the shift difference between the cis and trans protons of the cisoid isomer would be expected to be the sum of the shift differences produced by (Y and /3 nitroso groups. Using the known values of these effects, 0.48 ppm for an a-group and 0.26 ppm for a P-group (I), the expected shift difference is: AT = 0.48 -I- 0.26 = 0.74 ppm The observed shift diBerence is 0.74 ppm, suggesting that the conformation of this isomer is probably a chair. The vicinal coupling constants for this isomer cannot be obtained to confirm this conclusion. In the transoid isomer the shift difference expected for a chair conformation is obtained by subtracting the effect of a fi-nitroso group from that for an a! group. AT = 0.48 -
0.26 = 0.22 ppm.
As the observed shift difference is 0.47 ppm, the ring conformation is clearly not a perfect chair. The Gina1 coupling constants, 4.88 Hz and 7.17 Hz, (7), are intermediate between those expected for a chair and those expected for a twistboat conformation (12). It is possible that several conformations are of similar energy for this compound. a-DNTMP There are two possible chair conformations, one with all four methyl groups equatorial, the other with the methyl groups axial. The expected conformation is therefore that with the methyl groups axial, for both the cisoid and transoid isomers. In this case there are no a-equatorial methyl groups cis to a nitroso
NMR
STUDIES
OF NITROSAMINES.
87
III.
oxygen atom. The observed vicinal coupling constants, -1.9 and 2.7 Hz in the cisoid isomer, and 2.5 Hz in the transoid isomer, are close to the value expected for an equatorial-equatorial coupling, and are much smaller than the 11.1 Hz axial-axial vicinal coupling in the parent amine (4). The difference in the two vieinal couplings in the cisoid isomer indicates some distortion of the chair conformation. If the chemical shift data are treated in the same way as those for 1,4-dinitrosopiperazine, the effects of the two nitroso groups appear to be approximately additive. For the effect of a nitroso group on the a-methyl chemical shifts one obtains 0.37 and 0.35 ppm, close to the value of 0.34 ppm observed for axial a-methyl groups in a mononitrosamine (1) . The effect on the P-methyl groups is 0.13 or 0.11 ppm, which is rather smaller than the 0.20 ppm estimated for an axial P-methyl group (see the last section of this paper). The a-methine proton shift is scarcely affected by the orientation of the nitroso group (shift differences 0.00 or +0.02 ppm) ; in mononitrosamines the cis a-equatorial proton resonance is to low field of the tram resonance by 0.21 ppm. The effect of a nitroso group on the /3-methine proton is 0.11 or 0.14 ppm, compared with 0.18 ppm for the p-equatorial protons in mononitrosamines. The methine chemical shift data suggest that there is distortion from a chair form, as is to be expected because of the 1-3 diaxial interactions between the methyl groups. &DNTik!P If the chair conformations of this molecule are considered, it is found that there are only two forms which do not involve an interaction between a nitroso group and an equatorial cis a-methyl group, namely: Cisoid
0
i/
MN
I
ZIb
-
88
HARRIS
AND
SPRAGG
XIa for the cisoid isomer, and XIIIa for the transoid isomer. Only two isomers are found, and the observed chemical shifts are readily assigned to these two conformations. The two forms XIa and XIIIa differ only in the orientation of one of the nitroso groups, so that the chemical shift differences between the isomers may be regarded as cis/trans shift differences caused by that group. The chemical shifts are therefore assigned so that the shift differences between the two isomers correspond to those observed between cis and trans protons in mononitrosamines. This is illustrated in Table III, where the observed shift differences are tabulated together with the cisjtrans shift differences for the equivalent positions in mononitrosamines. For the methyl groups the shift differences are almost exactly equal to those observed in the mononitrosamines. The shifts for the methine protons do not agree so well with the expected values, suggesting some distortion from the chair form. The vicinal coupling constants are slightly different in the two isomers, being 6.25 and 4.6 Hz for the axial-equatorial coupling Jz3 , and <0.5 and 1.5 Hz for the equatorial-equatorial coupling J 56, in the cisoid and transoid isomers respectively. This indicates that the conformations of the two isomers differ slightly, but it is not possible to decide the form of this distortion. In a mononitrosamine with two axial methyl groups, cis-1 ,3,5-trimethyl-4_nitrosopiperazine, the vicinal couplings are 4.6 Hz for J,, and 1.2 Hz for J,, . y-DNTMP According to our empirical rules the dinitroso derivative of y-tetramethylpiperazine cannot have a chair conformation since both methyl groups adjacent TABLE III CHEMICAL SHIFT DIFFERENCES BETWEEN THE RESONANCES FOR CORRESPONDING PROTONS IN DIFFERENT ISOMERS OF &DNTMP IN CDCh SOLUTION Position relative to 4-nitroso 2-CH3 2-CH 3-CH3 3-CH 5-CH3 5-CH 6CH8 6-CH
p-equatorial p-axial a-axial a-equatorial a-axial a-equatorial p-axial P-equatorial
TOi8 -
7ttans
(Observed)” +0.10 +0.36 +0.33 -0.02 +0.33 -0.15 +0.20 +o.os
Standard valuesb
+o.ot3 +0.33 +0.34 -0.21 +0.34 -0.21 +0.20 +0.18
& The subscript to 7 refers to the orientation of the proton relative to the 4-nitroso group. b The values for mononitrosamines corresponding to those of the previous column (Ref. (f) and the text of the present paper). These standard values are, however, for CC14 solutions.
NMR STUDIES
OF NITROSAMINES.
III.
89
to one nitrogen atom would be equatorial. In order to explain the occurrence of the transoid isomer only, it is necessary to consider twist-boat forms. Inspection of models shows that the least crowded conformation is the following:
Such a conformation would give a single XsABM, spectrum, as is observed. The angle between the NNO plane and the bond to the cis a-methyl group is about 90”, whereas for the trans a-methyl group it is about 40”. In the cisoid isomer, therefore, the interaction between the nitroso groups and the cis a-methyl groups would be much larger, and this explains why the transoid isomer only is found. The dihedral angle between the vicinal CH bonds in XV is about 50”, and the observed vicinal coupling of 3.8 Hz is reasonable for this. It is possible, however, that other twist-boat conformations may contribute, although they are probably of higher energy than the one shown. Rapid ring inversion between equivalent chair forms would also give the observed XJBMB spectrum, but perfect chair forms are highly unlikely for steric reasons. Moreover, the occurrence of the transoid isomer alone is evidence against y-DNTMP having a chair conformation, since the energy difference between cisoid and transoid chair forms would be low (as it is for 1,4-dinitrosopiperazine). The observed chemical shifts are consistent with formulation XV. The shift difference for the methyl resonances (0.589, assumed to be positive) is not greatly different from that for the 6 isomer (0.61)) which whould be surprising if both isomers had chair conformations. &DNTMP Consideration of the chair conformation of this molecule suggests that only the transoid isomer will occur, as is observed. The expected conformation has the cis a-methyl groups axial, and the trans groups equatorial:
The very large shift difference between the methine protons, 1.41 ppm with the cis proton at lower field, is as expected for this conformation, although it is not possible to relate this directly to shifts observed in mononitrosamines because of the uncertain effects of the methyl groups. However, the contrast with the relatively small methine shift difference for -r-DNTMP provides a clear distinction
90
HARRIS
AND SPRAGG
between the y and ii isomers and strongly supports the assignment of configurations proposed in a later section of this paper and assumed at this stage. The vicinal coupling, 4.0 Hz, is consistent with the axial-equatorial orientation expected for the above conformation of LDNTMP. E-DNTMP This molecule exists as both cisoid and transoid isomers, which is surprising as only the cisoid isomer can have a chair conformation according to our empirical rules. The expected chair conformation for the cisoid isomer has the cis methyl groups axial and the bans groups equatorial:
Thevicinal couplings show clearly that this is the conformation; the large coupling 10.2 Hz, between the trans protons is typical for an axial-axial coupling, and the small, < 1.0 Hz, coupling between the ci.s protons is consistent with an equatorialequatorial coupling with nitrogen atoms tram to each proton (13). As in the transoid d-isomer the cis a-methine proton is equatorial and the tram proton axial, and again the cis/trans shift difference is very large, 1.33 ppm, with the cis proton at lower field. The remarkable feature of the spectrum of the transoid isomer is the 10.8 Hz vicinal coupling between the methine protons, which indicates that the dihedral angle between them must be near 180”. This can be accomplished only in a twistboat form as shown below:
In this form the dihedral angle between the vicinal CH bonds is about 160°, explaining the large coupling. The tram a-methyl groups are much closer to the NNO plane than are the cis groups, so that this twist-boat formisnot favoured for the cisoid isomer. The differences in conformation suggested for the two isomers is strongly supported by the marked non-additivity of the influence of the two nitroso groups on the chemical shifts (e.g. for the /3-methine resonances the the negative signs two values obtained for r,is - rtralzsare -0.094 and -0.783, themselves indicating that conformational differences between the isomers are important).
