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								913
				O			O
				C6 H5C
K15NO3 + AgClO4		Ag15NO3		Cl
							C6 H5C
				− 15 °C
							15NO
						3
			−15 °C
CH	15NO			CH	3	H
3	2
	N					N

SCHEME 12

			CH3		O
				C
		O		O
				C	O	O
		HC
O2 N		OH, Et3 N		H
	*	H2 N	*	−15 °C		HC NH		*
		5% Pd/C, 100 °C
				methyl sulfide
						borane	0 °C
			CH3	H			CH3	NO2
			N					N
						O
					C6 H5C
						NO3
			*					*

* = 14 C

SCHEME 13

is concerted, and the authors concluded that both reactions occur via a radical mechanism where nitrogen nitrogen bond rupture of the intermediate formed by protonation of the substrate is rate-determining (equation 21).

		H		CH3 + H
CH3	NO2	CH3	NO2
	N	N	+	N

(21)

+ H+ slow + NO2

914

NH2

* NO2

NaNO2 , 0 °C

H3 PO2 , Cu2 O

O

HC NH *

O

O C Cl

A g15NO3

CH3 CN

CH3

O

15NH2

MnO2

∆

OCH3

Kenneth C. Westaway

*	NO2		HC		O			*	NH2
					OH, Et3 N
			5% Pd/C, 100 °C
	CH3		C		O
		O
			C		O
		H
					−15 °C
					CH3	H			CH3	NO
										2
						N				N
						*		O		*
							C6	H5C
borane		0 °C						NO3

methyl sulfide

* = 13 C

SCHEME 14

	CH3
OH	O
15NO	15NO
2	2

(CH3 )2 SO4

NaOH/MeOH

Zn
OCH3	OCH3
15N	15N
aq, acetone	Zn, NH4 Cl

OCH3

15NH 15NH

SCHEME 15

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

915

Confirmation of the radical mechanism was provided by Ridd and Sandall35, who detected radical cations by nitrogen-15 NMR of the reaction mixture for the nitramine rearrangement of 2,6-dibromo-N-nitroaniline and of N-methyl-N-nitroaniline labelled with nitrogen-15 in the nitro group. The results did not allow the authors to indicate whether the products were formed within the solvent cage or from separated radicals.

Shine and coworkers36 also investigated the mechanism of the one-proton benzidine rearrangement of 2,20 -dimethoxyhydrazobenzene. The doubly labelled 2,20 - dimethoxy-[15N,15N]hydrazobenzene, the 2,20 -dimethoxy-[4,402H2]hydrazobenzene and the 2,20 -dimethoxy-[4,4013C2]hydrazobenzene required for this study were synthesized using the reactions in Schemes 15, 16 and 17, respectively.

	O		O
CO2 H	C		C
	Cl		NH2
SOCl		NH3
2
OCH3		OCH3		OCH3
NO2	NO2		NO2	NaOBr
	+			NH2
D	N2
D3 PO2			t-BuNO2
			BF3 etherate
OCH3		OCH3			OCH3
NO2	NO2			NO2
H2
PtO
D			OCH3	OCH3
	MnO2	D	N	N	D
	∆
OCH3
NH2			NH4 Cl	Zn
			OCH3	OCH3
		D	NH	NH	D

