Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 0893 948

20. The synthesis and uses of amino and quaternary ammonium salts

903

*

HBF4

*

+

O2 N

NH2

O2 N

N N

NaNO2 , 0°C

Na2 CO3

Cu2 O, H3 PO2

NO2

O2 N

*

H

*

N N

Zn, NaOH

aq. acetone

Zn, NH4 Cl

*

NH

NH

*

= 14 C

SCHEME 3

O

OH

N

N

*

N

C

CH3

C

H

N

Cl

N

N

C6 H5

*

−

C

O + O2 N C

C

K2 CO3 , acetone N

CH3

C

O

N

O

H

*

C6 H5

NO2

40˚C

H2 , Pd/c

NO2

**

	+	MnO2	*	N	N	*
		∆
NH2		NHOH		aq. acetone	Zn, NH4 Cl
*=13 C			*	NH	NH	*

SCHEME 4

904	Kenneth C. Westaway

The next benzidine-type rearrangement studied by Shine and coworkers was the p-semidine rearrangement of 4-methoxyhydrazobenzene26. In this reaction, 4-methoxy hydrazobenzene rearranges in acidic medium to form p-semidine (4) and an o-semidine

(5); see equation 12.

MeO

NH NH

2H+

++

	MeO	NH2 NH2		(12)
			NH2
MeO	NH	NH2	NH	OMe
	(4)		(5)

These rearrangements are especially interesting because one of the nitrogens from the hydrazo group attacks the ortho- or the para-position of the activated benzene ring. Thus, an intramolecular, concerted mechanism seems even more unlikely in these rearrangements. Heesing and Schinke have shown, using substrates labelled with 15N at both nitrogens, that both the 4-methoxy- and the 4-chlorohydrazobenzene rearrange in an intramolecular reaction27,28. Some of these rearrangements involve a single proton while others require two protons. In the two-proton transfer reactions, the second proton is thought to add to the ipso position of the benzene ring producing a bent cyclohexyadienyl-like configuration that brings the para-position of the benzene ring close to the unprotonated nitrogen of the hydrazo linkage (Scheme 5). The formation of the o-semidine is also thought to involve ipso protonation of the benzene ring (Scheme 5).

In the one-proton rearrangement, it is generally accepted that the protonation must occur at the nitrogen of the hydrazo group. Shine and coworkers synthesized 4-methoxyhydrazobenzene labelled with nitrogen-15 at both nitrogens and another sample labelled with carbon-14 at the 4-position of the unsubstituted benzene ring. The synthesis of the nitrogen-15 labelled substrate began with the commercially available 15N-aniline (Scheme 6) while the carbon-14 labelled substrate was synthesized from 4-14C-nitrobenzene that had been prepared earlier in Shine’s laboratory (Scheme 7).

The products from the rearrangement in 60% aqueous dioxane under oxygen-free argon at 0 °C at a pH of 4.43 were benzoylated, separated and analyzed by whole-molecule isotope ratio mass spectrometry. The nitrogen isotope effect for the formation of both the 4-amino-40-methoxysemibenzidine (4) and 2-amino-3-methoxysemibenzidine (5) were 1.029 and 1.074, respectively. The carbon-12/carbon-14 isotope effect for the formation of the 4-amino-40 -methoxysemibenzidine was 1.039. The nitrogen and carbon isotope effects found for the formation of the 4-amino-40-methoxysemibenzidine indicate that the nitrogen nitrogen bond is breaking and that the nitrogen carbon bond is forming in the slow step of the reaction forming the 4-amino-40 -methoxysemibenzidine. Obviously,

20. The synthesis and uses of amino and quaternary ammonium salts					905
					H
		−2H	+		+
					NH
X	NH	NH2			2
			+
				N
					H
		2H +	X
X	NH NH
		2H +
				N	H
		NH2
		−2H +	+	+
	NH
				NH2

X

X H

X = Cl, OCH3

SCHEME 5

this is only consistent with a concerted mechanism for the formation of 4-amino-40 - methoxysemibenzidine. It is worth noting that the magnitude of these isotope effects are almost identical to those found in the concerted benzidine rearrangement (1.029 and 1.022 for the nitrogen isotope effects and 1.039 and 1.028 for the carbon isotope effects, respectively).