NRM
THE
STUDIES
CONFIGURATION
OF
OF NITROSAMINES.
91
III.
&2,3,5,6_TETRAMETHYLPIPERAZINE
The two possible (4) con$gurations of r-tetramethylpiperazine are readily distinguished from the spectrum of the 1-methyl-4-nitroso derivative. The expected conformations for the two configurations are:
For configuration XIX the a-methyl groups are expected both to be axial and the cr-methine protons equatorial; for configuration XX the cis a-methyl group is expected to be axial and the tram a-methyl group equatorial. The chemical shifts found for a CCI, solution are shown in Table IV, together with an assignment based on configuration XIX. Comparison of rciS - ftrans with standard values quoted in Table IV shows that this configuration provides a reasonable explanation of the spectrum. In particular 7,is - 7transis very small for the ar-methine protons; for configuration XX a shift difference of ca. 1 ppm would be expected if the effects of the P-methyl groups are ignored. In addition, the largest difference in methyl chemical shifts is 0.345 ppm whereas for configuration XX a considerably larger value would be expected (for tram-2,6-dimethyl-1-nitrosopiperidine the shift difference between cis axial and tram equaTABLE IV SHIFTS FOR ~-METHYL-~-NITRO~O-~-~,~,~,~-TETRAM~THYLPIPER.~ZINE
CHEMICAL
Assignment
7
8.991 8.646 8.937 8.839 ,-5.32 -5.32 7.899d 7.535e 7.837
cis
Tcis
-
‘Ttmns
(Observed) b
trans cXII~(axial)
+o. 35‘l
cis trans P-CIII(eqnatorial)
+0.098
IN CClra
Standard values”
cis i ol-CH(equatoria1) trans( cis ‘i p-CH(asiali
tmns(
NMe
R Obtained at 100 MHz. ‘I See footnotes to Table III. c This value is for cis-2,6-dimethyl-d-nit,rosomorpholine; more relevant values are -0.0 for cis-2,6-dimethyl-1-nitrosopiperidine and +O.ll for cis-1,3,5-trimethyl-4_nitrosopiperaaine (these two compounds have axial methyl groups). d %Jnu = 1.3 Hz. e lJn~ = 3.8 Hz.
92
HARRIS AND SPRAGG
torial methyl groups is 0.59 ppm). It is clear that the y isomer has configuration XIX, as has been assumed in the preceding discussion. This confirms the tentative conclusion from chemical evidence (5). The S isomer must have configuration XX. The methyl resonances at 7 = 8.839 and 8.937 are due to the P-methyl groupsthe bands exhibit values of 3JEMein common with the &methine multiplets, The two values of “J,, (b et ween methine protons) are of reasonable magnitude for axial-equatorial orientations, but they are unequal, indicating that the nitroso group induces some distortion of the ring. The value of T,~ - 7t7andfor the (II methine protons aIso indicates some ring-distortion, in this case presumably due to interaction between the two axial methyl groups. CONCLUSIONS The occurrence of non-chair conformations in these compounds is not unexpected, and has been suggested previously for 1,4-dinitrosopiperazine on the basis of electric polarization measurements (14). The earlier work, however, did not consider restricted rotation about the N-N bonds and the existence of cisoid and transoid isomers. The difference in conformation between the cisoid and transoid isomers of 1,4-dinitrosopiperazine is surprising, particularly since the energy difference between the two forms is small, (ca. 60 % transoid in acetone solution at 37” (7)). There is no obvious steric reason why the conformations of the two isomers should differ, since interactions in the chair forms of both isomers should be the same apart from the change in dipole moment. The difference in symmetry, however, leads to a difference in the interactions in possible twist-boat forms. Transoid
cisoid
fN-N”wN-jj-x~-j XXIb
XXIa
w/ jN
N\ '0
XXEa
N\ N\.
w N/
04
N\N %
Xllb
In the forms XXI the interactions are the same for both isomers, but the forms XXII differ, the transoid isomer having Cz symmetry which is absent in the cisoid isomer. There are two possible types of interaction between the nitroso groups
NMR STUDIES
OF NITROSAMINES.
III.
93
and the cis (r-CH2 protons in conformations of the form XXII. In the cisoid isomer there must be one of each type of interaction, but the transoid isomer has two identical interactions. It may be that the difference in energy between the two types of interaction is sufficient to produce a difference in population of twist-boat forms for the two isosmer (chair forms probably still predominate, at least for the cisoid isomer) resulting in the observed anomalies in nuclear spin parameters. Alternatively the trunsoid isomer may have a distorted chair form. The two cases in which twist-boat conformations are predominant (y and e DNTMP) are also trunsoid isomers. It is interesting to note that the related molecule cyclohexane-1,4-dioxime apparently has the same twist-boat conformation for both cisoid and transoid isomers, the long-range shielding effects of the two oxime groups being additive (15). It should be noted that although the twistboat form is regarded as flexible, the mere fact that there are relatively small barriers (on the NMR time-scale) between the different conformations does not mean that these conformations do not differ significantly (as far as populations are concerned) in energy. The tmnsoid isomer of E-DNTMP, for example, must be almost exclusively in the single twist-boat form illustrated to account for the observed “J = 10.6 Hz. The coupling constants for the molecules discussed herein cannot, in general, be obtained very accurately because; (a) overlapping of bands due to different isomers often occurs, (b) the lines are somewhat broadened by the presence of the nitrogen atoms, and (c) further broadening occurs due to the existence of cross-ring coupling. In addition, values of 3JHMo have not been quoted because of the uncertainty about 4JHMe(probably small and negative (4) ). However, it seems that values of 3JHMelie between 6.0 and 7.1 Hz. Values at the upper end of this range occur when the methyl groups are axial; lower values are observed for equatorial methyl groups in accordance with previous work (1, 4, 16). For instance, the results for 1 -methyl-4-nitroso-y-2,3,5,6-tetramethylpiperazine are “JHMe = 7.00 f 0.05 Hz for the axial methyl protons and 3JHMe= 6.60 f 0.05 Hz for the equatorial methyl protons. This provides a valuable check on the correctness of the c*onformational assignment. The value of “J,,, for the twist-boat (trnnsoid) forms of r-DNTMP and t-DNTMP appear to be in the lower part of the range quoted above (ca. 6.3 Hz). It may be noted that the presence of the nitroso groups effectively inhibits chair-chair ring-inversion for the y, 6 and E isomers of DNTMP (such inversion is rapid on the NMR time scale for the parent hydrochlorides at room temperature (4)). The dinitroso derivatives which retain the chair conformation (6 and cisoid t) are markedly anancomeric (17 j. Consequently the fact that ring-inversion is normally a more rapid process than internal rotation about the N-N bond of N-introsamines is of no importance. However the flexibility of twist-boat forms may still be of significance (see above) and introduces some uncertaint> into the discussion of conformations.
