Group Title: radical pathway for reductive dehalogenation and nucleophilic substitution of hetaryl halides
Title: A radical pathway for reductive dehalogenation and nucleophilic substitution of hetaryl halides
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 Material Information
Title: A radical pathway for reductive dehalogenation and nucleophilic substitution of hetaryl halides
Physical Description: xii, 165 leaves. : illus. ; 28 cm.
Language: English
Creator: Oestreich, Terence Miller, 1942-
Publication Date: 1973
Copyright Date: 1973
 Subjects
Subject: Halides   ( lcsh )
Reduction (Chemistry)   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
 Notes
Thesis: Thesis -- University of Florida.
Bibliography: Bibliography: leaves 159-164.
General Note: Typescript.
General Note: Vita.
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Bibliographic ID: UF00098378
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000585101
oclc - 14181806
notis - ADB3733

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A RADICAL PATHWAY FOR REDUCTIVE
DEIIALOGENATION AND NUCLEOPHILIC
SUBSTITUTION OF HETARYL HALIDES







By



TERENCE MILLER OESTREICH


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA IN PARTIAL
FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY


UNIVERSITY OF FLORIDA
1973






















To My .v ife,

Martha













ACKNOWLEDGEMENT


The author will always be indebted to Dr. John A.

Zoltewicz, Chairman of his Supervisory Committee, for

his perceptive guidance and patient support during the

course of this research. Appreciation is also extended

to the other members of his Committee: Dr. Merle A.

Battiste, Dr. Richard D. Dresdner, Dr. Paul Tarrant,

and Dr. Robert B. Bennett.

Special gratitude is due his wife, Martha, for her

unfailing support and understanding during the disap-

pointments and achievements of these years.

The friendship and assistance of other members of

his research group will always be remembered.

Thanks are extended to his wife, Martha, and Mrs.

Judi Nielsen for their help in preparing the manuscript.

Financial support from the Chemistry Department of

the University of Florida and from the National Science

Foundation is gratefully acknowledged.















TABLE OF CONTENTS

Page
ACKNOWLEDGEMENT ......................................... iii

LIST OF TABLES......................................... vi

LIST OF FIGURES. ....................................... viii

ABSTRACT ................ ........................ ...... xi

CHAPTER

1. INTRODUCTION.................................. 1

2. ALKOXIDE ION PROMOTED REDUCTIVE
DEHALOGENATION OF HETARYL HALIDES............. 5

Results .................. .................... 5

Discussion .................................... 37

3. ALKOXIDE ION PROMOTED NUCLEOPHILIC
SUBSTITUTION OF IETARYL HAL1DES............... 52

Results....................................... 52

Discussion................................... 80

4. AIDE ION PROMOTED NUCLEOPHILIC SUBSTITUTION
OF 4-HALOISOQUINOLINES........................ 91

Results....................................... 91

Discussion ................................... 104

5. COVALENT AMINATION AND ANIONIC SIGMA COMPLEXES
OF ISOQUINOLINE DERIVATIVES................... 110

Results................... .................... 110

Discussion.................................... 118

6. EXPERIMENTAL .................................. 123

Instrumentation............................... 123








Page
Chemicals ...................................... 124

Preparations ................................... 125

Thin Layer Chromatography Plates............... 134

Gas-Liquid Phase Chromatography Columns........ 134

Stock Solutions................................ 135

Solutions for Kinetic Runs..................... 136

Methods of Kinetic Runs........................ 137

Reactions in Liquid Ammonia.................... 147

Control Experiments............................ 151

BIBLIOGRAPHY .......................................... 159

BIOGRAPHICAL SKETCH.................................... 165














LIST OF TABLES


Table Page

1. Variation of the Product Ratio in the Reductive
Dehalogenation of 4-Bromoisoquinoline........... 7

2. Stoichiomctric Relationship Between Methoxide
Ion and Isoquinoline in the Reductive
Dehalogenation of 4-Bromoisoquinoline ........... 13

3. Reaction of 0.58 M 4-Bromoisoquinoline at 1650
with 1.3 MI Sodium Methoxide in the Presence and
Absence of 10.01 M Copper (II) Chloride........ 19

4. Reductive Dehalogenation of 4-Bromoisoquinoline
by Sodium Methoxide Under Pseudo-first-order
Conditions at 165 ............................... 30

5. Reaction of Various Hetaryl Halides with Sodium
Methoxide ..................................... 32

6. Reductive Dehalogenation of Hetaryl Halides by
Metal Alkoxides ............................... 36

7. Product Ratios for the Reaction of
4-Bromoisoquinoline with Sodium Methoxide and
Sodium Thiophenoxide .............................. 54

8. Product Ratios for the Reaction of
4-Bromoisoquinoline with Sodium Methoxide and
Sodium Thiophenoxide in the Presence of
Inhibitors..................... .................. 56

9. Product and Reactant Ratios at Various Times for
the Reaction of 0.52 M 4-Bromoisoquinoline with
0.98 M Sodium Methoxide and 0.98 M Sodium
Thiophenoxide at 147 ........................... 58

10. Product Ratios at Various Times for the Reaction
of 0.52 M 4-Bromoisoquinoline with 0.98 NM Sodium
Thiophenoxide in the Presence of 0.2 M
Azobenzene at 1470 .............................. 60

11. Kinetic Results for Concurrent Pseudo-first-
order Reaction of 4-Bromoisoquinoline with
Sodium Methoxide and Sodium Thiophenoxide at
1650 .............................................. 70














Table


Page


12. Reactions of N0.4 M 4-Bromoisoquinoline with
Sodium Methoxide and/or Sodium Methylmercaptide
at 1650.......................................... ... 76

13. Summary of the Reactions of Substituted
Isoquinolines with Various Bases in Refluxing
Ammonia........................................ 98

14. Chemical Shifts and Coupling Constants for
Aminodihydro Compounds from the Addition of
Ammonia to Various Heteroaromatic Ions.......... 111

15. Chemical Shifts of Anionic Sigma Complexes
Formed by the Addition of the Amide Ion to
Isoquinolines .................. ................. 117

16. Chemical Shifts for Low Field Protons of
Reactant and Products in the Reaction of
4-Bromoisoquinoline with Metal Alkoxides and
Sulfur Nucleophiles in Methanol................. 139














LIST OF FIGURES


Figure Page

1. Rate of Consumption of Methoxide Ion in the
Reductive Dehalogenation of 4-Bromoisoquinoline
at 1650; [NaOCli3]o = 0.79 IM, [4-Bromoisoquinoline]o
= 0 .37 M ...... ............ ... ...... ... ............. 21

2. Rates of Disappearance of 0.66 M
4-Bromoisoquinoline in 1.6 M Sodium Methoxide
with and without 0.6 M
1,1-Diphenylethylene at 147 0....................... 23

3. Superimposed Plots for Rates of Disappearance of
4-Bromoisoquinoline and Sodium Methoxide at 1470
in the Presence of 0.6 M
1,1-Diphenylethylene ............................... 24

4. Rates of Disappearance of 0.60 M
4-Bromoisoquinoline in 1.6 M Sodium Methoxide
with and without 0.3 M
2,2'-Dinitrobiphenyl at 147 ....................... 26

5. Superimposed Plots for Rates of Disappearance of
4-Bromoisoquinoline and 2.5 M Sodium Methoxide at
1470 in the Presence of 0.3 M
2,2'-Dinitrobiphenyl .............................. 27