The much larger nitrogen isotope effect of 1.074 found for the formation of the 2-amino- 3-methoxysemibenzidine suggests that this reaction occurs by a different mechanism. Thus, the authors concluded that the 2-amino-3-methoxysemibenzidine formed in a twostep mechanism with the nitrogen nitrogen bond rupture rate-determining. The nitrogen isotope effect in this reaction is similar to the isotope effect of 1.063 found for the twostep benzidine rearrangement. Finally, it is worth noting that the observed kinetic isotope effects were in good agreement with those calculated for the concerted and two-step rearrangements.

Disproportionation (equation 13) is one of the side reactions that can occur in benzidine rearrangements. Shine and coworkers measured the nitrogen and carbon kinetic isotope effects for the disproportionation reaction of 4,40 -diiodohydrazobenzene, which

only yielded disproportionation products, at	25 °C in 70% aqueous dioxane that was
0.376 M in perchloric acid29. The reaction	was first order in hydrazobenzene and it

has been assumed that an intermediate was involved in the disproportionation reaction. This intermediate must be one of: a radical ion30 (equations 14 and 15), a -complex31 (equation 16) or a quinonoid structure32 (equation 17).

906	Kenneth C. Westaway
15NH2	+ MnO2	∆	15N	15N
			AcOH	H2 O2
			15N	15N
			O −
				H2 SO4
		HO	15N	15N

(CH3 )2 SO4

CH O	15N 15N
3

SCHEME 6

		NO2	Zn		N O
			HCl
			H2 N		OCH3
		N	N		OCH3
		aq. acetone
			Zn, NH4 Cl
		N	N		OCH3

=14 C

SCHEME 7

20. The synthesis and uses of amino and quaternary ammonium salts

907

2	NH NH	H	+
			2
	+	N	N

I	NH	NH	I + 2H+
I	+	+	I	slow
	NH2	NH2
			−2H+
			I
2	I		NH2 + I

I	NH	NH		I + H+
I		+
		NH2	NH	I
		slow
	+	+ I
I	NH2			NH
		−H+
			I	NH NH

NH2

(13)

+ 2H+

	+
2 I	NH2

(14)

NH NH I

N N I

(15)

I

2 I

NH2 + I

N N

I

908		Kenneth C. Westaway
I	NH NH	I + 2H+

++

I	NH2 NH2	I
	slow
	2 +			(16)
I
	I			I
+	I	NH NH		I
		−2H+		2
NH2	NH2			NH2
+
	a π-complex
	+ I	N	N	I

I

NH NH

I + 2H+

++

I		NH2	NH2	I
		slow
+		I	+	(17)
H2 N			NH2
	I
− 2H	+	I	NH NH	I

2 I

NH2 + I

N N

I

20. The synthesis and uses of amino and quaternary ammonium salts

909

4,40-Diiodohydrazobenzene labelled at both nitrogens with nitrogen-15 was synthesized from the commercially available 15N-aniline (Scheme 8), and another sample, with carbon-13 at the 4-position of both rings, was synthesized from [1-13C]-4-nitrophenol that was available in Shine’s laboratory (Scheme 9).

15NH2	KH2	PO4	I	15NH2
	+ KI + I2
	Na2 HPO4
		∆
		MnO2
I	15N 15N		I
		Zn, NH4 Cl
	aq. acetone
I		15NH 15NH		I

SCHEME 8

Some 4,40 -diiodohydrazobenzene labelled with carbon-14 at one of the 4-positions of the phenyl rings was prepared from [4-14C]azobenzene that had been synthesized previously in Shine’s laboratory (equation 18).

N	N	*	H2	H2 N	*
			Pd/C
		KH2 PO4 , Na2 HPO4
			KI, I2
						(18)
		H2 N	I
H2 N	*	I		I	N N	* I
		MnO2 , ∆
				aq. acetone
					Zn, NH4 Cl
		I		NH NH	*	I