HARRIS
94 ADDENDA
AND
AND
SPRAGG
CORRIGENDA
TO
PART
II
(REF.
(1))
The values of the methyl chemical shifts for 2-methyl-1-nitrosopiperidine were accidentally listed for benzene solution (T = 9.29 and 8.86). The correct values for CC14 solution are 7 = 5.94 (cis) and 7 = 8.50 (truns). We are grateful to Dr. Y. L. Chow for pointing out this error. Further double resonance experiments show that the (rCH2 protons of the tram isomer have chemical shifts of 6.28~ and 6.437 (the latter corresponding to the proton having the slightly longer lifetime in an axial position). The average chemical shift of these protons is 6.357 compared to 6.31~ for N-nitrosopiperidine itself. The axial/equatorial chemical shift difference is thus 0.15 ppm rather than
=
3 Methyl chemical shifts for a CC& solution 8.916, ~fr,,na= 8.779.
(in admixture
with the cis isomer)
are rcia
NMR Studentship available. RECEIVED:
and a Research
July
“2
STUDIES
OF NITROSAMINES.
Studentship
III.
to one of us (R. A. S.) and made computer
95 facilities
19% REFERENCES
1. R. K. HARRIS AND R. A. SPRAGG, J. Mol. Spectry. 23, 158 (1967). b. W. J). KUMLER AND A. C. HUITRIC, J. AVL. Chem. Sot. 78, 3369 (1956). ;7. F. B. KIPPING, J. Chenl. Sot. (a) 2289 (1929); (b) 1160 (1931); (c) 1336 (1332); (d) 143 (1933); (e) 368 (1937). 4. R. K. HARRIS AND N. SHEPPARD, J. Chem. Sot. (B), 200 (1966). 5. J. DICKINSON AND F. B. KIPPING, (unpublished work). 6. C. E. LOONEY, W. D. PHILLIPS AND E. L. REILLY, J. Am. Chem. Sot. 79, 6136 (1957). 7. R. K. HARRIS, J. Mol. Speclry. 16, 100 (1965). 8. P. SCHNEIDER, Ber. 28, 3072 (1895). 9. R. K. HARRIS, Can. J. Chem. 42, 2275 (1964). IO. F. JOHNSONAND S. K. MALHOTRA, J. Am. Chem. Sot. 87,5492 (1965). 11. G. J. KARABATSOS AND R. A. TALLER, J. Am. Chem. Sot. 86,4373 (1964). 12. J. B. LAXBERT, J. Am. Chem. Sot. 89, 1836 (1967). IS. H. BOOTH, Tetrahedron Letters, 411 (1965). 14. M. 1.. GEORGE AND G. F. WRIGHT, J. Am. Chem. Sot. 80, 1200 (1958). 15. II. SAITO AND K. NUICADA, J. ilfol. Spectry. 18, 355 (1965). 16. J. L. JUNGNICKELAND C. A. REILLY, J. ~Vfol. Spectry. 16, 135 (1965). f7. RI. AXTEUNIS, D. TAVERNIER, AND F. BORREnlANS, BUZZ.sot. chim. Belges76,396 (1966).
OF MOLECULAR
SPECTROSCOPY
NMR
30,
77-95
(1969)
Studies
of N-Nitrosamines
III. Saturated
Dinitrosaminesl
R. K. HARRIS AND R. A. SPRAGG’ School of Chemical Sciences, University of East Anglia, Norwich, NOR 88C, England The predominant conformations of the five isomeric 1,4-dinitroso-2,3,5,6tetramethylpiperazines were established from measurements of proton chemical shifts and proton-proton coupling constants. Three of the isomers exist as mixtures of forms with cisoid and transoid orientations of the two nitroso groups; the remaining two isomers are almost exclusively transoid. It is suggested that the transoid y and transoid e isomers prefer to be in twist-boat conformations, while the 01 isomer has a chair conformation with all four methyl groups axial. The conformation of N, N’-dinitrosopiperazine itself is also discussed. The N ,N’-dinitroso derivative of N, N’-dimethylethylenediamine was used as a model compound to establish additivity of chemical shift effects from the two nitroso groups in the absence of conformational differences between isomers. The configurations of the y and 6 isomers of 2,3,5,6-tetramethylpiperazine were established by an NMR study of the 1-methyl+nitroso derivative of the y isomer.
In a previous paper (1) the NMR spectra of saturated cyclic mono-nitrossamines were discussed in relation to the molecular conformations. It was shown that in these compounds a six-membered ring exists in a chair conformation, and that a-methyl groups cis to a nitroso group (i.e. to the oxygen atom of the N=O group) show a strong preference to adopt the axial position. The form of the long-range shielding by the nitroso group was evaluated by measuring chemical shift differences between protons cis and tram to the nitroso oxygen atom. We consider here the spectra of a number of 1,4-dinitrosopiperazines. These compounds are of interest since, with two sp2 hybridized nitrogen atoms in the ring, they are likely to adopt a twist-boat ring conformation (2). In addition to 1,4-dinitrosopiperazine itself, the dinitroso derivatives of the five isomeric 2,3,5,6-tetramethylpiperazines were studied. The configurations of three of these isomers have been established from chemical evidence (3)) and confirmed 1Part II is J. Mol. Spectry. 23, 153 (1967). 2 Present address: Universidade de Site Paulo, Departamento de Quimica FFCL, C. P. 8105, SIto Paulo, Brazil. 77
75
HARRIS
AND
SPRAGG
by the XRIR spectra of the dihydrochlorides (4). The configurations of the remaining two isomers have been tentatively assigned from chemical evidence (5), and these assignments are confirmed here from the N&MR spectrum of the mononitroso derivative of r-2,3,4,5,6-pentamethylpiperazine. The configurations of the five isomers are shown diagrammatically below:
U IV:
y
v:
6
The atoms of a nitroso group and the carbon atoms directly bonded to it are considered to be planar (6). In dinitroso compounds there is the possibility of isomerism arising from different relative orientations of the two nitroso groups (although these will not, in general, be in the same plane). There may be two, three, or four different isomers of a dinitroso compound, depending on the symmetry of the parent amine. 1,4-Dinitrosopiperazine, for example, has been shown to exist as a mixture of two isomers, cisoid and trunsoid (7) :
VI:
cisoid
VII:
transoid
The chemical shifts in a dinitroso compound are dependent on the orientations of both nitroso groups, and it is therefore necessary to determine whether the long-range shielding effects of the two groups are additive. To investigate this, an acyclic compound, N, N’-dinitroso-N, N’-dimethylethylenediamine, was studied. In this molecule the molecular conformation is expected to be independent of the relative orientation of the two nitroso groups.
