Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 0857 891

19. Rearrangement reactions involving the amino, nitro and nitroso groups 877

N-nitro glycine derivative. Another example69 to obtain a tetranitro compound is given in Scheme 14. Here the product was then used to generate polynitrodiazophenols.

	NH2			NHNO2
					NO2
		HNO3
		HOA c/H2 SO4
O2 N	NO2	0˚C	O2 N		NO2
	Me			Me
			Room Temp		H2 SO4
				NH2
			O2 N		NO2
			O2 N		NO2
				Me

SCHEME 14

In the 1960s and 1970s there was something of a controversy regarding the mechanism of the nitramine rearrangement, and arguments were presented in favour of a ‘cartwheel’ mechanism and one involving the formation of radical pair intermediates. Now, two pieces of work, using modern techniques not available earlier, have produced conclusive evidence in support of the mechanism first put forward by White and coworkers70 (Scheme 15), in which the reactant is protonated at the amino nitrogen atom and N N bond fission occurs homolytically to give a radical radical ion pair 64. This intermediate can react within the solvent cage intramolecularly at the two positions of highest unpaired-electron density (i.e. the 2- and 4-positions) to give the observed products. This is the major pathway. Separation of the fragments of 64 allows reaction to occur also intermolecularly. This mechanism also can account for the formation of some of the minor products detected, e.g. the unsubstituted aniline formed by reduction of the radical cation.

Ridd and coworkers71 have now shown unequivocally that radical pairs are indeed involved in this rearrangement by observation of strong enhancement of 15N NMR signals in both the reactant and product, when reaction was carried out with 15N-labelled nitro groups in both N-methyl-N-nitroaniline and also in N-methyl-N-nitro-2,5-dichloro (and dibromo) aniline.

Further, Shine and coworkers72 have applied their heavy-atom kinetic isotope effect technique (widely applied in investigations into the mechanism of the bendizine rearrangement discussed in Section II of this chapter) to the nitramine rearrangement. Substantial nitrogen KIE values were recorded (for the formation of both 2- and 4-nitro products) when [15NO2] labelled N-methyl-N-nitroaniline underwent rearrangement, whereas there was no ring carbon KIE (in both products) for the reaction of both [2-14C] and [4-14C] labelled materials. This means that N N bond fission and N C bond formation cannot occur in a single synchronous process as is proposed in the ‘cartwheel’ mechanism73. On the other hand, the results are wholly consistent with the radical pair mechanism (Scheme 15), in which N N bond fission is the rate-limiting step.

878	D. Lyn H. Williams
	+		+
RNNO2	RNHNO2		RNH

NO2 Side

products

X X

(64)

R

N NHNO2

(65)

N

NO2

(68)

	Intramolecular and
	Intermolecular pathways
RNH	RNH
	NO2
	+
X	X

NO2

SCHEME 15
NHNO2
		Br	Br
			N
N	R	Br	N
			NO2
(66)			(67)

N

H NO2

(69)

NO2

+

N

H

(70)

19. Rearrangement reactions involving the amino, nitro and nitroso groups 879

The nitramine rearrangement is also well known in heterocyclic systems. Fairly recent examples reported include the reaction of the pyridine derivatives74 65 and 66, and the tribromo-1-nitro-1H-pyrazole 67, which results in bromine displacement by the nitro group75. Reaction is also known for N-nitroindazoles, N-nitrotriazoles and N- nitroimidazoles. N-Nitrocarbazole 68 rearranges to give the 1-nitro (69) and 3-nitro (70) products76. Many of these reactions also take place thermally in organic solvents and also photochemically. The latter reactions are discussed elsewhere in this volume.

B. Rearrangement of Nitro Aromatics

It has long been known that nitro-substituted aromatic compounds undergo positional rearrangements of nitro groups within the aromatic ring when treated with strong acids (usually H2SO4) at high temperatures. Normally the reactions are quite slow, yields are low and the reactions are not suitable for synthesis. Now the use of trifluoromethanesulphonic acid (triflic acid CF3SO3H) has enabled reactions to proceed much more rapidly and the yields can often be quantitative. Normally in these reactions, a 1,3-migration of the nitro group occurs. Some examples77 79 are given below:

Me			Me
NO2			O2 N
	CF3 SO3 H
	100 °C
Me			Me
OH			OH
NO2			NO2
	CF3 SO3 H
	100 °C
NO2			O2 N

In some cases80 where the nitro group is ortho to an ethyl group, there is a competing reaction which leads, via cyclization probably involving the nitronic acid form of the nitro group, to the corresponding anthranil 71.