6. Rates of Disappearance of 0.44 M
4-Bromoisequinoline in 2.5 M Sodium Methoxide
Showing the Effects of 0.05 M Azoxybenzene and
0.05 M Nitrobenzene at 143 0........................ 28

7. Disappearance of 1.2 M 4-Bromoisoquinoline in
0.67 M Sodium Methoxide and 1.1 M Sodium
Thiophenoxide at 1650 .............................. 62

8. Rates of Disappearance of 0.52 M
4-Bromoisoquinoline and Appearance of
Isoquinoline in 0.98 M Sodium Methoxide and
0.98 M Sodium Thionhenoxide at 1470 with and
without 0.2 M Azobenzene............................. 63


viii













9. Rates of Appearance of 4-Phenylthioisoquinoline
from 0.52 M 4-Bromoisoquinoline in 0.98 M
Sodium Methoxide and 0.98 M Sodium
Thiophenoxide at 1470 in the Absence and
Presence of ,0.2 M Azobenzene and Rates of
Appearance of 4-Phenylthioisoquinoline from
0.52 M 4-Bromoisoquinoline and 0.98 M Sodium
Thiophenoxide at 1470 in the Absence and
Presence of .0.3 MN Azobenzene...................... 64

10. Rates of Appearance of 4-Phenylthioisoquinoline
from 1.2 M 4-Bromoisoquinoline in 1.1 M Sodium
Thiophenoxide at 165 in the Presence of 0.67 M
Sodium Methoxide and in the Absence of Sodium
Methoxide........................................ 66

11. Relative Rates of Reaction of 0.60 M1
4-Bromoisoquinoline in 1.5 M Sodium Methoxide and
1.6 M Sodium Thiophenoxide at 1430 in the
Presence and Absence of 0.03 M Azoxybenzene...... 68

12. Appearance of 4-Methylthioisoquinoline and
Isoquinoline from 0.47 M 4-Bromoisoquinoline in
u2.2 M Sodium Methoxide at 127 with and without
'0.1 M Azoxybenzene .............................. 78

13. Rates of Appearance of 4-(4-Chlorophenylthio)-
isoquinoline from 0.51 M 4-Bromoisoquinoline in
0.98 M Sodium 4-Chlorothiophenoxide and 0.98 M
Sodium Methoxide at 1470 with and without 0.4 M
Azoxybenzene..................................... 79

14. Product Ratios Versus Base Ratios in the
Competition Reaction of 4-Bromoisoquinoline with
Sodium Methoxide and Thiophenoxide at 165 0....... 88

15. Calibration Curve Used to Determine the
Concentration of Sodium Methoxide in Methanol by
NMR ................................................ 142

16. Rate of Column Temperature Rise with Program Set
at Maximum Power as Used in All GPC Analyses
Requiring Temperature Changes.................... 146

17. Second-order Plot for the Rate of Cleavage of
0.71 M 4-Methoxyisoquinoline by 1.1 M Sodium
Methoxide in Methanol at 1650..................... 153


Figure


Page











Figure


Page


18. Pseudo-first-order Plot for the Rate of Cleavage
of 0.020 M 4-Methoxyisoquinoline by 0.91 M
Sodium Methoxide in Methanol at 1650............ 155

19. Second-order Rate Plot for the Reaction of 1.17
M 4-Bromoisoquinoline with 1.13 M Sodium
Thiophenoxide in Methanol at 1650.............. 156

20. Second-order Rate Plot for the Reaction of 0.52
H 4-Bromoisoquinolinc with 0.98 M Sodium
Thiophenoxide at 1470........................... 158













Abstract of Dissertation Presented to the Graduate Council
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

A RADICAL PATHWAY FOR REDUCTIVE
DEIIALOGENATION AND NUCLEOPHILIC
SUBSTITUTION OF HETARYL HALIDES

by

Terence Miller Oestreich

March, 1973

Chairman: Dr. John A. Zoltewicz
Major Department: Chemistry


Evidence for a radical chain mechanism of reductive

dehalogenation of 4-bromoisoquinoline by methanolic sodium

methoxide was obtained from product and kinetic studies.

Known radical and electron traps were employed to inhibit

the reaction and to alter the product ratio. The reductive

dehalogenation appears to be a general reaction for hetaryl

halides which do not undergo rapid substitution by methoxide

ion. It is concluded that methoxide ion is a better hydrogen

atom donor to the proposed 4-isoquinolyl radical than is

methanol.

Methoxide ion was also shown to promote nucleophilic

substitution of 4-bromoisoquinoline by thiophenoxide ion.

Known radical and electron traps provided evidence for a

radical chain mechanism for nucleophilic substitution of

the hetaryl halide by negatively charged sulfur

nucleophiles.








It was shown that the amide ion promoted substitution

of 4-bromoisoquinoline by methylmercaptide ion in refluxing

ammonia may not occur solely via a hetaryne mechanism;

rather, a radical chain mechanism is suggested.

The existence and structure of some anionic sigma

complexes of isoquinoline derivatives with amide ion in

liquid ammonia was demonstrated, and the covalent amination

products of some quaternized heteroaromatic salts in

liquid ammonia were studied.












CHAPTER 1

INTRODUCTION

In 1940 Bergstrom and Rodda reported some very curious

results.' In attempting to carry out what they expected to

be a simple substitution reaction, they found that 4-bromo-

isoquinoline in the presence of methanol-sodium methoxide

(7 hours at 235) or t-butyl alcohol-potassium t-butoxide

(2000 and apparently the same time) gave isoquinoline instead

of the expected 4-alkoxyisoquinoline, equation 1. The iso-

quinoline was isolated in 43-54% yields from several experi-

ments. No explanation was offered for the unexpected result.


Br H

lJ M Rt QO N i(1)
ROH





In 1967 Bunnett and Wamser reported the reductive de-

iodination of m-chloroiodobenzene in methanolic sodium meth-

oxide in the presence of a source of radicals to initiate

the reaction, equation 2.2 They demonstrated that this new
type of reaction proceeds by a radical chain mechanism.

Their new results suggested to us the possibility that the

reductive debromination of 4-bromoisoquinoline observed by







Bergstrom and Rodda proceeded by a similar radical chain

mechanism. This prompted the investigation into the mechanism

of the reductive debromination of 4-bromoisoquinoline.

Results are presented in Chapter 2 and show that our expecta-

tions are met.

I II

Cl lONa (2)

Radicals

Once it became apparent that radical species were

involved in the reductive debromination of 4-bromoisoquino-

line, further studies were initiated in the form of trapping

experiments with sulfur nucleophiles in hopes of shedding

light upon the nature of the intermediate radicals and the

details of the mechanism. The use of sodium thiophenoxide

as a radical trap was very successful and led to the illuci-

dation of a new mechanism for the substitution of hetaryl

halides as the investigations in Chapter 3 will show. The

reaction of 4-bromoisoquinoline with sodium methoxide and

sodium thiophenoxide in methanol results in simultaneous

reductive dehalogenation and substitution, equation 3.