NMR
STUDIES
OF NITROSAMINES.
III.
79
EXPERIMENTAL
N, N’-Dinitroso-N, N’-dimethylethylenediamine was prepared by nitrosation of N, N’dimethylethylenediamine; the melting point, 61-62”C, was in agreement with the literature value (8). The dinitroso derivatives of the 2,3,5,6tetramethylpiperazines originated from the work of the late Dr. I?. B. Ripping: Their preparation has been described in a series of papers (3). Dinitrosopiperazine itself was purchased from Eastman Organic Chemicals. A CCL solution of l-methyl-4-nitroso-y-2,3,5,6-tetramethylpiperazine was obtained by extraction of a neutralized aqueous solution of the hydrochloride. The spectra were obtained at ambient probe temperatures using three spectrometers: (a) Perkin Elmer 40 MHz instrument, (b) Perkin Elmer RlO at 60 MHz, and (c) Varian Associates HA-100 at 100 MHz. Both (b) and (c) are equipped with homonuclear double resonance facilities. The dinitroso compounds were studied in solution in deuterochloroform, with tetramethylsilane as internal reference. No attempt was made to standardize concentrations since in some cases there were limitations due to sample solubility and availability; in certain instances there was evidence of variation of chemical shifts with concentration but such effects are not expected to be of sufficient importance to alter the conforma-
40 c/see
: (iii)
IIV)
A r=5.00
I p t J&d@ I
7:
T = 5.00
FIG. 1. 40 MHz proton spectra of the methine region for chloroform solutions of (i) or-DNTMP, (ii) &DNTMP, (iii) r-DNTMP, and (iv) E-DNTMP. In (iv) the resonances of the transoid isomer are indicated by asterisks and those of the trans-trans protons of the cisoid isomer are marked by arrows.
80
HARRIS
AND
SPRAGG
FIG. 2.1OOMHz proton spectrum of the methine region for a CDCls solution of p DNTMP. The chemical shifts of the protons of the cisoid (C) and trunsoid (T) isomers are indicated using the numbering of schemes XI and XIII, respectively. TABLE
I
CHEMICALSHIFTS (T-VALUES)FOR DINITROSOCOMPOUNDS(CDC13 SOLUTIONS) Compound N,N’-dimethyl-N,N’-dinitroso ethylenediamine” 1,4-Dinitrosopiperazined (YDNTMP” p DNTMPe
y DNTMPe 6 DNTMPd E DNTMP
Signala,b CH, CH2’ CH, CH, CH Z-CHa 2-CH 3-CH, 3-CH 5-CH3 5-CH 6-CH3 6-CH CHI CH CHs CH CHad CHe
Position relative to both nitroso groups cis-cis 6.940 6.260 6.19 8.897 5.085
Cis-trans Trans-cis Tram-tram 6.917 6.066 6.01 8.765 4.972
6.212 5.596 5.54 8.527 5.087 8.304 5.725
8.930 4.769 8.998 5.014 8.949 4.626
9.05 4.654
6.183 5.411 5.45 8.419 4.952 8.202 5.372 8.597 4.793
8.671 5.155 8.746 4.548 8.858 5.395 8.97 4.50 8.78 5.437
8.269 5.367 8.36 5.91 8.20 5.893
8.13 5.987
a For the B isomer the lone equatorial methyl group is taken to be at position 2 (see schemes XI and XIII). b In certain cases it is assumed that the methyl signal at highest field is for cis or-CHp protons. c 60 MC/S data. d 40 MC/S data. e 100 MHz data. f Analysis of the AA’BB’ spectrum of isomer IX gives 3JHH= 5.45 and 6.75 Hz, together with the chemical shifts listed.
NMR
STUDIES
OF NITROSAMINES. TABLE
I-ICINAL
COUPLING CONSTANTS (Hz)
II
IN I,~-DINITR~~~-~,~,~,~-TETR.~METHYLPIPERA~INE~
Isomer
Compound
Positions8
Cisoid
Couplingb
J e* J .3e J 6e J ae J
Cis-cis
Trans-tram Transoid Cisoid
2-3 5-6 2-3 5-6
Transoid
the
b Between e Twist-boat
fi isomer XI
2.7 2.5 4.25 SO.5 4.6 1.5 3.8 4.0
J:: Je, J OB J ec J (Ia J Arms
Cis-cis Tram-tram
TransoS a For
-1.9
JCiS
Transoi& Transoid Cisoid
2 (see schemes
Sl
III.
the
lone
equatorial
methyl
group
is taken
$1.0
10.2 10.8 to
be
at
position
and XIII).
methine
protons.
conformation
stable.
tional conclusions of this paper. The coupling constants and chemical shifts are summarised in Tables I and II; Figs. 1 and 2 show representative spectra. NMR
N, N’-Dinitroso-N,
SPECTRA
N’-Dimethylethylenediamine
There are three possible isomers of this compound, shown in the “extended” conformation below: \
B N-N
4 \
\
N--N\,
0
0
a
N-N
N-N
/p
/-/ \
NO4
In isomers VIII and X the two methyl groups are equivalent, as are also the methylene protons, so that the spectrum of each isomer consists of two single peaks (long-range coupling between CH2 and CH, protons being negligible). In isomer IX the methyl groups are not equivalent, being respectively cis and trans to the adjacent nitroso group. The two methylene groups are also not equivalent, and form an AA’BB’ spin system. The spectrum is easily recognized as being that of a mixture of all three isomers, and the assignment of the signals to the different isomers is straightforward on the basis of the chemical shifts
82
HARRIS
AND SPRAGG
and intensity ratios. Integration shows that in CDCh solution the relative isomer populations for VIII, IX and X are 1.00: 0.85:0.17. The N , N’-Dinitroso-2 ,S ,5,6-Tetramethylpiperazlines,
General Comments
In the spectra of the dinitrosotetramethylpiperazine (abbreviated to DNTMP) isomers the resonances of the methyl protons occur at 8.0-9.0 T, and those of the methine protons between 4.5 and 6.0 r. The separation between these is much greater than the coupling constants, thus simplifying analysis of the spectra. The two CH&HCHCH3 groups of each isomer may be treated separately, since any cross-ring coupling will be small, so that the spectrum of each molecule may be regarded as the superposition of two subspectra. These subspectra are of two kinds; if the two methyl groups (and the methine protons) are chemically equivalent, an XZAA’X~’ spin system is formed, if they are not equivalent the spin system is X3ABM3 . Since the LY,y, 6, and e-tetramethyl isomers have (on a time-average over the conformations) either a plane of symmetry or a two-fold rotation axis through the two nitrogen atoms, the only possible isomerism arises from the relative orientation of the two nitroso groups. Thus there may be cisoid or transoid isomers of each dinitroso derivative, as with 1,4-dinitroso-piperazine (7). Each cisoid isomer gives two XsAA’Xa’ subspectra; one from the protons cis to both nitroso groups, the other from the truns protons. Each transoid isomer gives a single X3ABM3 spectrum, as the two CH&JHCHCHs groups are equivalent, being related by an axis of rotation. In these cases it is simple to identify the subspectra arising from the cisoid and trunsoid isomers. The P-tetramethyl isomer is more complicated, since there are four possible isomers, two cisoid and two transoid, each of which gives two XJBM, subspectra. Exact isomer cisoid: transoid isomer ratios are not usually obtained for the DNTMP compounds because the closeness of peaks precludes accurate integration and the presence of second-order fine structure for both XdA’X3’ and X,ABM, spin systems means that methyl doublet peak-heights are unreliable measures of relative intensities. ar-DNTMP The methyl region appears as four doublets, showing that both cisoid and transoid isomers are present; the intensities show that the isomers occur in roughly equal amounts. Two of the doublets show additional structure characteristic of X&A’X,’ spectra (9), and are therefore assigned to the cisoid isomer. Values of the vicinal coupling constants between the methine protons, J,,,r , between methine and methyl protons, J,*o, , and of the long range coupling, J Hf,CH3, are obtained from these methyl resonances. Less information is obtained from the methyl resonances of the transoid isomer. The methine region is very complex (Fig. 1) because of the small shift differences between the protons, but considerable simplification is obtained by
SMR
STUDIES
OF NITltOSAMINES.