* = 14 C

910

Kenneth C. Westaway

O2 N

*

OH

NH2 NH2

H2 N

*

OH

Pd/C, ∆

K2 CO3 , ∆

N

N

N

N

N

C

N

N

C

N

Cl

O

C6 H5

C6 H5

*

H2

H N

*

H

Pd/C

2

NH2

KH2 PO4 , Na2 HPO4

KI, I2

I

*

N N

*

I

MnO2

H2 N

* I

∆

aq. acetone

Zn, NH4 Cl

I *

NH

NH

*

I

*=13 C

SCHEME 9

The nitrogen and carbon kinetic isotope effects were determined for the disproportionation reactions in 70% aqueous dioxane that was 0.376 M in perchloric acid. A nitrogen isotope effect of 1.037, a carbon-13 kinetic isotope effect of 1.023 and a carbon-14 isotope effect of 1.045 were observed for the disproportionation reaction forming 4,40-diiodoazobenzene. The excellent agreement between the carbon-13 and carbon-14 isotope effects (the carbon-14 isotope effect should be 1.044 or 1.9 times the magnitude of the carbon-13 isotope effect33) which were measured by whole-molecule isotope ratio mass spectrometry and by scintillation counting, respectively, confirmed that the large carbon isotope effects were correct. Since the reaction is first order in substrate, these isotope effects demonstrated that an intermediate was formed and that nitrogen nitrogen bond rupture and the formation of the 4,40 carbon carbon bond both occurred in the rate-determining step of the decomposition of this intermediate. These results obviously rule out the radical ion and the -complex mechanisms because they only involve nitrogen nitrogen bond rupture in the rate-determining step of the reaction. Thus, the disproportionation reaction, like the benzidine rearrangement, is thought to proceed via a quinonoid intermediate that is formed in the slow step of the reaction. The quinonoid intermediate is then oxidized in a fast step by another hydrazobenzene

20. The synthesis and uses of amino and quaternary ammonium salts					911
molecule (equation 19).
+	I	+	+
H2 N		NH2	2H3 N	I
I
				+	(19)
H		H
N		N
		I	N	N	I
I		I

The next reaction of this type investigated by Shine and coworkers was the nitramine rearrangement34 (equation 20).

CH3	NO2	CH3	H	CH3	H
	N		N		N
		H+		NO2	(20)
				+
					NO2

The rearrangements are first order in substrate and in acid and are mainly intramolecular in nature, although a small intermolecular component has been identified. Shine and coworkers investigated this reaction to try to prove that the process occurred by the nonconcerted (the favored) pathway (Scheme 10) rather than the concerted pathway (Scheme 11).

The N-methyl-N-[15N]nitroaniline, the N-methyl-N-nitro-[4-14C]aniline and the N-methyl-N-nitro-[2-14C]aniline required for this study were prepared using the reactions shown in Schemes 12 14.

The nitrogen isotope effects were determined by whole-molecule isotope ratio mass spectrometry on the 2-nitro and the 4-nitro-N-methylanilines recovered from the reaction in 0.205 M hydrochloric acid at 30 °C. The large nitrogen isotope effects of 1.045 and 1.039 observed for the formation of the 2-nitro and the 4-nitro-N-methylanilines, respectively, clearly demonstrate that nitrogen nitrogen bond cleavage occurs in the rate-determining step for the formation of both products. Although the carbon isotope effects were determined under conditions where a small amount of intermolecular reaction occurred, the isotope effects are effectively those for the intramolecular rearrangements. The carbon-12/carbon-14 isotope effects for the formation of both the 2-nitro- and the 4-nitro-N-methylanilines are, within experimental error, zero, i.e. they were 1.006 and 1.005 for the formation of the 2-nitro- and the 4-nitro-N-methylanilines, respectively, when the substrate was the N-methyl-N-nitro-[2-C14]aniline, and 1.008 and 1.005 for the formation of the 2-nitro- and the 4-nitro-N-methylanilines, respectively, when the substrate was the N-methyl-N-nitro-[4-C14]aniline. The absence of a carbon isotope effect clearly indicates that there is no carbon carbon bond formation in the rate-determining step of either of the nitramine rearrangements. Clearly, neither of the nitramine rearrangements

912			Kenneth C. Westaway
CH3	NO2	CH3	H	CH3	H
			NO2
	N		N +		N
	+ H+				+ NO2

CH3	+ H	CH3	+ H	CH3	H	CH3	H
	N		N	N			N
	H					NO2
			−H+
	NO2	+				+
		H	NO2				NO2
			SCHEME 10
		H		H
CH3	NO2	CH3	NO2	CH3	O
N		N+		N+		N

O

+ H+

CH3	+	H	CH3	H		CH3	H
			N
	N						N
		H		O N O			NO2
			−H+
		O
		N
		O
CH3	+	NO2	CH3	NO2	CH	NO
					3	2
	N		N			N
		−H+
H		O N O	O	N O		NO2

SCHEME 11