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				923
naphthalene rings will be close enough to form the new carbon			carbon	bond in the
transition state.
Rhee	and Shine39 used an impressive combination of nitrogen			and	carbon
kinetic	isotope effects to demonstrate that a quinonoidal-type intermediate is				formed
in the	rate-determining step of the acid-catalyzed disproportionation			reaction of

4,40 -dichlorohydrazobenzene (equation 26). When the reaction was carried out at 0 °C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate, extensive product analyses indicated that the major pathway was the disproportionation reaction. In fact, the disproportionation reaction accounted for approximately 72% of the product (compounds 6 and 7) while approximately 13% went to the ortho-semidine (8) and approximately 15% was consumed in the para-semidine (9) rearrangement.

	NH2
	Cl	N N	Cl
		(7)
	Cl
	(6)
	H+
Cl	NH NH	Cl	(26)

H+

NH2

NH

Cl

Cl

NH

NH2

(9)

(8)

Cl

The doubly nitrogen-15 labelled substrate required for determining the nitrogen isotope effect for this reaction was obtained by the reactions shown in Scheme 2340. The series of reactions used in the synthesis of the [4,40-13C2]-4,40 -dichlorohyrazobenzene is shown in Scheme 2440, and the preparation of the [2-14C]- and the [4-14C]-4,40 - dichlorohyrazobenzene are described in Schemes 25 and 26.

The reaction was second order in acid and first order in substrate, so both rearrangements and the disproportionation reaction proceed via the doubly-protonated hydrazobenzene intermediate formed in a rapid pre-equilibrium step. The nitrogen and carbon-13 kinetic isotope effects were measured to learn whether the slow step of each reaction was concerted or stepwise. The nitrogen and carbon-13 kinetic isotope effects were measured using whole-molecule isotope ratio mass spectrometry of the trifluoroacetyl derivatives of the amine products and by isotope ratio mass spectrometry on the nitrogen and carbon dioxide gases produced from the products. The carbon-12/carbon-14 isotope

924				Kenneth C. Westaway
		O	+ 15NH4 Cl		NaOH			O
Cl	C							C
					Cl
		Cl							15NH2
				NaOBr
Cl		15NH2		MnO2	Cl			15N 15N	Cl
				∆
					aq. acetone
						Zn, NH4 Cl
	Cl				15NH 15NH			Cl
					SCHEME 23
				O
H3 C 13				C	H
	O + O2 N			−	NaOH	HO	13		NO2
C
H3 C				C	H
				O	∆
						(PhO)3 PCl2
		Cl	13		NO2	Sn	Cl	13	NH2
						HCl
						MnO2
						∆
			Cl	13	N	N		13	Cl
					aq. acetone
						Zn, NH4 Cl
		Cl	13		NH	NH		13	Cl

SCHEME 24

	20. The synthesis and uses of amino and quaternary ammonium salts						925
	NH2
14	NO2	14	NO2	14	NH2
	NaNO2 , Cu2 O		Et3 N
	0˚C, H3 PO2		10% Pd/C
			HOA c
			A c2 O
	14		14		14		NH2
	NHAc		NHAc
		NaOCl		H2 O
				H2 SO4
		Cl		Cl
			MnO2 , ∆
		14	Cl		NH2
	Cl	N	N	Cl
		aq. acetone	Zn, NH4 Cl
		14
	Cl		NH NH	Cl
		SCHEME 25
	NO2	NO2	NH2
	NaNO2 , HCl		SnCl2
	0˚C, Cu2Cl2		HCl
	14	14		14
	NH2	Cl	Cl
		Cl	NH2	MnO2 , ∆
		Cl	N N		14	Cl
			aq. acetone	NH4 Cl, Zn
		Cl	NH	NH	14	Cl

SCHEME 26

926	Kenneth C. Westaway

effects were determined by scintillation counting on the trifluoroacetyl derivatives of the products. The isotope effects for the formation of all three products are presented in Table 4.