III.
SY
decoupling the methyl groups. Irradiating one methyl signal from the cisoirl isomer reduces the corresponding methine resonance to a singlet, from which the chemical shift is obtained. Irradiating one methyl signal of the transoid isomer reduces the spin system to X&S ( withJBX very small), the B resonance of which approximates to a doublet of separation JAB ; this gives the chemical shift of B.
The methyl region of the spectrum consists of four doublets, one of which shows additional structure typical of an S&A’Xs system. Both cisoicl and transoid isomers are present in this case too, in roughly equal amounts. The methine region (Fig. 1) shows a quartet at low field, arising from an XSAA’S,’ spin system (cisoicl isomer) in which J,,, is less than the linewidth, about 1 Hz. Double resonance experiments show that this is associated with the methyl signal at highest field. In the rest of the methine region the AB part of an S,iZBdI, spectrum (transoicl isomer) is readily picked out, giving JAB and the =1 and B chemical shifts. As JAs = JeM, this part of the spectrum is symmetrical, but the A and B signals can be related to the X and M signals by partial decoupling. The remaining cisoicl peaks in the methine region are overlapped by lines from the transoid isomer, but can be assigned to an S3AA’S,’ system with J,,r = 10.2 Hz.
y and &DNTMP Both compounds have relatively simple spectra which may be interpreted as arising from XdBMs spin systems i.e. only the transoid isomers are present. In both cases the methyl region consists of two doublets with slightly different splittings. The methine regions differ markedly (Fig. I), the chemical shift differences between the two methine protons being 0.03 ppm for the y isomer and 1.41 ppm for the 6 isomer. In both cases double resonance experiments showed which methyl and methine resonances arose from the same CH,CH group. In the case of the 6 isomer, this assignment was confirmed by measurement of the methylmethine coupling constants (the two values differ by ,-0.4 Hz). The spectrum of the y isomer is of some interest because the methyl resonances are not simple doublets; in very dilute solution in CDC13 there are additional weak bands at the centers of the doublets (see Fig. 3) and also slight shoulders on the doublet lines. Similar features are shon-n by the methyl resonances of the transoid CYisomer. It can be shown that t,hese second order effects may be expected for the SaABd~a spin system even when Ja, s JBs :Z 0. In particular the absorption at ca. v.+~ occurs n-hen / v,* & SiJAX - vg 1w Jg.w. Th is condition does not give such bands for the SABX system. In more concenttrated solutions in CDCl, than that of Fig. 3, 1vA - vB / increases and the second-order features disappear from the S and .11 resonances. Bands at vx are not present for the X,AA’X3’ system with values of coupling constants typical for the present cases.
84
HARRIS AND SPRAGG
FIG. 3.100 MHz proton spectrum of the methyl region for &dilute solution of y DNTMP in CDCls, showing the second-order effects for the XaABMs spin system. &DN TMP In this case there are four possible isomers, each of which would give two XglBM3 subspectra. The methyl region of the spectrum is readily assigned as consisting of eight doublets, some of which overlap so that only thirteen peaks are observed at 100 MHz. This shows that only two isomers are present in significant amounts, since each isomer will give four methyl doublets. The methine region is much more complex (Fig. 2), but the eight different methine resonances can be recognized. The vicinal couplings between the methine protons are all sufficiently different to enable the pairs of protons which are coupled together to be identified. The methine signals can be assigned to the corresponding methyl signals by double resonance. By irradiating at a series of positions in the methine region, while observing the collapse of the methyl double splittings, most, of the methine and methyl signals can be related. The remaining ambiguities are removed by irradiating the methyl region and observing the methine signals. It is not possible to tell directly which pairs of XABIM3 subspectra arise from the same isomer, as the two isomers are present in almost equal amounts. ASSIGNMENT OF CONFORMATIONS General Discussion In a mononitxosamine the chemical shift differences between protons cis and trans to the nitroso group may be used to determine the positions of the protons relative to that group (1) . These results may be applied to dinitroso compounds if the shielding effects of the two nitroso groups can be considered separately. Chemical shift, differences within a single isomer result from the effects of both nitroso groups; in order to separate the effects of the two nitroso groups it is necessary to consider the shift differences between the different, isomers. In this way one can obtain chemical shift differences between protons whose environment,s differ only in their positions relative to one nitroso group, provided that the molecular conformation is the same in the two isomers. In general, if the chemical shift effects of the two nitroso groups in a dinitroso compound are not additive, the conformations of the different. isomers are highly unlikely to be identical. For the cyclic compounds considered here, such differences in conformation between cisoid and transoid isomers can in principle arise in at least three ways, namely (a) from differences in chair-chair ring-inversion equilibria, (b) by
NMR
STUDIES
OF NITROSAMINES.
s5
III.
distortion from the ideal chair form for one of the isomers, and (c) from occurrence of twist-boat forms for one isomer. In some of the cases considered here (e.g. (r-DNTMP) (a) has been rejected for steric reasons or because it cannot of itself provide a reasonable explanation of the observed chemical shifts and coupling constants. The ring conformation in the dinitrosotetramethylpiperazines is determined principally by interactions between the nitroso groups and the methyl groups. In mononitrosamines the interaction between a nitroso group and a cis a-methyl group is such that the methyl group adopts an axial position even if this results in a l-3 interaction between two axial methyl groups (1). This effect has been found (10) to be general for 6-membered rings with a substituent at a planar (effectively sp’) ring site and a possible neighbouring equatorial substituent. The conformations in the compounds discussed here can be rationalized just by considering the interaction between both nitroso groups and the cis a-methyl groups. There are two empirical rules which describe the occurrence of cisoid and transoid isomers, and the ring conformation adopted: 1. If an isomer can have a chair conformation in which both cis a-methyl groups are axial, this conformation is found. 2. If there is no chair conformation in which both cis a-methyl groups are axial, either this isomer is not present in significant amounts, or a non-chair ring conformation is adopted.