Br H SCfHs


woj NaOCI 0 ^ Qa +ON (3)








Bergstrom and Rodda also reported that treatment of 4-

bromoisoquinoline with potassium or sodium amide in reflux-

ing ammonia yielded only tar.' Originally it appeared to

us that the tar could have resulted from the reactions of

the elusive, highly reactive 2,3-pyridyne type intermediate

(in this case 3,4-isoquinolyne).3-s It was decided to

attempt to trap this intermediate using negatively charged

sulfur nucleophiles as had been successfully done for

3,4-pyridyne;6 the proposed reaction scheme is illustrated

by equation 4. As the results of our substitution studies

on 4-bromoisoquinoline in methanol began to unfold, a second


Br SR

QRS (4)




mechanism, a radical chain process, also appeared as a

possibility. The results of these studies are presented

in Chapter 4.

Finally, several experiments which were directed to

the observation of possible intermediates in the reactions

of 4-bromoisoquinoline in ammonia are reported in Chapter 5.

The existence and structure (I) of sigma anionic complexes

resulting from amide ion addition to an isoquinoline ring

were established. These studies were extended so as to

include the addition of ammonia to quaternized hetero-





4


aromatic compounds to give covalent amination products such

as II.


G



N-
H NH2


I













CHAPTER 2

ALKOXIDE TON PROMOTED REDUCTIVE
DEHALOGENATION OF 1IETARYL HALIDES


Results

Products and product ratios from the reaction of

4-bromoisoquinoline with sodium methoxide.-4-Bromoisoquin-

oline was reduced to isoquinoline by sodium methoxide at

temperatures ranging from 143 to 1650 in yields greater

than 90 percent, Table 1. Reactions were generally carried

out in sealed nmr tubes. The reaction mixtures were analyzed

directly by nmr with t-butyl alcohol often serving as an

internal area standard. The identity of isoquinoline was

confirmed using tlc and glpc. At 1650 in the presence of

0.79 M sodium methoxide, the reaction was complete after one

hour. Reductive dehalogenation could also be made to take

place on a larger scale. For example, 5.3 g of 4-bromo-

isoquinoline in the presence of excess sodium methoxide was

reduced to isoquinoline in 97 percent yield (nmr analysis

of the reaction mixture) after heating in a Monel bomb at

1650 for 1000 minutes.

Two other isoquinoline products were detected in the

reaction mixtures. Comparison (nmr spectra) with authentic

materials revealed that they are 4-methoxyisoquinoline and

4-hydroxyisoquinoline. The latter compound is believed to

arise from methoxide ion induced cleavage of 4-methoxyiso-








quinoline. Those reaction mixtures heated for long periods

of time showed a decrease in the amount of 4-methoxyiso-

quinoline product while the amount of 4-hydroxyisoquinoline,

present in its ionized form, increased. The conversion of

4-methoxyisoquinoline to 4-hydroxyisoquinoline was confirmed

in separate experiments. Authentic 4-methoxyisoquinoline

was converted to 4-hydroxyisoquinoline in methanol-sodium

methoxide solution at 1650; this reaction has a rate constant

of 9.7 X 10-5 mol-' sec-'. It is assumed that methyl ether

is the other product of the cleavage reaction, equation 5.


OCII3 ONa


W "N + NaOCI3 ----- + CHICICH3 (5)




In the absence of additives, the yields of substitution

products were less than 10 percent. Hence the reduction to

substitution ratio was always greater than 10, Table 1.

Sodium format is believed to be present as well. This

identification rests on the observed chemical shift (T 1.30)

and reports that sodium format forms when redox reactions

are carried out in methanol-sodium methoxide solution.7'8

From a reaction mixture which had been carried to completion,

all solid was removed by filtration. This solid failed to

melt below 274, and therefore could not have contained a

significant amount of sodium format, mp 2530.9 The solu-

tion (which must contain all the sodium format formed) was








Table 1. Variation of the Product Ratio
4-Bromoisoquinoline.


in the Reductive Dehalogenation of


[NaOClIs]




None

0.79

0.79

1.0

1.3

1.3

1.6

2.5

1.3

1.6

1.6

1.8


[Substrate]




2.9

0.30

0.37

0.40

0.58

0.51

0.66

0.44

0.51

0.66

0.66

0.42


Additive


T,C




165

165

165

165

165

165

147

143

165

165

165

147


% Reduction
% Substitution



No reaction

>10

>10

>10

>10

>10

>10

>10

>10

>10

>10

>10


None

None

None

None

None

None

None

None

(Amber nmr tube)

N2 Saturated

02 Saturated

30% (V:V) Benzene


~I_










Table 1. Continued.


[NaOCH3] [Substrate] T,C Additive % Reduction
% Substitution


0.3 M 2,2'-
1.6 0.66 147 Dinitrobiphenyl 0.9

0.6 M 1,1-
1.6 0.66 147 Diphenylethylene 5

2.5 0.44 143 0.05 M Nitrobenzene 4

2.5 0.44 143 0.5 M Azoxybenzene 5

3.3 0.5 143 0.6 M Azoxybenzene 1

0.87 0.38 165 0.95 M Hydrazinec 7

0.99 0.37 165 50% DMSOd 3

0.39 0.23 ,23 90% DMSOd >10

0.39 0.36 100 90% DMSOd' 1

0.39 0.37 165 90% DMSOd 0.7

1.3 0.58 165 0.01 M CuC12 4

0.80 0.38 165 0.05 M CuC12 0.25

0.80 0.37 165 0.05 M CuCI 7










Table 1. Continued.


[Substrate]




0.50

0.46


T,Co




141

100


Additive


50% DMSO; CuC12

50% DMSO; CuC12


% Reduction
% Substitution



1

4


aConcentrations (mol/l) are corrected for thermal expansion of methanol except
when DMSO is present.

The product ratios were determined at or near completion of the reaction.

c[NaOMe] is actually less than 0.87 M due to water in the 95+% hydrazine.

Percent by volume of DMSO in methanol.


[NaOCH 3]




2.5

2.3


~ ~I~Y~^__ El~









analyzed by nmr, and the isoquinoline to format ion ratio

was determined to be 2.0. The precipitate which failed

to melt below 274 is believed to be sodium bromide.

Since sodium format is only slightly soluble in

methanol, some question exists as to whether the nmr analyses

give a valid measure of the amount of sodium format formed

in the reaction. NMR analyses of a standard solution of 0.55 M

isoquinoline and 0.26 M sodium formate in methanol gave an

isoquinoline to sodium format molar ratio of 2.04. The

molar ratio was 2.12 by weight, and no precipitate was

present in the prepared solution. Addition of excess sodium

format to this standard solution and subsequent analysis

by nmr showed the saturated concentration of sodium format

to be 0.48 M in the absence of sodium methoxide. (In the

presence of sodium methoxide, the solubility of sodium format

is reduced by the common ion effect.) Therefore the stoichio-

metric relationship between isoquinoline and sodium format

established by nmr analysis in the preceding experiment in

which the isoquinoline concentration was near 0.5 M is valid.

An attempt to prepare a methanol solution of 2.0 M

sodium methoxide and 1.5 M methyl format resulted in the

immediate formation of a large volume of white precipitate.

This precipitate was presumed to be sodium format, and

analysis by nmr confirmed this presumption. It seems likely

that the hydrolysis reaction involves residual water present

in the solvent. In the presence of a relatively high con-

centration of sodium methoxide, the sodium format was less








soluble than usual, and, with the addition of water, all

remaining methyl format was immediately converted to sodium

format, and a homogeneous solution was obtained.