	Me
CH2 Me	C	O
	NO2	N
	CF3 SO3 H
	100 °C
	R	R
	(71)

Substituted 2-nitroanilines also rearrange in concentrated sulphuric acid at 110 °C to give both products of rearrangement 72 and 73, where again 1,3-nitro group migration occurs81.

880 D. Lyn H. Williams

NH2			NH2		NH2
NO2			O2 N
	H2 SO4			+
	110 °C
X				X		X
					NO2
		(72)			(73)
Labelling experiments using		both 15N and 2H		indicate	that the	rearrangement
is intramolecular. Reactions are		also acid-catalysed		and are	believed	to occur via

the Wheland intermediates 74 and 75. The most likely interpretation is that the rearrangement occurs within the Wheland intermediate by a direct 1,3-shift rather than by consecutive 1,2-shifts, and that the process can be regarded as a typical [1,5]-sigmatropic rearrangement.

R					R			R
NO2						H		O2 N
			+		+	NO2	+
		H
								H
						R
R								R
					(74)		(75)
								−H +

R

O2 N

R

Nitro group rearrangements have also been postulated during aromatic nitration reactions, particularly those associated with reaction pathways involving ipso attack by the reagent (NO2C or NO2). This topic is more fully discussed elsewhere in this volume and so just a few examples will be presented here.

The nitronium acetate adducts 76 and 78, made by nitration with nitric acid in acetic anhydride, both undergo the nitro group rearrangements shown, to give 77 and 79 respectively82. The former can be regarded as a [1,5]- and the latter as a [1,3]-sigmatropic shift. Similarly a 1,3-shift of the nitro group occurs in the nitration of aromatic amines. The nitration of 80 gives the ipso adduct 81 in quite high concentrations, detected and characterized by NMR measurements83. This then reacts by rearrangement to give (after proton loss) the 2-nitro product 82. Similar reactions are common in the nitration of phenols and aromatic ethers84.

19. Rearrangement reactions involving the amino, nitro and nitroso groups 881

	Me	NO2	R
				H
		H
				OAc
		OAc
				H
	X		X	NO2
	(76)		(77)
	Me	NO2	Me
	Me		Me
			H
		CN	NO2	CN
	H	OAc		OAc
			H
	(78)		(79)
	+		+	+
	HNMe2		NMe2	HNMe2
		+		NO2
	NO2
	Me	Me	NO2	Me
	(80)		(81)	(82)

Some insight into the mechanism of these 1,3-NO2 group shifts has been obtained from measurements of the 15N CIDNP effect85. There appear to be two mechanisms. During the reaction of 83 to give 84 there is a strong enhancement of 15N nuclear polarization indicative of reaction via a radical pair, whereas for the reaction of the isomer 85 to give 86 there is no such enhancement, indicative of a mechanism which does not involve a radical pair.

O

OH

NO2

Me NO2	Me
(83)	(84)

882		D. Lyn H. Williams
O			OH
	Me	O2 N	Me
	NO2
(85)			(86)

C. Other Rearrangements

A 1,3-nitro group rearrangement from O to N has been reported86. This occurs in the reaction of an imidate, 87 (generated from the chloro compound and silver nitrate in acetonitrile), which gives an N-nitroamide (88). Reaction is believed to be intramolecular involving a radical pair following O N homolytic bond fission.

		NO2
		O		O		O
					NO2	NO2
	Ar	NR	Ar	NR	Ar
						N
						R
		(87)				(88)

A number of reactions of compounds containing the nitro group are postulated to occur by an isomerization to give the nitrite form NO2 ! ONO, which is often followed by O N homolytic bond fission releasing nitric oxide. The reaction has been extensively examined theoretically, for example in nitromethane. Calculations have led to values for the barrier height and characteristics of the transition state have been established (see, for example, Reference 87). The question of the nitro nitrite rearrangement within the

O2 N	Ph		O2 N	Ph
		NO2
		Benzene
	OH			O
	Me		Me	NO2
	(89)	(90)

O2 N	Ph	O2 N	Ph
	O		O
Me	OH	Me	ONO
(92)		(91)

19. Rearrangement reactions involving the amino, nitro and nitroso groups 883

reaction of nitramide decomposition has been examined in a number of photochemical processes (which will not be discussed here) and thermal reactions. For example, in the pyrolysis of Me2NNO288 two pathways have been established, one involving N N bond breaking and the other involving NO2 ! ONO rearrangement.