N , N’-Dinitroso-N, N’-Dimethylethylenediamine The additivity of shift effects due to two nitroso groups may be tested with the chemical shift data for N, N’-dinitroso-N, N’-dimethylethylenediamine. For each group of protons there are four possible positions relative to the two nitroso groups: cis to both, (cis-cis) ; cis to the adjacent nitroso group and trans to the more distant group, (cis-trans); trans to the adjacent group and cis to the more distant group, (transcis) ; and trans to both groups, (trans-trans). There are two ways of calculating the shift difference between protons cis and trans to the adjacent nitroso group (eliminating the effect of the more distant group), namely either from the difference in the chemical shifts for the cis-cis and trans-cis positions or from the difference between the cis-trans and trans-trans resonances. Similarly two values may be obtained for the shift differences between protons cis and trans to the more distant group. The results (in ppm) of applying this approach to N, N’dinitroso-N, N’-dimethylethylenediamine are shown below: Adjacent Distant
nitroso nitroso
group: group:
(cis-cis (cis-tram) (cis-cis) (truns-cis)
-
(trans-cis) (t?ms-t?ms) (CL-tru?zs) (truns-hns)
NCH, 0.728 0.734 0.023 0.029
NCH, 0.664 0.655 0.194 0.185
In each case the shift differences obtained from the two methods differ by less than 0.01 ppm, showing that the chemical shift effects of the two nitroso groups are additive. Most of the above shift differences produced by each nitroso group
86
HARRIS
AND SPRAGG
are similar to those observed in acyclic mononitrosamines (11). However, the effect of the distant nitroso group on the methyl protons is noteworthy as these protons are separated from the nitroso oxygen atom by seven chemical bonds. Such a long-range effect has not been reported before, but it should be observed that certain molecular conformations allow the oxygen and hydrogen atoms in question to approach closely in space. In this molecule the populations of the different conformers produced by rotations about the carbon-carbon and carbonnitrogen bonds are unlikely to be affected by the relative orientation of the nitroso groups. If the conformations were different in the different isomers, the chemical shift effects of the two nitroso groups would not appear to be independent and additive. 1,4-Dinitrosopiperazine The chemical shift difference between protons which are cis and trans relative to the adjacent nitroso group (see VI and VII) is given by (~1 - TV) or (TV - Q) ; and for protons cis and trans to the more distant group by (TV- TV) or (TV -Q). Thus one obtains (Table I, CDC13 solution) for the effect of the a-nitroso group 0.65 or 0.56 ppm, and for the /3-nitroso group 0.18 or 0.09 ppm. In this case there is apparent non-additivity of the chemical shift effects of the two nitroso groups, indicating that the ring conformations of the two isomers are somewhat different. For a chair conformation the shift difference between the cis and trans protons of the cisoid isomer would be expected to be the sum of the shift differences produced by (Y and /3 nitroso groups. Using the known values of these effects, 0.48 ppm for an a-group and 0.26 ppm for a P-group (I), the expected shift difference is: AT = 0.48 -I- 0.26 = 0.74 ppm The observed shift diBerence is 0.74 ppm, suggesting that the conformation of this isomer is probably a chair. The vicinal coupling constants for this isomer cannot be obtained to confirm this conclusion. In the transoid isomer the shift difference expected for a chair conformation is obtained by subtracting the effect of a fi-nitroso group from that for an a! group. AT = 0.48 -
0.26 = 0.22 ppm.
As the observed shift difference is 0.47 ppm, the ring conformation is clearly not a perfect chair. The Gina1 coupling constants, 4.88 Hz and 7.17 Hz, (7), are intermediate between those expected for a chair and those expected for a twistboat conformation (12). It is possible that several conformations are of similar energy for this compound. a-DNTMP There are two possible chair conformations, one with all four methyl groups equatorial, the other with the methyl groups axial. The expected conformation is therefore that with the methyl groups axial, for both the cisoid and transoid isomers. In this case there are no a-equatorial methyl groups cis to a nitroso
NMR
STUDIES
OF NITROSAMINES.
87
III.
oxygen atom. The observed vicinal coupling constants, -1.9 and 2.7 Hz in the cisoid isomer, and 2.5 Hz in the transoid isomer, are close to the value expected for an equatorial-equatorial coupling, and are much smaller than the 11.1 Hz axial-axial vicinal coupling in the parent amine (4). The difference in the two vieinal couplings in the cisoid isomer indicates some distortion of the chair conformation. If the chemical shift data are treated in the same way as those for 1,4-dinitrosopiperazine, the effects of the two nitroso groups appear to be approximately additive. For the effect of a nitroso group on the a-methyl chemical shifts one obtains 0.37 and 0.35 ppm, close to the value of 0.34 ppm observed for axial a-methyl groups in a mononitrosamine (1) . The effect on the P-methyl groups is 0.13 or 0.11 ppm, which is rather smaller than the 0.20 ppm estimated for an axial P-methyl group (see the last section of this paper). The a-methine proton shift is scarcely affected by the orientation of the nitroso group (shift differences 0.00 or +0.02 ppm) ; in mononitrosamines the cis a-equatorial proton resonance is to low field of the tram resonance by 0.21 ppm. The effect of a nitroso group on the /3-methine proton is 0.11 or 0.14 ppm, compared with 0.18 ppm for the p-equatorial protons in mononitrosamines. The methine chemical shift data suggest that there is distortion from a chair form, as is to be expected because of the 1-3 diaxial interactions between the methyl groups. &DNTik!P If the chair conformations of this molecule are considered, it is found that there are only two forms which do not involve an interaction between a nitroso group and an equatorial cis a-methyl group, namely: Cisoid
0
i/
MN
I
ZIb
-
88
HARRIS
AND
SPRAGG
XIa for the cisoid isomer, and XIIIa for the transoid isomer. Only two isomers are found, and the observed chemical shifts are readily assigned to these two conformations. The two forms XIa and XIIIa differ only in the orientation of one of the nitroso groups, so that the chemical shift differences between the isomers may be regarded as cis/trans shift differences caused by that group. The chemical shifts are therefore assigned so that the shift differences between the two isomers correspond to those observed between cis and trans protons in mononitrosamines. This is illustrated in Table III, where the observed shift differences are tabulated together with the cisjtrans shift differences for the equivalent positions in mononitrosamines. For the methyl groups the shift differences are almost exactly equal to those observed in the mononitrosamines. The shifts for the methine protons do not agree so well with the expected values, suggesting some distortion from the chair form. The vicinal coupling constants are slightly different in the two isomers, being 6.25 and 4.6 Hz for the axial-equatorial coupling Jz3 , and <0.5 and 1.5 Hz for the equatorial-equatorial coupling J 56, in the cisoid and transoid isomers respectively. This indicates that the conformations of the two isomers differ slightly, but it is not possible to decide the form of this distortion. In a mononitrosamine with two axial methyl groups, cis-1 ,3,5-trimethyl-4_nitrosopiperazine, the vicinal couplings are 4.6 Hz for J,, and 1.2 Hz for J,, . y-DNTMP According to our empirical rules the dinitroso derivative of y-tetramethylpiperazine cannot have a chair conformation since both methyl groups adjacent TABLE III CHEMICAL SHIFT DIFFERENCES BETWEEN THE RESONANCES FOR CORRESPONDING PROTONS IN DIFFERENT ISOMERS OF &DNTMP IN CDCh SOLUTION Position relative to 4-nitroso 2-CH3 2-CH 3-CH3 3-CH 5-CH3 5-CH 6CH8 6-CH
p-equatorial p-axial a-axial a-equatorial a-axial a-equatorial p-axial P-equatorial
TOi8 -
7ttans
(Observed)” +0.10 +0.36 +0.33 -0.02 +0.33 -0.15 +0.20 +o.os
Standard valuesb
+o.ot3 +0.33 +0.34 -0.21 +0.34 -0.21 +0.20 +0.18
& The subscript to 7 refers to the orientation of the proton relative to the 4-nitroso group. b The values for mononitrosamines corresponding to those of the previous column (Ref. (f) and the text of the present paper). These standard values are, however, for CC14 solutions.