A control run was conducted on a sodium methoxide

solution (1.9 M) at 165, After adding t-butyl alcohol for

an internal area standard and flushing with nitrogen, the

sealed tube was heated for 210 minutes. No methoxide ion

was consumed, and no format ion was formed. Therefore, it

appears that format ion formation is associated with the

formation of isoquinolinc.

Another control run showed that sodium methoxide is

essential to the reductive dehalogenation process. When

a solution of 4-bromoisoquinoline was heated in pure methanol

at 1650 for 1146 minutes, no reaction was detected by nmr.

So long as sodium methoxide was present in a greater

than two-fold excess, the reductive dehalogenation reaction

proceeded to completion. No rate retardation was detected

when the reaction was carried out in an amber nmr tube, and

therefore photocatalysis is not essential to the reaction.

Saturation of the reaction solution at 0 with oxygen or

nitrogen produced no dramatic rate change. After 10 minutes

at 165 identical solutions, one saturated with nitrogen

and one with oxygen, were analyzed by nmr, and the ratio of

starting material to product was the same in both cases; the

reaction was half complete at this point (0.4 M 4-bromoiso-

quinoline and 0.4 M isoquinoline). However, nmr analysis

showed that the methoxide ion concentration was 0.16 M less








in the tube containing oxygen. The initial methoxide ion

concentration was 2.0 M; this dropped to -1.5 M after 10

minutes for the solution saturated with nitrogen and to

~1.3 M for the solution saturated with oxygen. A control

experiment in which methanol was saturated with oxygen at

-780 (dry ice-acetone) followed by addition of some sodium

methoxide-methanol failed to show any methoxide ion consump-

tion when the mixture was heated at 1650. If there were

inhibition in the presence of oxygen, it was over quickly

and could not be detected by only one analysis after 10

minutes at 1650. The reason for the apparent additional meth-

oxide ion consumption in the presence of oxygen is unclear.

The relationship between methoxide ion consumption and

isoquinoline formation is presented in Table 2. Results

from three different reaction mixtures at two temperatures

are given. They show that the molar ratio of methoxide ion

consumed to isoquinoline formed is in the range of 1.5 to 2.1.

Several experiments were conducted to investigate the

effects of potential radical inhibitors on the course of the

reaction. Those organic compounds which had a noticeable

effect on the reaction included 2, 2'-dinitrobiphenyl, 1,1-

diphenylethylene, nitrobenzene, azoxybenzene, and hydrazine.

The results are summarized in Table 1.

In the case of 2, 2'-dinitrobiphenyl (0.3 M), it was

obvious from the slower rate of disappearance of 4-bromoiso-

quinoline that inhibition had occurred, but it was impossible

to determine the reduction to substitution product ratio










Table 2. Stoichiometric Relationship Between Methoxide Ion and Isoquinoline in the
Reductive Dehalogenation of 4-Bromoisoquinoline.


[NaOClls]o Minutes A [NaOCH3]


1.0


2

4

6

9

12

15

18

21

24

28

32

36

108


0

0.040

0.11

0.28

0.45

0.50

0.57

0.63

0.67

0.71

0.73

0.78

0.90


[Substrate]
[Substrate]


A [NaOCH,]
[Isoquinoline]


[Isoquinoline]




0

0.020

0.062

0.14

0.22

0.25

0.28

0.31

0.34

0.37

0.42

0.44

0.45


_CII_











Table 2. Continued.


[Substrate]




0.38b


[NaOCH3]




0.99


Minutes




4

8

12

16

20

28

36

60

120


A[NaOCH3]




0

0.20

0.32

0.42

0.47

0.54

0.57

0.66

0.70


_ Igl


[Isoquinolire] A[NaOCH,]
[Isoquinoline]



0

0.10 2.0

0.19 1.7

0.23 1.8

0.22 2.1

0.35 1.5

0.38 1.5

0.40 1.7

0.41 1.7











Table 2. Continued.


Minutes




5

10

15

S20

25

30

40

50


A[NaOCH3




0.28

0.62

0.90

1.06

1.14

1.16

1.20

1.28


[Isoquinoline]




0.18

0.38

0.50

0.57

0.61

0.63

0.65

0.69


A [NaOCCH3]
[Isoquinoline]



1.6

1.6

1.8

1.9

1.9

1.8

1.8

1.9


[Substrate]l




0.80c


aConcentrations (mol/l) are not corrected for thermal expansion of methanol.
Initial concentrations of reactants are indicated.

b
16 50

C1470.


[NaOCHa]o




2.0


_ I_








directly by nmr because of overlap between the downfield

singlet of 4-methoxyisoquinoline and the singlet from format

anion. However, the concentration of 4-methoxyisoquinoline

may be estimated by assuming no new products or mass loss

and by knowing the concentration of 4-bromoisoquinoline and

isoquinoline. The product ratio calculated in this manner

is 0.9 and differs from the product ratio in the absence of

2, 2'-dinitrobiphenyl by a factor of >10.

It was possible to determine the product ratio directly

for the other four inhibitors used. In these cases overlap

of the 4-methoxyisoquinoline and format ion peaks did not

preclude successful analysis by nmr. A concentration of

much less than 0.6 M 1, 1-diphenylethylene reduced the ratio

by at least factor of 2. The exact concentration of 1,-

1-diphenylethylene is unknown because it is partially

immiscible with methanol.

Nitrobenzene (0.05 M) and azoxybenzene (0.05 M) also

reduced the product ratio by at least a factor of 2. In the

case of nitrobenzene (and also 2, 2'-dinitrobiphenyl), the

identity of the actual inhibitor(s) is uncertain. Nitro-

benzene is known to react with methoxide ion at 690 to give

azoxybenzene.7 Nitrosobenzene and phenylhydroxylamine are

postulated as intermediates in this reaction. A higher

concentration (0.6 M) of azoxybenzene further reduces the

product ratio to unity.

The product ratio was lowered by addition of (95%+)

hydrazine. A known hydrogen atom donor,10 hydrazine was

the least effective of the additives and lowered the product









ratio by less than a factor of 2 despite being present at a

nearly 1 M concentration. The mechanism effecting this

change is not certain.

An attempt to trap intermediate radicals by the addition

of 30 percent by volume of benzene to a methanolic solution

of 4-bromoisoquinoline (0.42 M) and sodium methoxide (1.8 M)

with t-butyl alcohol as an internal area standard failed.

After 40 minutes at 1470, analysis by nmr indicated that

isoquinoline was present in 94 percent yield. Although

small amounts of 4-methoxyisoquinoline and 4-phenylisoquino-

line may have been present, they could not be detected by nmr.

Use of DMSO as a cosolvent had a profound influence on

the reaction rate and product ratio. The change in product

ratio may arise from an enhancement of the direct substitu-

tion reaction by the excellent solvation properties of DMSO.

The product ratio decreased by at least a factor of 3 in a

1:1 (V:V) DMSO and methanol solution, and the amount of

.material which normally precipitated from the reaction

mixture was reduced. A more dramatic effect was observed

when a 9:1 (V:V) DMSO-methanol solvent system was employed.

In this solvent system 4-bromoisoquinoline was reduced to

isoquinoline; no other products were present in sufficient

quantity to be detected by nmr. This exclusive reduction

occurred at room temperature over a 2 1/2 day period. When

the reaction was carried out at 165, it was complete within

1 minute and gave a 0.7 product ratio. This represents a

decrease in the product ratio by at least a factor of 10

relative to that at room temperature.