SCHEME 16

		O
	CH3	C
		O + O2 N C− H	NaOH
	C13
	CH3	C O
		H

CH3 O

N

N Ph

N a H, ∆

13

CH3 O

O N Ph

325°C

N

N

N

916

NO2

N

N

NH2

Cl

N

13

Raney-Ni

C

6 H5

N

N

A c2 O

N

N

Pd /C

H2 O

N2 H4

K2 CO3

N

C

N

C

H2

H2 SO4

13

13

N O 13

N

O 13

OH

OH

C6 H5

C6 H5

O

NH2

NH2

NHCCH3

HN O 2

13

13

13

13

13

piperidine

CH2 N2

(1) H2 SO4

N a O H, D M F

CH3 O

HO

(2) H2 O2

O

C l

N O 2

O

OH

O

NO2

OH

O C

O

C

C6 H5

O

C

NO2

O

C

NO2

C6 H5

C6 H5

C6 H5

13

13

OCH3

CH3 O

OCH3

CH3 O

CH3 O

KOH

MnO2

N

N

13

Zn, NH4 Cl

NH

NH

13

N

O

∆

∆

13

13

aq . acetone

CH3 O

N

Ph

NH2

SCHEME 17

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

917

Then, the nitrogen, the carbon and the deuterium kinetic isotope effects for these oneproton benzidine rearrangements (equation 22) were measured in buffered 60% aqueous dioxane at 0 °C. The 2,20-dimethoxybenzidine formed in the reaction was isolated and converted into its bis(trifluoroacetyl) derivative and analyzed by whole-molecule isotope ratio mass spectrometry. The nitrogen kinetic isotope effect was 1.029 š 0.005, the carbon-13 kinetic isotope effect was 1.029š0.005 and the secondary hydrogen deuterium kinetic isotope effect was 0.93 š 0.03. The substantial nitrogen and carbon isotope effects indicate that the nitrogen nitrogen bond is breaking as the carbon carbon bond is forming in the rate-determining step of the reaction. Thus, the rearrangement is a concerted reaction. The inverse secondary hydrogen deuterium kinetic isotope effect also confirms that the rearrangement is concerted. An inverse isotope effect is observed because carbon carbon bond formation changes the hybridization of the 4 and 40 carbon atoms of the benzene rings from sp2- to sp3-like in the transition state. Thus, the one-proton transfer benzidine reaction occurs by a pre-equilibrium proton transfer to nitrogen followed by a rate-determining concerted rearrangement. Finally, it is worth noting that all three of the isotope effects in this reaction are almost identical to those found for the two-proton benzidine rearrangement (Table 1). This suggests that the transition states for the oneproton and two-proton benzidine rearrangements are very similar. The authors suggest that the transition states have two bent cyclohexadiene-like rings. This brings the two reacting carbons close enough to react (Figure 3).

OCH3 CH3 O

NH NH

+ H +

OCH3	CH3 O
+		(22)
NH2	NH

CH3 O	OCH3
H2 N	NH2

TABLE 1. The nitrogen, carbon-13 and secondary hydrogen deuterium kinetic isotope effects found for the oneand two-proton benzidine rearrangements

Rearrangement	k14/k15	k12/k13	kH/kD
One-proton	1.029	1.029	0.93
Two-proton	1.022	1.021	0.94

918	Kenneth C. Westaway
	+	(H)
		N
		H
		H
	+	N
		H

FIGURE 3. The transition state for the oneand two-proton benzidine rearrangement

The thermal rearrangement of 2,20-hydrazonapthalene has also been investigated by Shine and coworkers37. This reaction was of interest because these compounds undergo

(i) a high yield of the ortho,ortho0-rearrangement with virtually no disproportionation in the normal acid-catalyzed reaction, and (ii) a clean thermal ortho,ortho0-rearrangement (equation 23). In fact, it is believed that the carbazole product is formed from the diamine produced in the rearrangement reaction, so the kinetic isotope effects used to elucidate the mechanism of this reaction are determined only by the rearrangement reaction.

NH NH

H+

	(23)
NH2
+	NH
NH2

The 2,20-hydrazonaphthalene doubly labelled with nitrogen-15 for the nitrogen isotope effect experiments and the [1,10 -13C2]-2,20 -hydrazonaphthalene required for measuring the carbon isotope effect were synthesized by the reaction sequence shown in Schemes 18 and 19.

The normal acid-catalyzed reaction was carried out at 0 °C in 70% aqueous dioxane that was 1 ð 10 3 M in perchloric acid while the thermal rearrangement was carried out in 95% ethanol at 80 °C. The nitrogen and carbon-13 kinetic isotope effects found in these two rearrangements are presented in Table 2. The large nitrogen and significant carbon13 kinetic isotope effects for both reactions indicate that both the acid-catalyzed and the thermal rearrangements are concerted. The larger nitrogen isotope effect for the acidcatalyzed reaction indicates that the transition state for the acid-catalyzed reaction has more

20. The synthesis and uses of amino and quaternary ammonium salts		919
OH	15NH2

1.15NH4 Cl, A cONa, A cOH

2.H2 O

HCl, Na15NO2

15N 15N

NH4 Cl, Zn aq. acetone

15NH 15NH

OH

PBr3

13

CH3

Zn (Hg)

HCl

10% Pd/C

13

CH3

Na2Cr2O7

H2 SO4

SCHEME 18

	Br	MgBr
	Mg
	dry ether
O		2. HCl 1. 13CO2
13	CH3	13 CO2 H
		MSA
13	CO2 H	13
		NH2
	NH2OH
	PPA
		NaNO2 HCl, 0˚C
13		13
	N	N
aq. acetone		Zn, NH4 Cl
13		13

NH NH

SCHEME 19

920 Kenneth C. Westaway

TABLE 2. The nitrogen and carbon-13 kinetic isotope effects for the acid-catalyzed and for the thermal benzidine rearrangement of 2,20 -hydrazonaphthalene in 70% aqueous dioxane at 0 °C and in 95% ethanol at 80 °C, respectively

Reaction	k14/k15	k12/k13
Acid-catalyzed	1.090 š 0.004	1.0086 š 0.0004
Thermal	1.0611 š 0.0001	1.0182 š 0.0001

nitrogen nitrogen bond rupture than the transition state for the thermal rearrangement. Unfortunately, the small carbon isotope effect is consistent with a transition state with either very little or almost complete carbon carbon bond formation. Measuring the secondary hydrogen deuterium kinetic isotope effect for this reaction would probably differentiate between these two possibilities.