NMR STUDIES
OF NITROSAMINES.
III.
89
to one nitrogen atom would be equatorial. In order to explain the occurrence of the transoid isomer only, it is necessary to consider twist-boat forms. Inspection of models shows that the least crowded conformation is the following:
Such a conformation would give a single XsABM, spectrum, as is observed. The angle between the NNO plane and the bond to the cis a-methyl group is about 90”, whereas for the trans a-methyl group it is about 40”. In the cisoid isomer, therefore, the interaction between the nitroso groups and the cis a-methyl groups would be much larger, and this explains why the transoid isomer only is found. The dihedral angle between the vicinal CH bonds in XV is about 50”, and the observed vicinal coupling of 3.8 Hz is reasonable for this. It is possible, however, that other twist-boat conformations may contribute, although they are probably of higher energy than the one shown. Rapid ring inversion between equivalent chair forms would also give the observed XJBMB spectrum, but perfect chair forms are highly unlikely for steric reasons. Moreover, the occurrence of the transoid isomer alone is evidence against y-DNTMP having a chair conformation, since the energy difference between cisoid and transoid chair forms would be low (as it is for 1,4-dinitrosopiperazine). The observed chemical shifts are consistent with formulation XV. The shift difference for the methyl resonances (0.589, assumed to be positive) is not greatly different from that for the 6 isomer (0.61)) which whould be surprising if both isomers had chair conformations. &DNTMP Consideration of the chair conformation of this molecule suggests that only the transoid isomer will occur, as is observed. The expected conformation has the cis a-methyl groups axial, and the trans groups equatorial:
The very large shift difference between the methine protons, 1.41 ppm with the cis proton at lower field, is as expected for this conformation, although it is not possible to relate this directly to shifts observed in mononitrosamines because of the uncertain effects of the methyl groups. However, the contrast with the relatively small methine shift difference for -r-DNTMP provides a clear distinction
90
HARRIS
AND SPRAGG
between the y and ii isomers and strongly supports the assignment of configurations proposed in a later section of this paper and assumed at this stage. The vicinal coupling, 4.0 Hz, is consistent with the axial-equatorial orientation expected for the above conformation of LDNTMP. E-DNTMP This molecule exists as both cisoid and transoid isomers, which is surprising as only the cisoid isomer can have a chair conformation according to our empirical rules. The expected chair conformation for the cisoid isomer has the cis methyl groups axial and the bans groups equatorial:
Thevicinal couplings show clearly that this is the conformation; the large coupling 10.2 Hz, between the trans protons is typical for an axial-axial coupling, and the small, < 1.0 Hz, coupling between the ci.s protons is consistent with an equatorialequatorial coupling with nitrogen atoms tram to each proton (13). As in the transoid d-isomer the cis a-methine proton is equatorial and the tram proton axial, and again the cis/trans shift difference is very large, 1.33 ppm, with the cis proton at lower field. The remarkable feature of the spectrum of the transoid isomer is the 10.8 Hz vicinal coupling between the methine protons, which indicates that the dihedral angle between them must be near 180”. This can be accomplished only in a twistboat form as shown below:
In this form the dihedral angle between the vicinal CH bonds is about 160°, explaining the large coupling. The tram a-methyl groups are much closer to the NNO plane than are the cis groups, so that this twist-boat formisnot favoured for the cisoid isomer. The differences in conformation suggested for the two isomers is strongly supported by the marked non-additivity of the influence of the two nitroso groups on the chemical shifts (e.g. for the /3-methine resonances the the negative signs two values obtained for r,is - rtralzsare -0.094 and -0.783, themselves indicating that conformational differences between the isomers are important).
NRM
THE
STUDIES
CONFIGURATION
OF
OF NITROSAMINES.
91
III.
&2,3,5,6_TETRAMETHYLPIPERAZINE
The two possible (4) con$gurations of r-tetramethylpiperazine are readily distinguished from the spectrum of the 1-methyl-4-nitroso derivative. The expected conformations for the two configurations are:
For configuration XIX the a-methyl groups are expected both to be axial and the cr-methine protons equatorial; for configuration XX the cis a-methyl group is expected to be axial and the tram a-methyl group equatorial. The chemical shifts found for a CCI, solution are shown in Table IV, together with an assignment based on configuration XIX. Comparison of rciS - ftrans with standard values quoted in Table IV shows that this configuration provides a reasonable explanation of the spectrum. In particular 7,is - 7transis very small for the ar-methine protons; for configuration XX a shift difference of ca. 1 ppm would be expected if the effects of the P-methyl groups are ignored. In addition, the largest difference in methyl chemical shifts is 0.345 ppm whereas for configuration XX a considerably larger value would be expected (for tram-2,6-dimethyl-1-nitrosopiperidine the shift difference between cis axial and tram equaTABLE IV SHIFTS FOR ~-METHYL-~-NITRO~O-~-~,~,~,~-TETRAM~THYLPIPER.~ZINE
CHEMICAL
Assignment
7
8.991 8.646 8.937 8.839 ,-5.32 -5.32 7.899d 7.535e 7.837
cis
Tcis
-
‘Ttmns
(Observed) b
trans cXII~(axial)
+o. 35‘l
cis trans P-CIII(eqnatorial)
+0.098
IN CClra
Standard values”
cis i ol-CH(equatoria1) trans( cis ‘i p-CH(asiali
tmns(
NMe
R Obtained at 100 MHz. ‘I See footnotes to Table III. c This value is for cis-2,6-dimethyl-d-nit,rosomorpholine; more relevant values are -0.0 for cis-2,6-dimethyl-1-nitrosopiperidine and +O.ll for cis-1,3,5-trimethyl-4_nitrosopiperaaine (these two compounds have axial methyl groups). d %Jnu = 1.3 Hz. e lJn~ = 3.8 Hz.