Copper salts had a dramatic effect on the reduction to

substitution product ratio, Table 1. The effect of copper

(II) chloride appears to be greater than that of copper (I)

chloride. Solutions were heterogeneous, owing to the poor

solubility of the copper salts; indicated concentrations do

not reflect the actual amounts in solution. Instead, they

indicate the amount of material which would have been present

in solution if the salts were soluble. The substitution

reaction increases in importance in the presence of these

salts, and in one instance (0.05 M copper (II) chloride) the

substitution product became the major product.

Closer examination of the effect of copper (II) chloride,

Table 3, shows that the copper salt apparently simultaneously

slowed the conversion of 4-bromoisoquinoline to isoquinoline

and speeded up the substitution reaction by methoxide to give

4-methoxyisoquinoline. The net effect was a slower rate of

disappearance of 4-bromoisoquinoline to give more substitution

product. Note that the amount of substitution product does

not increase after the initial observation. When the reaction

was repeated on a preparative scale using one equivalent of

the copper salt, a 47 percent yield of 4-methoxyisoquinoline

was obtained. This suggests that copper (II) chloride may

not be of great value as an inhibitor in kinetic studies

involving radical chain reactions of hetaryl halides because

of its effect on competing mechanisms such as direct sub-

stitution. The acceleration of the non-radical chain

process masks the inhibition of the radical chain process










Table 3. Reaction of 0.58 M 4-Bromoisoquinoline at 1650 with 1.3 M Sodium Methoxide
in the Presence and Absence of '\0.01 M Copper (II) Chloride.


% 4-Bromoisoquinoline
No CuC12 With CuC12


% Reduction
No CuC12 With CuC1,


Substitution
No CuC1 With CuCIl


trace

3

3


Minutes


12.9

19.9


aIn the absence of an internal standard, the percentages given are based upon the
assumption that there is no mass loss and that starting material, isoquinoline,
and 4-methoxyisoquinoline are all the compounds present.








by increasing the rate of disappearance of hetaryl halide.

However, the preparative use of copper (II) chloride is

apparent and was utilized.

A control run showed that when copper (II) chloride is

allowed to react with a sodium methoxide solution at 1650

in the absence of hetaryl halide, elemental copper is formed

immediately.

Attempts to initiate the reduction of 4-bromoisoquino-

line were made using ABIN (2,2'-azobis-isobutyronitrile).

In two experiments ABIN was added to reaction mixtures which

were heated at 1000. In one case a 0.32 M solution of

4-bromoisoquinoline in 0.30 M sodium methoxide and 0.63 M

ABIN (assuming all dissolved) was heated for 90 minutes with

no reaction. Then a 0.15 M solution of substrate was heated

for 30 minutes in 0.30 M ABIN and 1.5 M sodium methoxide to

give a 30 percent conversion to isoquinoline. These results

indicate that high concentrations of methoxide ion are an

essential requirement of the reaction. It is clear that ABIN

does accelerate the reduction reaction because no reaction

occurs under the same conditions over 3 hours in the absence

of ABIN.

Kinetics of reduction of 4-bromoisoquinoline by sodium

methoxide.-Data for the rate of disappearance of 4-bromo-

isoquinoline and methoxide ion, and for the rate of appearance

of isoquinoline were obtained in the presence and absence of

inhibitors using nmr. Figure 1 shows a typical plot for the

rate of disappearance of sodium methoxide in a reaction













0.9

0.8

0.7

S0.6

< 0.5

0.4

0.3

0.2

0.1



0 10 20 30 40 50 60 70 80 90
Minutes

Figure 1. Rate of Consumption of Methoxide Ion in the Reductive Dehalogenation
of 4-Bromoisoquinoline at 1650; [NaOCH3]o = 0.79 M, [4-Bromoiso-
quinoline]o = 0.37 M. (The difference in chemical shift between the
13CH and the hydroxyl proton peaks of methanol is used to determine
the methoxide ion concentration. Subscripts o, t, and 1 stand for
time zero, intermediate time, and the last time, respectively.)









mixture containing 4-bromoisoquinoline and no added inhibitor.

The shape of the concentration-time plot is similar to that

(not shown) for the disappearance of the hetaryl halide.

Note that the consumption of methoxide ion is slow in the

very early stages of the reaction, suggesting the presence

of an induction period. A mass balance calculated on the

basis of starting material, and reduction and substitution

products indicate that there is no build-up of intermediates

at a level detectable by nmr analysis. Attempts to obtain

second-order rate constants by considering the reaction to

be first-order in 4-bromoisoquinoline and sodium methoxide

are unsuccessful. Curvature results using experimentally

determined sodium methoxide concentrations. These concentra-

tions reflect the stoichiometry given in Table 2. This is

not unexpected, considering the presence of an induction

period.

Figure 2 shows the effect of 1, 1-diphenylethylene on

the rate of disappearance of 4-bromoisoquinoline. A meth-

anolic solution of substrate and sodium methoxide was divided

between two nmr tubes, one of which contained some 1, 1-di-

phenylethylene. t-Butyl alcohol was added as an internal

standard. The 1, 1-diphenylethylene was not completely miscible

with the reaction mixture. However on heating, there was

obvious inhibition of the reaction of 4-bromoisoquinoline,

and the peaks representing 1, 1-diphenylethylene underwent

change. Figure 3 gives superimposed plots for the rates of

disappearance of substrate and methoxide ion in ; presence

of the inhibitor, 1, 1-diphenylethylene. The close fit of

















8o 80
0

70

0" 60




RH 40
0
e, 30

U
S 20 B-
-) B
10



0 50 100 150 200 250 300 350

Minutes

Figure 2. Rates of Disappearance of 0.66 M 4-Bromoisoquinoline in 1.6 M Sodium
Methoxide with (A) and without (B) 0.6 M 1,1-Diphenylethylene at 1470.













1.00 "

0.90 0

0.80
0
0.70

S0.60

" 0" .50

0.40

0.30 0
0
0.20

0. 10

0
50 100 150 200 250 300 350

Minutes

Figure 3. Superimposed Plots for Rates of Disappearance of 4-Bromoisoquino-
line (0) and Sodium Methoxide (A) at 1470 in the Presence of
0.6 M 1,1-Diphenylethylene. (Reactant concentration is [R];
subscripts are the same as those in Figure 1.)









the two curves indicates that in the presence of 0.6 M 1,

1-diphenylethylene the rate of the reaction as measured by

the disappearance of methoxide ion is the same as that

measured by the disappearance of 4-bromoisoquinoline. There-

fore, methoxide ion is not being consumed by another route,

e.g., reaction with the inhibitor.

The results of a similar experiment using 2, 2'-dinitro-

biphenyl are given in Figure 4. Again inhibition of the

reaction pathway for consumption of 4-bromoisoquinoline is

obvious, and it appears to be more effective than that by

1, 1-diphenylethylene. Superimposed plots comparing the

rates of disappearance of substrate and methoxide ion in the

presence of 2,2'-dinitrobiphenyl are presented in Figure 5.

In this case the line representing methoxide ion consumption

lies below that for 4-bromoisoquinoline indicating that some

methoxide was consumed by reaction with another substance,

most likely to be the inhibitor, 2, 2'-dinitrobiphenyl.