Another area in which NO2 ! ONO rearrangement has been postulated is within aromatic nitration, again principally when ipso attack has occurred, in order to explain the formation of phenolic products. One example89 comes from the nitration of aromatic systems by N2O4/NO2 typically in benzene solution. This involves reaction of a nitrophenol derivative (89) to give the ipso adduct (90), rearrangement of the nitro group to the nitrite (91) followed by hydrolysis to give the OH product 92 (which in this system then reacts further with NO2).

Nitrites are also believed to be intermediates in nitration reactions where nitronium ion is the nitrating agent. Hydroxy compounds analogous to 92 are often products from the nitration of alkyl phenols90. Apart from the observation of hydroxy products there is convincing NMR evidence for the existence of the nitrite intermediates91 and there is also spectroscopic evidence for their existence during the photochemical nitration of 1,4,5,8-tetramethylnaphthalene using tetranitromethane as the nitrating agent92.

VII. REARRANGEMENT INVOLVING NITROSO GROUPS

A. The Fischer Hepp Rearrangement

The case for an intramolecular mechanism for the rearrangement which takes place in parallel with a reversible denitrosation (Scheme 16) was presented in an earlier volume in this series93. Denitrosation is brought about by nucleophilic attack by Y at the nitroso nitrogen atom forming the secondary amine and a free nitrosating agent YNO. Generally Y is a halide ion or, in their absence, the solvent, water or ethanol. The crucial experiments which supported this mechanistic framework were those carried out in the presence of a ‘nitrite trap’ (such as sulphamic acid, hydrazine, hydrazoic acid, urea etc.), which

RNNO	+		RNH
	RNHNO
	H +	Y	−
			+ YNO
	Intramolecular		(94)

RNH

NO

(93)

SCHEME 16

884	D. Lyn H. Williams

removes YNO and ensures the effective irreversibility of the denitrosation process. Under those circumstances when there is sufficient ‘nitrite trap’ present, a constant product ratio [93]/[94] was obtained as the concentration of the ‘nitrite trap’ was increased further. The ratio decreased as the concentration of [Y ] was increased and also as Y was made more nucleophilic (e.g. Cl ! Br ). These results are entirely consistent with the mechanism in Scheme 16, but cannot be accommodated by the earlier suggestion that 93 is formed by direct C-nitrosation of 94 by YNO. If that were the case, then the product ratio [93]/[94] should decrease towards zero as the concentration of the ‘nitrite trap’ is increased. Further experimental results have now been presented94 using 3-methoxy-N-nitrosoaniline (95) which gives a much higher [93]/[94] ratio than does N-methyl-N-nitrosoaniline (because of the activating effect of the OMe substituent). Table 2 shows the constancy of the % rearrangement product and of the rate constant (which will be the sum of the rate constants for denitrosation and rearrangement) over a range of different ‘nitrite traps’ and different concentrations. Table 3 shows the decreasing % rearrangement as the concentration of Br is increased; at 0.600 M Br , reaction is almost quantitatively that of denitrosation. Where it can be easily measured the rate constant increases with increasing [Br ] concentration, since the [Br ] term is included in the first-order rate constant for denitrosation. Similarly for different nucleophiles at the same concentration, % rearrangement decreases sharply as the nucleophilicity of Y increases. Similar results were obtained for reactions in HCl/EtOH and H2SO4/EtOH solutions using thiourea as the nucleophile and the solvent as the ‘nitrite trap’ (giving ethyl nitrite).

MeNNO

OMe

(95)

Some workers95 continue to regard the rearrangement as being intermolecular, using the evidence of the formation of 94 and products derived from YNO. This makes the common error that the detection of an intermediate does not necessarily mean that the intermediate is on the pathway to the product under consideration.