Nitrogen, carbon-13 and carbon-14 kinetic isotope effects have been determined38 for the analogous acid-catalyzed ortho,ortho0-rearrangement of the N-2-naphthyl-N0- phenylhydrazine (equation 24). The labelled compounds required for this study were prepared by the sequence of reactions shown in Schemes 20 22.

NH NH

H+

	(24)
NH2
+	NH
NH2

The isotope effects in Table 3 were measured at 0 °C in 60% aqueous dioxane that was 0.1 M in perchloric acid. The nitrogen isotope effect was determined for both the doubly labelled nitrogen-15 substrate and using the nitrogen gas from a sample with the natural abundance of nitrogen in the starting material. The doubly labelled nitrogen isotope effect was determined by whole-molecule isotope ratio mass spectrometry while that for the unlabelled substrate was measured by converting the nitrogen into nitrogen gas and determining the isotopic composition by isotope ratio mass spectrometry. The carbon-13 isotope effect was obtained by isotope ratio mass spectrometry on CO2 while the carbon-14 isotope effect was measured by a scintillation counting technique.

The nitrogen kinetic isotope effect of 1.0197 found using the substrate with the natural abundance of nitrogen isotopes corresponds to an isotope effect of 1.04 for the reaction of the doubly labelled compound. Thus, the nitrogen isotope effects found using two different analytical techniques to measure the isotope effect are in excellent agreement.

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

921

15NH2

+ O215N

180˚C NaOH

15N 15N

aq. acetone

Zn, NH4 Cl

15NH 15NH

SCHEME 20

13	13
NH2	N	N
+ O2 N	NaOH
	180˚C
	aq. acetone	Zn, NH4 Cl

13

NH NH

SCHEME 21

TABLE 3. The nitrogen, the carbon-13 and carbon14 kinetic isotope effects found for the acid-catalyzed ortho,ortho0 -rearrangement of N-naphthyl-N-phenyl- hydrazine in 60% aqueous dioxane at 0 °C

Isotope effect				kL/kH
15	15
15N			N	1.043 š 0.005
13N		N		1.0197 š 0.0009
14C				1.0042 š 0.0001
C				1.0142 š 0.0005

922

NH2

14

O2 N

HBF4

NaNO2

Kenneth C. Westaway

		+
		N2
		14	14
	O2 N		O2 N

H3 PO2

NaOH, 180 °C

NH2

14

N N

aq. acetone

Zn, NH4 Cl

14

NH NH

SCHEME 22

The carbon-13 kinetic isotope effect of 1.0074 estimated33 for this rearrangement using the equation

log (k12/k14)/ log (k12/k13) D 1.9

25

is in reasonable agreement with the observed value of 1.0042. This agreement is satisfactory when one considers that (i) the two isotope effects are very small and that (ii) the carbon isotope effect indicates what is happening at the two carbons that are forming the new carbon carbon bond in the transition state.

The nitrogen, carbon-13 and carbon-14 isotope effects clearly indicate that the rearrangement is concerted. However, the large nitrogen isotope effect accompanied by the small carbon isotope effects indicates that the transition state is unsymmetrical. It is worth noting that an unsymmetrical transition state with substantial nitrogen nitrogen bond rupture and a small carbon isotope effect was also found for the acidcatalyzed ortho,ortho0-rearrangement of the closely related 2,20 -hydrazonaphthalene (vide supra). The nitrogen isotope effect for the 2,20 -hydrazonaphthalene rearrangement is approximately twice that for the N-naphthyl-N-phenylhydrazine rearrangement whereas the carbon-13 kinetic isotope effects are almost identical. The greater amount of nitrogen nitrogen bond rupture in the transition state of the 2,20 -hydrazonaphthalene reaction has been attributed to the fact that the 2,20 -hydrazonaphthalene rearrangement is a two-proton reaction whereas the N-naphthyl-N-phenylhydrazine rearrangement requires only one proton. Another possibility is that nitrogen nitrogen bond rupture has to be more advanced in the 2,20 -hydrazonaphthalene rearrangement so that the two large