92
HARRIS AND SPRAGG
torial methyl groups is 0.59 ppm). It is clear that the y isomer has configuration XIX, as has been assumed in the preceding discussion. This confirms the tentative conclusion from chemical evidence (5). The S isomer must have configuration XX. The methyl resonances at 7 = 8.839 and 8.937 are due to the P-methyl groupsthe bands exhibit values of 3JEMein common with the &methine multiplets, The two values of “J,, (b et ween methine protons) are of reasonable magnitude for axial-equatorial orientations, but they are unequal, indicating that the nitroso group induces some distortion of the ring. The value of T,~ - 7t7andfor the (II methine protons aIso indicates some ring-distortion, in this case presumably due to interaction between the two axial methyl groups. CONCLUSIONS The occurrence of non-chair conformations in these compounds is not unexpected, and has been suggested previously for 1,4-dinitrosopiperazine on the basis of electric polarization measurements (14). The earlier work, however, did not consider restricted rotation about the N-N bonds and the existence of cisoid and transoid isomers. The difference in conformation between the cisoid and transoid isomers of 1,4-dinitrosopiperazine is surprising, particularly since the energy difference between the two forms is small, (ca. 60 % transoid in acetone solution at 37” (7)). There is no obvious steric reason why the conformations of the two isomers should differ, since interactions in the chair forms of both isomers should be the same apart from the change in dipole moment. The difference in symmetry, however, leads to a difference in the interactions in possible twist-boat forms. Transoid
cisoid
fN-N”wN-jj-x~-j XXIb
XXIa
w/ jN
N\ '0
XXEa
N\ N\.
w N/
04
N\N %
Xllb
In the forms XXI the interactions are the same for both isomers, but the forms XXII differ, the transoid isomer having Cz symmetry which is absent in the cisoid isomer. There are two possible types of interaction between the nitroso groups
NMR STUDIES
OF NITROSAMINES.
III.
93
and the cis (r-CH2 protons in conformations of the form XXII. In the cisoid isomer there must be one of each type of interaction, but the transoid isomer has two identical interactions. It may be that the difference in energy between the two types of interaction is sufficient to produce a difference in population of twist-boat forms for the two isosmer (chair forms probably still predominate, at least for the cisoid isomer) resulting in the observed anomalies in nuclear spin parameters. Alternatively the trunsoid isomer may have a distorted chair form. The two cases in which twist-boat conformations are predominant (y and e DNTMP) are also trunsoid isomers. It is interesting to note that the related molecule cyclohexane-1,4-dioxime apparently has the same twist-boat conformation for both cisoid and transoid isomers, the long-range shielding effects of the two oxime groups being additive (15). It should be noted that although the twistboat form is regarded as flexible, the mere fact that there are relatively small barriers (on the NMR time-scale) between the different conformations does not mean that these conformations do not differ significantly (as far as populations are concerned) in energy. The tmnsoid isomer of E-DNTMP, for example, must be almost exclusively in the single twist-boat form illustrated to account for the observed “J = 10.6 Hz. The coupling constants for the molecules discussed herein cannot, in general, be obtained very accurately because; (a) overlapping of bands due to different isomers often occurs, (b) the lines are somewhat broadened by the presence of the nitrogen atoms, and (c) further broadening occurs due to the existence of cross-ring coupling. In addition, values of 3JHMo have not been quoted because of the uncertainty about 4JHMe(probably small and negative (4) ). However, it seems that values of 3JHMelie between 6.0 and 7.1 Hz. Values at the upper end of this range occur when the methyl groups are axial; lower values are observed for equatorial methyl groups in accordance with previous work (1, 4, 16). For instance, the results for 1 -methyl-4-nitroso-y-2,3,5,6-tetramethylpiperazine are “JHMe = 7.00 f 0.05 Hz for the axial methyl protons and 3JHMe= 6.60 f 0.05 Hz for the equatorial methyl protons. This provides a valuable check on the correctness of the c*onformational assignment. The value of “J,,, for the twist-boat (trnnsoid) forms of r-DNTMP and t-DNTMP appear to be in the lower part of the range quoted above (ca. 6.3 Hz). It may be noted that the presence of the nitroso groups effectively inhibits chair-chair ring-inversion for the y, 6 and E isomers of DNTMP (such inversion is rapid on the NMR time scale for the parent hydrochlorides at room temperature (4)). The dinitroso derivatives which retain the chair conformation (6 and cisoid t) are markedly anancomeric (17 j. Consequently the fact that ring-inversion is normally a more rapid process than internal rotation about the N-N bond of N-introsamines is of no importance. However the flexibility of twist-boat forms may still be of significance (see above) and introduces some uncertaint> into the discussion of conformations.
HARRIS
94 ADDENDA
AND
AND
SPRAGG
CORRIGENDA
TO
PART
II
(REF.
(1))
The values of the methyl chemical shifts for 2-methyl-1-nitrosopiperidine were accidentally listed for benzene solution (T = 9.29 and 8.86). The correct values for CC14 solution are 7 = 5.94 (cis) and 7 = 8.50 (truns). We are grateful to Dr. Y. L. Chow for pointing out this error. Further double resonance experiments show that the (rCH2 protons of the tram isomer have chemical shifts of 6.28~ and 6.437 (the latter corresponding to the proton having the slightly longer lifetime in an axial position). The average chemical shift of these protons is 6.357 compared to 6.31~ for N-nitrosopiperidine itself. The axial/equatorial chemical shift difference is thus 0.15 ppm rather than
=
3 Methyl chemical shifts for a CC& solution 8.916, ~fr,,na= 8.779.
(in admixture
with the cis isomer)
are rcia
NMR Studentship available. RECEIVED:
and a Research
July
“2
STUDIES
OF NITROSAMINES.
Studentship
III.
to one of us (R. A. S.) and made computer
95 facilities
19% REFERENCES
1. R. K. HARRIS AND R. A. SPRAGG, J. Mol. Spectry. 23, 158 (1967). b. W. J). KUMLER AND A. C. HUITRIC, J. AVL. Chem. Sot. 78, 3369 (1956). ;7. F. B. KIPPING, J. Chenl. Sot. (a) 2289 (1929); (b) 1160 (1931); (c) 1336 (1332); (d) 143 (1933); (e) 368 (1937). 4. R. K. HARRIS AND N. SHEPPARD, J. Chem. Sot. (B), 200 (1966). 5. J. DICKINSON AND F. B. KIPPING, (unpublished work). 6. C. E. LOONEY, W. D. PHILLIPS AND E. L. REILLY, J. Am. Chem. Sot. 79, 6136 (1957). 7. R. K. HARRIS, J. Mol. Speclry. 16, 100 (1965). 8. P. SCHNEIDER, Ber. 28, 3072 (1895). 9. R. K. HARRIS, Can. J. Chem. 42, 2275 (1964). IO. F. JOHNSONAND S. K. MALHOTRA, J. Am. Chem. Sot. 87,5492 (1965). 11. G. J. KARABATSOS AND R. A. TALLER, J. Am. Chem. Sot. 86,4373 (1964). 12. J. B. LAXBERT, J. Am. Chem. Sot. 89, 1836 (1967). IS. H. BOOTH, Tetrahedron Letters, 411 (1965). 14. M. 1.. GEORGE AND G. F. WRIGHT, J. Am. Chem. Sot. 80, 1200 (1958). 15. II. SAITO AND K. NUICADA, J. ilfol. Spectry. 18, 355 (1965). 16. J. L. JUNGNICKELAND C. A. REILLY, J. ~Vfol. Spectry. 16, 135 (1965). f7. RI. AXTEUNIS, D. TAVERNIER, AND F. BORREnlANS, BUZZ.sot. chim. Belges76,396 (1966).