The Fischer Hepp rearrangement generally gives only the 4-isomer and, apart from examples in the naphthyl series, the 2-isomer has rarely been identified. Now the 2-isomer has been characterized96 as the minor product from the reaction of the diphenylamine derivative 96. The 2-nitroso product gives the cyclized product 97 on treatment with hydrogen peroxide (Scheme 17).

TABLE 2. Variation of the rate constant and % rearrangement with added ‘nitrite traps’ for the reaction of 95 in 3.5 M H2SO4

Nitrite trap								% Rearrangement	103k0 (s 1)
HN3	1	ð 10 3				M		84	3.10
HN3	5	ð	10 3			M		85	3.22
+			1		10 3		M	85	3.25
NH3NH2				ð
+
NH3NH2			5 ð 10 3				M	85	3.39
NH2SO3H 1 ð 10 3							M	84	3.33
NH2SO3H 5 ð 10 3							M	84	3.48

19. Rearrangement reactions involving the amino, nitro and nitroso groups 885

TABLE 3. Rearrangement yields and rate constants for the reaction of 95 (in 3.5 M H2SO4 and 5 ð 10 3 M HN3) in the presence of added nucleophiles

Nucleophile		% Rearrangement	103k0 (s 1)
H2O	M Cl	80	3.27
0.077		73	3.51
0.077	M Br	16
0.077	M SCN	0
0.077	M SC(NH2)2	0
0.004	M Br	65	3.86
0.008	M Br	56	4.14
0.016	M Br	36	6.60
0.032	M Br	29	9.40
0.077	M Br	16
0.100	M Br	11
0.600	M Br	ca 2

ON	NH	75%
NO
OMe
N	NO
OMe	NH	15%
(96)	H2 O2
OMe
	−O
	+N
OMe	N
	(97)
SCHEME 17

No evidence has been forthcoming on the nature of the intramolecular shift of the NO group to the 4-position (generally) in the aromatic ring. It would be helpful to have KIE values such as those obtained for the benzidine rearrangement as a first step in order to see if rearrangement is a concerted process.

B. Other Rearrangements

Quite different from the Fischer Hepp rearrangement is the reaction of N- nitrosodehydromorpholine 98 which, in methylene chloride containing HCl, gives at room temperature 1-azo-4-oxa-3-oximinocyclohexene 99, which ring-opens on treatment

886	D. Lyn H. Williams

with aqueous acid97. This is believed to be an intermolecular process, based on the results of cross-over experiments using 15NO and ring deuterium labelling. The suggested mechanism involves C-protonation and that this ion 100 acts as a nitrosating agent reacting with the nitrosomorpholine derivative at the ring alkene position leading eventually to the oxime product 99. A similar rearrangement of N-nitrosodehydropiperidine to give also the 3-oximino derivative was reported earlier98, but was not subjected to a mechanistic investigation.

NO
N			N
	HCl
	CH2 Cl2
O			O	NOH
(98)	(99)
NO			NO
N			+ N
		HCl		H
O			O
				H

(100)

Examples continue to be reported of 1,2- and 1,3-rearrangements of the nitroso group in acyclic systems, showing that this is a widespread process. Scheme 18 shows the reaction of hydrazine derivatives (where G is an electron-withdrawing group). Evidence has been presented99 which suggests that the 1-nitroso compound is first formed, but that subsequently this rearranges to the more thermodynamically stable 2-nitroso isomer. A 1,3-shift has been reported for a nitrosourea 101 in CCl4100. Kinetic evidence based on the nature and slopes of Bronsted plots and the application of Eigen theory101,102 suggests that in the nitrosation of amides, ureas and carbamates by nitrous acid, the NO group becomes attached first of all to the oxygen atom of the carbonyl group, and after proton loss the nitroso group undergoes a 1,3-rearrangement to give the final N-nitrosoamide product (Scheme 19). It is known that other electrophilic reagents (e.g. HC and alkylating agents) attack the oxygen atom in amides preferentially. A similar rearrangement has been proposed (Scheme 20) for the mechanism of the nitrosation of tryptophan at low acidities103. The evidence comes from the observation that at these acidities reaction rates are independent of the acidity and also are independent of added nucleophiles and

		NO2
	R	NCONHCH2 Ph	CCl4
			33 ˚C
		NO

NO2

R	NHCONCH2 Ph

NO

(101)