Figure 6 shows the effectiveness of azoxybenzene and

nitrobenzene in inhibiting the reduction of 4-bromoisoquino-

line. Inhibition by nitrobenzene is particularly effective,

and the plot shows complete inhibition and a classical induc-

tion period for 40 minutes. The extremely low concentrations

of these inhibitors necessary to produce inhibition are also

a good measure of their effectiveness.

Attempts were made to make the reduction and substitution

reactions zero-order in sodium methoxide. This was done by

decreasing the concentration of 4-bromoisoquinoline to


















90
r 80
80
"70
70
S 60




40

30

2u 0
10




0 50 100 150 200 250 300 350

Minutes

Figure 4. Rates of Disappearance of 0.60 M 4-Bromoisoquinoline in 1.6 M
Sodium Methoxide with (A) and without (B) 0.3 M
2,2'-Dinitrobiphenyl at 1470.












1.00

0.90

0.80 -

0.70

S0.60 O 0
\ o
0.s50o

0.40 -

0.30 -

0.20

0.10


50 100 150 200 250 300 350
Minutes

Figure 5. Superimposed Plots for Rates of Disappearance of 4-Bromo-
isoquinoline (0) and Sodium Methoxide (A) at 1470 in the
Presence of 0.3 M 2,2'-Dinitrobiphenyl. (Reactant
subscripts are the same as those in Figure 1).














100

S 90
80

rl C
o 70
0
o 60
B
0 50


o 40

aC 30
U

20 A

10


0 10 20 30 40 50 60 70 80

Minutes

Figure 6. Rates of Disappearance of 0.44 M 4-Bromoisoquinoline in 2.5 M
Sodium Methoxide (A) Showing the Effects of 0.05 M Azoxybenzene
(B) and 0.05 M Nitrobenzene (C) at 1430









approximately 0.02 M while maintaining the sodium methoxide

concentrations near 1 M. This change required that analysis

of the reaction mixtures be carried out by glpc. With the

columns that were tried, the peaks for 4-bromo- and 4-methoxy-

isoquinoline could not be separated. Moreover, the method

did not measure the amount of 4-isoquinolyl oxide formed from

the cleavage of 4-methoxyisoquinoline.

The last two experiments in Table 4 were conducted to

determine by isolation the amount of oxide formed in a

reaction mixture initially about 0.02 M in substrate. The

oxide was precipitated as 4-hydroxyisoquinoline by neutral-

izing a water-methanol solution with hydrochloric acid. The

identity of the 4-hydroxyisoquinoline was confirmed by

its melting point. A control run established that the rate

constant for cleavage of 4-methoxyisoquinoline under condi-

tions where the reaction is zero-order in sodium methoxide

is 8.3 X 10 5 mol' sec 1.

Table 4 presents the date obtained from several reaction

mixtures analyzed by glpc. The mass balance was low in all

runs and appeared to decrease with time in the one run for

which analyses were conducted at various times. A control

experiment was conducted to determine the stability of

isoquinoline under the reaction conditions. A solution of

0.036 M isoquinoline and 0.99 M sodium methoxide was heated

at 1650 for 1210 minutes. Analysis by glpc indicated that

over 75 perce:-: of the isoquinoline was recovered unchanged.

The reason for the poor mass balance is unclear, and so studies

were discontinued.










Table 4. Reductive Dehalogenation of 4-Bromoisoquinol ne by Sodium Methoxide
Under Pseudo-first-order Conditions at 1650.


[Substrate]



0.016





0.016

0.016

0.015

0.017


Minutes



60

310

885

800

1090

950

1063


Results


24% Isoquinoline; 103% mass balance

35% Isoquinoline; 56% mass balance

51% Isoquinoline; 51% mass balance

88% Isoquinoline

34% Isoquinoline

7% 4-Hydroxyisoquinolineb

20% 4-Hydroxyisoquinolineb


aConcentrations (mol/1) are


corrected for thermal expansion of methanol.


brsolated yields; no information is available concerning isoquinoline yields in
these runs.


[NaOCH3]



0.91


0.91

0.79

0.75

0.76









Reduction of other hetaryl halides by sodium methoxide.-

Studies of the reduction of hetaryl halides other than 4-

bromoisoquinoline were conducted on a limited basis. 4-Bromo-

3-methylisoquinoline, 4-chloroisoquinoline, 3-bromoquinoline,

and 3-iodopyridine underwent reductive dehalogenation. All

reactions were studied by nmr. The formation of sodium

format accompanied each of these reductions. The product

ratios resulting from competing direct substitution and

reduction processes are given in Table 5. Almost exclusive

reduction occurs in the brominated quinoline and isoquinoline

substrates, whereas the 4-chloroisoquinoline and 3-iodopyri-

dine undergo relatively more substitution. The reduction

to substitution ratio for 3-iodopyridine was further reduced

by the presence of azoxybenzene and copper (II) chloride.

In the presence of copper (II) chloride, no reduction product

could be detected by nmr in the case of 3-iodopyridine; only

substitution product was detected.

Several potential inhibitors were used in attempts to

inhibit the reduction of 4-bromo-3-methylisoquinoline. These

included benzophenone, phenanthrene, phthalazine, pyridine

N-oxide, 7,8-benzoquinoline, sodium format, 2,2-diphenyl-l-

picrylhydrazyl, and meta-dinitrobenzene. No inhibition was

observed, but none of these potential inhibitors was shown

to be effective in the case of 4-bromoisoquinoline. Methoxide

ion consumption and decomposition occurred in the runs using

2,2-diphenyl-l-picrylhydrazyl and meta-dinitrobenzene.










Table 5. Reaction of Various Hetaryl Halides with Sodium Methoxide.a


Substrate (M)b


4-Bromo-3-methylisoquinoline
(0.36)

4-Chloroisoquinoline (0.33)d

3-Bromoquinoline (0.36)

3-Iodopyridine (0.42)

3-Iodopyridine (0.42)

3-Iodopyridine (0.95)


[NaOCHa ]b




1.5


1.2

0.79

2.5

2.5

1.3


T,C


Additives (M)


165


165

165

143

143 Azoxybenzene (0.05)

100 and 165g CuC12h


%Reduction
% Substitutions


>10


6e

>10

2.5
0f
1

<0.1


aReactions were carried out and analyzed in sealed nmr tubes.

bConcentrations (mol/l) are corrected for thermal expansion.

CThe product ratios were determined at or near completion of the reaction.










Table 5. Continued.


dThis kinetic run was conducted by Dr. A. A. Sale.

eThis is the upper limit of the product ratio. The ratio is actually smaller due to
cleavage of 4-methoxyisoquinoline to give the oxide which has the same chemical
shift as isoquinoline H-3.

fThere is considerable overlap of peaks, and product ratios are only approximate.

gConcentrations given are at 1650.

hThe concentration of CuC12 was not determined, but it is about 0.05 M.








Copper (II) chloride not only drastically changed the

product ratio as shown in Table 5, but it also had a marked

influence on the rate of disappearance of 3-iodopyridine.

A solution of 3-iodopyridine (0.95 M) and sodium methoxide

(1.3 M) was divided between two nmr tubes, one containing

copper (II) chloride. Neither solution showed evidence of

reaction after 25 minutes at 1000, but the solution contain-

ing copper (II) chloride reacted completely in an additional

10 minutes at 1650. No reaction was detected in the absence

of the copper salt under identical conditions.