The nitrogen isotope effects measured by whole-molecule isotope ratio mass spectrometry and by isotope ratio mass spectrometry are in excellent agreement, i.e. the 15N 15N kinetic isotope effect should be twice the 15N kinetic isotope effect for the formation of the disproportionation product and the para-semidine. The large nitrogen isotope effects indicate that there is substantial nitrogen nitrogen bond rupture in the transition state of the rate-determining step for the formation of all three products. However, all of the carbon isotope effects are, within experimental error, unity and the obvious conclusion is that there is no concomitant carbon carbon bond formation in the transition states of any of these reactions. The authors believe this simple explanation is correct for the formation of the ortho-semidine which would occur via an unacceptable concerted 1,3-sigmatropic shift that contravenes orbital-symmetry requirements. However, they are less willing to accept the obvious interpretation for the para-semidine reaction. The authors suggest that the lack of a carbon isotope effect in the formation of the para-semidine (9) might be observed because of the cancellation of two isotope effects. This seemed possible because the formation of 9 could arise by an allowed concerted 1,5-sigmatropic shift. Finally, the disproportionation reaction is thought to proceed by a multistep mechanism where the formation of the 4,40 -quinonoidal intermediate 10 (equation 27) is the slow step of the reaction. The para-semidine and the disproportionation products are then formed by a rapid oxidation of 10 by a second molecule of starting material (equations 28 and 29), respectively.

++

Cl NH2 NH2 Cl

(27)

	+ Cl	+
Cl	NH2	NH2
	(10)

	+	+	Cl	NH		NH2
Cl	NH2	NH2
	Cl
	H	H		HCl +	2H+	(28)
	N N
			Cl	N	N	Cl
Cl		Cl

TABLE 4. The nitrogen, carbon-13 and carbon-14 kinetic isotope effects found for the acid-catalyzed formation of the disproportionation product, the ortho- semidine and the para-semidine at 0 °C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate

Isotope effect

Reaction

15N

15Na

15Nb

(15N)2calc

4,40 -13C2b

2-14Cc

4-14Cc

Disproportionation

1.026 š 0.003

1.014 š 0.0015

1.028

1.002 š 0.002

1.000 š 0.001

0.997 š 0.002

o-Semidine

1.0155 š 0.0003

0.9993 š 0.0009

1.000 š 0.002

1.003 š 0.004

p-Semidine

1.028 š 0.007

1.0162 š 0.0005

1.033

0.997 š 0.003

1.001 š 0.003

a These 15N 15N kinetic isotope effects were measured by whole-molecule isotope ratio mass spectrometry. b These 15N and 12C/13C kinetic isotope effects were determined by isotope ratio mass spectrometry.

c These 12C/14C kinetic isotope effects were determined by scintillation counting.

927

928		Kenneth C. Westaway
	+ Cl	+
Cl	NH2	NH2
	H	H
	N	N
	Cl	Cl		(29)
		+
		NH3
	2	+ Cl	N N	Cl

Cl

The most recent addition to Shine’s extensive study of the benzidine-type rearrangements41 involved remeasuring the nitrogen and the carbon-13 and carbon-14 kinetic isotope effects at the 4- and at the 4- and 40 -carbons as well as determining the carbon-13 and carbon-14 isotope effects at the 1- and at the 1- and 10-carbons in the benzidine rearrangement of hydrazobenzene (equation 30). The reaction, which was carried out in 75% aqueous ethanol that was 0.1 M in hydrochloric acid and 0.3 M in lithium chloride at 0 °C, gave an 86% yield of benzidine (11) and a 14% yield of diphenyline (12). The kinetic isotope effects found for the formation of benzidine and diphenyline under these reaction conditions are presented in Table 5.

H2 N	NH2
H+	(11)

NH NH

(30)

NH2

H2 N

(12)

The significant nitrogen, carbon-13 and carbon-14 kinetic isotope effects at the 4- and at the 4 and 40 -positions for the formation of benzidine (11) indicate that benzidine is formed in a concerted reaction. The small, but real, carbon-13 and carbon-14 kinetic

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

929

TABLE 5. The nitrogen, carbon-13 and carbon-14 kinetic isotope effects found for the acid-catalyzed benzidine rearrangement of hydrazobenzene in 75% aqueous ethanol that was 0.1 M in hydrochloric acid and 0.3 M in lithium chloride at 0 °C