The reason for the rate enhancement of direct substi-

tution by copper (II) chloride is unclear. 3-Bromopyridine

and 3-chloropyridine react much more slowly than 3-iodo-

pyridine even in the presence of copper (II) chloride; 3-

bromopyridine underwent very little reaction and 3-chloro-

pyridine failed to react at all. In order to determine if

the iodide ion freed in the reaction of 3-iodopyridine is

essential to the rate enhancement process, a run was carried

out using 3-chloropyridine and added potassium iodide. A

solution of 3-chloropyridine (0.63 M), copper (II) chloride

(0.03 M), potassium iodide (0.05 M), and sodium methoxide

(1.6 M) was heated for 90 minutes at 165. Only a trace of

3-methoxypyridine was produced. Therefore iodide ion does

not play an essential role in the rate enhancement process.

The reaction of 4-chloroisoquinoline with sodium meth-

oxide was also studied. The rate of disappearance of 4-chloro-

isoquinoline is approximately 3 times slower than that of








4-bromoisoquinoline under similar conditions. After cor-

recting for the 14 percent of starting material which reacted

with 2 moles of methoxide ion to give one mole of 4-isoquinolyl

oxide ion, it was found that 1.2 moles of methoxide ion

reacted with one mole of 4-chloroisoquinoline to give

isoquinoline.

Reduction of hetaryl halides by alkoxides other than

sodium methoxide.-Alcoholic solutions of lithium methoxide,

sodium n-propoxide, and potassium t-butoxide reduced hetaryl

halides when heated at 1650. These results are presented

in Table 6. There are no gross differences in the rates of

reduction of 4-bromo-3-methylisoquinoline by sodium n-prop-

oxide or of 4-bromoisoquinoline by lithium methoxide from

those with sodium methoxide. The reductive dehalogenation

reaction appears to be a general reaction of alkalai metal

alkoxides with the hetaryl halide.

Potassium t-butoxide reacted with 4-bromoisoquinoline

at 1400 and 1650 in t-butyl alcohol to give what appeared by

nmr analysis to be isoquinoline and a large amount of tars.

The reaction mixture darkened immediately on heating and the

resolution of nmr spectra deteriorated with continued heating.

An external area standard (methanol) was employed, and the

total mass balance decreased with continued heating. However

both the degradation leading to tar formation and the forma-

tion of isoquinoline were retarded by small amounts of azoxy-

benzene (0.04 M) or 1,1-diphenylethylene (0.1 M).










Table 6. Reductive Dehalogenation of Hetaryl


Substrate (M)


4-Bromo-3-methyl-
isoquinoline (0.7)

4-Bromo-3-methyl-
isoquinoline (0.7)

4-Bromo-
isoquinoline (0.5)

4-Bromo-
isoquinoline (0.5)

4-Bromo-
isoquinoline (0.65)

4-Bromo-
isoquinoline (0.65)b

4-Bromo-
isoquinoline (0.65)b


Alkoxide (M)


Sodium n-
propoxide-(^l)

Potassium
t-butoxide (1l)

Lithium
methoxide (0.87)

Potassium
t-butoxide (,l)

Potassium
t-butoxide (1l)

Potassium
t-butoxide (1l)

Potassium
t-butoxide (l)


Additive (M)


T,C


165


Azoxybenzene
(0.04)

1,1-Diphenyl-
ethylene (0.1)


Results


30% Reduction
in 37 minutes

Reduction and
degradation

50% Reduction
in 30 minutes

Reduction and
degradation

Reduction and
degradation

Inhibition oF reduc-
tion and degradation

Inhibition of reduc-
tion and degradation


Reactions were carrie
thermal expansion.


d out in sealed nmr tubes. Concentrations are not corrected for


bMethanol was used as an external standard, and the concentration of potassium
t-butoxide was identical in these three runs.


_I~LI_~ __ I_


__


Halides by Meltal Alkoxides. a









More specifically, after 30 minutes at 1400 in the pre-

sence of -1 M potassium t-butoxide and 0.1 M 1,1-diphenyl-

ethylene, 90 percent of the 4-bromoisoquinoline (originally

0.65 M) remained unreacted. The hydroxyl peak moved upfield

by 10 cycles relative to the position before heating, sug-

gesting the consumption of alkoxide ion. Under identical

conditions in the absence of an inhibitor, only 40 percent

of the 4-bromoisoquinoline remained unreacted and 25 percent

isoquinoline was formed. The hydroxyl peak moved upfield

by 50 cycles relative to the position before heating in

this uninhibited run. Similar results were obtained using

azoxybenzene as an inhibitor.


Discussion

A proposed mechanism for'the sodium methoxide induced

reductive dehalogenation of 4-bromoisoquinoline.-Several

pieces of evidence support a radical chain process and

eliminate a purely ionic process for the reduction of 4-

bromoisoquinoline by sodium methoxide. These include (a)

a change in the reduction to substitution product ratio in

the presence of known radical and electron traps, (b) a

decrease in the rate of disappearance of 4-bromoisoquinoline

in the presence of known radical and electron traps, (c) an

acceleration of the reduction reaction by a known radical

initiator, and (d) the presence of induction periods in the

absence of added inhibitor. These four pieces of evidence

will be considered in turn in order to show that they are









consistent with a radical route leading to the formation

of isoquinoline.

It is not clear how much, if any, 4-methoxyisoquinoline

results from a radical substitution process. However, the

fact that the amount of 4-methoxyisoquinoline increases in

the presence of inhibitors does suggest that this product

can form by a non-radical process at a rate comparable to

that for the reduction reaction. This non-radical process

is likely to involve the "classical" ionic aromatic nucleo-

philic substitution pathway. A change in the reduction to

substitution product ratio in the presence of inhibitors

indicates the operation of multiple mechanisms which are

likely to be both radical and ionic.

In the absence of radical traps the reduction to sub-

stitution (by methoxide ion) ratio was always greater than

10, meaning that although 4-methoxyisoquinoline could be

detected in the nmr spectrum, it was not present in sufficient

quantity for meaningful integration, Table 1. The presence

of low concentrations of nitrobenzene (0.05 M) and azoxy-

benzene (0.05 M) reduced this product ratio by a factor of

about two. Nitrobenzenes are estabilished electron acceptors

and inhibitors of radical chain processes."-'6 Unfortunately,

under the reaction conditions employed, nitrobenzenes react

with methoxide ion to give azoxybenzenes.7'8 However, azoxy-

benzenes, as well as the intermediates (nitrosobenzenes and

phenylhydroxylamines)7 in the reaction of nitrobenzene with

methoxide ion, should also be electron acceptors and inhibitors









of radical chain processes. The presence of a high concen-

tration of azoxybenzene has a profound effect upon the pro-

duct ratio by effectively inhibiting the radical chain reac-

tion leading to the formation of isoquinoline. 2,2'-Dinitro-

biphenyl (0.3 M) also has a dramatic effect on the product

ratio reducing it by a factor of greater than 10, and these

results may be interpreted in the same manner as those for

nitrobenzene.

1,1-Diphenylethylene (<0.6 M) reduced the product ratio

by a factor of about two. This is a known radical trap

which has been used in an ethanolic solution of sodium eth-

oxide for inhibition of a radical chain process for the

decomposition of triarylsulfonium alkoxides.17

The retardation of the rate of disappearance of 4-

bromoisoquinoline in the presence of radical inhibitors

provides a strong argument for a radical chain process of

reductive dehalogenation. This retardation by 1,1-diphenyl-

.ethylene (<0.6 M), 2,2'-dinitrobiphenyl (0.3 M), azoxybenzene

(0.05 M) and nitrobenzene (0.05 M) can be seen in Figures 2,

4, and 6. In view of this rate retardation by four different

organic compounds, it would be very difficult to justify

consideration of any ionic mechanism for the reductive dehalo-

genation of 4-bromoisoquinoline by sodium methoxide.