Substratea

Isotope effect

Benzidine

Diphenyline

15N,15N0

k14

/k15

1.0410 š

0.0009b

1.0367

š

0.0009b

4,40 -13C2

k12

/k13

1.0127

š

0.0011b

1.001

š

0.001b

4-

14

C

k

12

/k

14

c

c

1.0121 š

0.0008

1.001 š 0.001

1,10 -13C2

k12

/k13

1.0035

š

0.0010b

1.000

š

0.003b

1-

14

C

k

12

/k

14

c

c

1.0051 š

0.0017

0.999 š 0.002

a The preparation of these labelled substrates has been described previously.

b The nitrogen and carbon-13 kinetic

isotope effects found using

the 15N

15N, the 1,10 -

13C2 and the 4,40 -13C2 substrates were measured by whole-molecule isotope ratio mass spectrometry on the bis-(trifluoroacetyl) derivative.

c The carbon-12/carbon-14 kinetic isotope effects found using the 1-14C and the 4-14C substrates were determined by scintillation counting on the bis-(trifluoroacetyl) derivative.

isotope effects found at the 1- and the 1- and 10-positions in the formation of benzidine also suggest a concerted mechanism for the formation of benzidine. The reasonably large nitrogen isotope effect and small carbon isotope effects indicate that nitrogen nitrogen bond rupture is well advanced compared to carbon carbon bond formation, i.e. both the nitrogen nitrogen and the carbon carbon bonds are long and weak in the transition state of the rearrangement reaction forming benzidine (equation 31).

	NH	NH			2H+	+	+
						NH2	NH2
H					+		+
	H	H	H	2+	NH2		NH2
δ+ N			N δ+
							(31)
δ +			δ +		H		H
						−2H+
					H2 N		NH2

The absence of both carbon-13 and carbon-14 kinetic isotope effects at the 1-, the 1- and the 10-, the 4- and the 4- and 40-carbons in the formation of diphenyline (12) confirms beyond any doubt that this compound is formed in a two-step rearrangement. Thus, the nitrogen nitrogen bond ruptures in the slow step of the reaction and then the product is

930	Kenneth C. Westaway

formed in a fast intramolecular step (equation 32).

	+ 2H+	+	+
NH NH		NH2	NH2

+	slow	(32)
NH2		NH2
2	−2H+
	H2 N

Finally, it is interesting that the nitrogen isotope effects for the formation of benzidine and diphenyline are almost identical. This suggests that both reactions have almost the same amount of nitrogen nitrogen bond rupture in the transition state of the rate-

determining step.
Boduszek and Shine42 studied the	acid-catalyzed quinamine rearrangement of
the quinamine, 6-bromo-2,4-dimethyl-4-(phenylamino)cyclohexa-1,4-dienone		(13), to
40-amino-6-bromo-2,4-dimethyldiphenyl	ether (equation 33). This study	involved

synthesizing the quinamine 13 (Scheme 27) labelled at (i) the nitrogen with nitrogen15, (ii) the para-position of the phenyl ring with carbon-14, (iii) the ortho position of the phenyl ring with carbon-14 and (iv) the carbonyl oxygen with oxygen-18.

Br

Br

CH3

	O	H+
	NH		O	CH3
		H2 N
	CH3			(33)
	(13)		CH3

The labelled substrates required for this study were obtained by substituting (i) the commercially available 15N-aniline, (ii) the [4-14C]aniline prepared by deaminating

the	commercially available 4-nitro[1-14C]aniline and reducing the nitro group with
tin	and HCl, (iii) the [2-14C]aniline formed by reducing the commercially available

[2-14C]nitrobenzene with tin and HCl and (iv) the 2,4-dimethyl[18O]phenol, respectively, in the synthesis described in Scheme 27. The 2,4-dimethyl[18O]phenol was synthesized by diazotizing 2,4-dimethylaniline with sodium nitrite and fluoroboric acid and treating the diazonium salt with oxygen-18 labelled water.

Miller43 showed that the quinamine rearrangement was intramolecular and that the reaction was first order in both the quinamine and acid. The isotope effects found for this quinamine rearrangement were measured in 83.3% aqueous methanol at 25 °C. The nitrogen isotope effect of 1.0089, the oxygen-18 isotope effect of 1.0399 and the carbon-14 isotope effect of 1.0501 at carbon-4 of the phenyl ring, found for this quinamine rearrangement, show that the nitrogen carbon-1 bond is breaking and that the carbon-4 oxygen bond is forming in the transition state of the rate-determining step of this reaction. This clearly indicates that the quinamine rearrangement is concerted. However, the nitrogen

	20. The synthesis and uses of amino and quaternary ammonium salts					931
				Br
HO	CH3		Br2	HO	CH3
CH3				CH3
	Br2 , HOA c
			NaOA c, − 5 °C
Br					Br
	CH3 NH2			, NaOA c	CH
O					3
					O
	Br			− 5 °C
					NH
CH3					CH
					3

SCHEME 27

kinetic isotope effect is much smaller than either the oxygen-18 or the carbon-14 isotope effect at carbon-4 of the phenyl ring. This suggests the slow step of the quinamine rearrangment involves a [5,5]sigmatropic shift via an unsymmetrical transition state with only a slight amount of carbon nitrogen bond rupture but extensive carbon oxygen bond formation (equation 34).

			+
CH3	NH	CH3	NH2
		H+
Br	CH3	Br	CH3
	O	O
			CH3
CH3		+	(34)
		NH2
		Br	CH3
		−H +	O
Br	CH3
	O
		H

NH2

932	Kenneth C. Westaway

Finally, although a very small inverse k12/k14 isotope effect of 0.990š 0.008 was found when the substrate with carbon-14 at the 2-position of the phenyl ring was used, the authors concluded that there was no carbon-14 isotope effect in the quinamine rearrangement to the phenyl ether. This was expected because no bond forms at carbon-2 in the transition state of the concerted [5,5]sigmatropic rearrangement. The authors attributed this very small inverse isotope effect of 0.990 to a large k12/k14 D 1.07 that was observed for the formation of a side product. The faster reaction of carbon-12 in forming the side product would enrich the unreacted substrate in carbon-14 and lead to the inverse isotope effect.

IV. USING KINETIC ISOTOPE EFFECTS TO MODEL THE SN 2 TRANSITION STATES FOR REACTIONS INVOLVING QUATERNARY AMMONIUM SALTS

A. The Menshutkin Reaction

Matsson and coworkers have measured the carbon-11/carbon-14 kinetic isotope effects for several Menshutkin reactions (equation 35) in an attempt to model the SN2 transition state for this important class of organic reaction. These isotope effects are unusual because they are based on the artificially-made radioactive carbon-11 isotope. The radioactive carbon-11 isotope is produced in a cyclotron or linear accelerator by bombarding nitrogen14 atoms with between 18and 30-MeV protons (equation 36).

		CH3						+	CH3	−
R	N	CH3	+ R′CH2			X		R′CH2 N	R X		(35)
									CH3
14 N	+	p+		11C		+ He					(36)

The 11C decays with a half-life of 20.34 minutes, to 11B, by emitting a positron that can be detected in a scintillation counter. In spite of the difficulties in producing the carbon-11 isotope, preparing the labelled substrate and carrying out the reaction in a very short time, these carbon-11/carbon-14 kinetic isotope effects are a very useful addition to the arsenal of tools available to the physical organic chemist. This is because the difference in mass between the carbon isotopes is three in a mass of only eleven. As a result, these isotope effects can be as large as 25%, which is in the range of some of the larger secondary hydrogen deuterium kinetic isotope effects. This means that these extremely large heavy-atom kinetic isotope effects should be capable of detecting very small changes in the structure of SN2 transition states.

The first report of this new type of kinetic isotope effect in a Menshutkin reaction was published by Matsson and coworkers in 198744. In this study, the alpha carbon k11/k14 kinetic isotope effect was measured for the Menshutkin reaction between N,N- dimethyl-para-toluidine and labelled methyl iodide in methanol at 30 °C (equation 35). The carbon-11 labelled methyl iodide required for this study was prepared from the 11C atoms produced in the cyclotron in three steps45 (equation 37).

11C		O2		11CO2	LiAlH4	11CH3OH	HI	11CH3I	37
	C		!		!		!

THF

The carbon-14 labelled methyl iodide used to measure the k11/k14 was commercially available.