This retardation of the rate of disappearance of 4-bromo-

isoquinoline in the presence of inhibitors cannot be due

entirely to side reactions which give the appearance of

inhibition. The retardation must reflect the ability of the









inhibitor to interfere with a radical chain process. Since

the reduction reaction is dependent on the concentration of

sodium methoxide (kinetic order unknown), it is possible that

the reduction reaction is retarded by side reactions between

inhibitors and the base. These side reactions may decrease

the concentration of the base and hence decrease the rate

of reduction. While in some cases this may be true, it

cannot be the entire explanation. These complications will

be considered individually.

Since nitro-compounds are known to react with methoxide

ion, it must be determined if retardation by nitrobenzene

and 2,2'-dinitrobiphenyl is due to destruction of methoxide

ion rather than to interception of radical intermediates.

The stoichiometry of the reduction of nitrobenzene by meth-

oxide ion to azoxybenzene requires that 3 moles of methoxide

ion be consumed for every 4 moles of nitrobenzene.'8 Thus,

the reaction of 0.05 M nitrobenzene would reduce the meth-

oxide ion concentration by 0.04 M; this is an insignificant

amount in light of the fact that the initial conce-':- tion

of methoxide ion was 2.5 M. In the case involving 2,2'-

dinitrobiphenyl the destruction of methoxide ion is likely

to be more significant, and the effective methoxide ion

concentration is expected to be reduced from 1.6 M to 1.2 M.

This effect can be seen in Figure 5 where it is obvious that

the rate -' consumption of methoxide is greater than would

be expe': on the basis of reaction with 4-bromoisoquinoline

alone. As a result the rate retardation in the presence of









2,2'-dinitrobiphenyl is probably due in small part to con-

sumption of methoxide ion.

Azoxybenzene and 1,1-diphenylethylene are not expected

to react with sodium methoxide under the reaction condi-

tions.7'17,18 Moreover, azoxybenzene was an effective

inhibitor at 0.05 M concentration; it would be most unusual

if azoxybenzene at this concentration level reacted to sub-

stantially effect a methoxide ion concentration initially

2.5 M. Figure 3 indicates that 1,1-diphenylethylene does

not react with methoxide ion under the reaction conditions;

that is, the rates of the reaction as measured by the dis-

appearance of 4-bromoisoquinoline and by the disappearance

of methoxide ion in the presence of 1,1-diphenylethylene

are the same. If massive amounts of methoxide ion underwent

reaction with 1,1-diphenylethylene, one would expect to see

a separation of the two curves as in Figure 5 where methoxide

ion did react with 2,2'-dinitrobiphenyl in addition to

4-bromoisoquinoline.

Interpretation of the results involving copper salts

is complicated by a number of factors, including the presence

of several oxidation states of copper and coordination of the

heterocycle and oxidized copper. Copper (I) is known to

form copper (I) methoxide which is unstable.19,20 Copper (II)

chloride undergoes reduction to elemental copper under the

reaction conditions in the absence of heterocycle. Copper

(II) ion forms a complex with 4-bromoisoquinoline at room

temperature in methanol, and such complexes are expected to








enhance greatly the electrophilic reactivity of the hetero-

cyclic ring. Copper (I) chloride, copper (II) chloride, and

the copper (II) complex of 4-bromoisoquinoline are only

slightly soluble under the reaction conditions.

However, copper salts are known to be electron acceptors

and effective radical traps.21,22 Copper (I) oxide is

known to catalyze the reduction and nucleophilic substitution

of aryl halides in alcoholic metal alkoxide mixtures, but

the mechanisms have not been established.23-26

The presence of very low concentrations (<0.05 M) of

copper (I) and copper (II) chlorides had a profound influence

on the product ratio, Table 1. Moreover, comparison of the

runs described in Table 3 after 5.9 minutes shows that the

overall rate of disappearance of 4-bromoisoquinoline in the

presence of -0.01 M copper (II) chloride is slower than in

the absence of the copper salt. This can only be due in

small part to the destruction of methoxide ion by the reduc-

tion of copper (II) ion because the copper (II) ion to meth-

oxide ion ratio is 130. But the rate of formation of sub-

stitution product, 4-methoxyisoquinoline, appears to be

accelerated in the presence of copper (II) chloride. There-

fore the rate of the reduction reaction has been retarded.

After 5.9 minutes it appears that the reaction consuming

copper (II) chloride is complete. There is no further

formation of the substitution product and the reduction

reaction appears to proceed at a normal rate. The reduction-

substitution product ratio after the first 5.9 minutes of








the reaction is 0.87; after additional minutes, the ratio

has increased to 2.5. It appears that copper (II) ion is

very effective in pro-,'ting substitution and inhibiting

reduction, but that fast side reactions with methoxide ion

giving clnmental copper cause this effect to be short lived.

Strong evidence for a radical chain process is the

initiation of the reduction reaction by a known free radical

source. This evidence was obtained using ABIN27 in the

reaction mixture to accelerate the formation of isoquinoline.

An initial short but real induction period, which is charac-

teristic of radical chain processes, was also observed in

all of the kinetic runs.

A radical chain mechanism of reduction of 4-bromoiso-

quinoline to isoquinoline is suggested in Schene I. There

is little in the experimental results to indicate the detailed

steps of the reduction mechanism, and so Scheme I represents

speculation. However much of this speculation has precedent.

Scheme I

Initiation:

Donor + 4Brlsoq P Donor' + [4Brlsoq] ( 6)

Propagation:

[4Brlsoq]' Isoq. + Br ( 7)
Isoq- + CH30O [IsoqH]" + CH20 ( 8)
Isoq- + CHI3OH Isoql + -CH20H ( 9)
Isoq- + C130- IsoqHl + '*CH 0- (10)
*CH20H + CHM30- CH1301 + *CHl20- (11)
*CH20- + 4Brlsoq CH20 + [4BrIsoq]' (12)
CH20- + 4BrIsoq BrCH20- + Isoq. (13)








The exact nature of the initiation step is not known.

The electron donor, Donor- in equation 6, could be methoxide

ion, which, on donation of an electron to 4-bromoisoquinoline.

would give a methoxy radical which would most likely react to

give the carbon radical, equation 15. The reaction in equa-

tion 15 has a rate constant of about 10' mol-I sec-'.21 It

has been suggested that the methoxide ion is a good reducing

agent by virtue of observations that paraquat (l,l'-dimethyl-

4,4'-bipyridylium ion) is reduced by methoxide ion.29,30

CH30- + 4Brlsoq 2 CH3aO + [4BrIsoqlJ (14)

CH30- + MeOH + -CH20H + MeOH (15)

Alternatively, the electron donor could be the anion

resulting from the addition of methoxide ion to 4-bromoiso-

quinoline, equation 16. Electron donation by pi-delocalized



Br Br

+ CH30- ---- 16)




anions is well documented,14 and the formation of radical

anions under conditions giving anionic sigma complexes has

also been reported.13 The formation of the 1-methoxy anionic

sigma complex of 4-bromoisoquinoline has not been directly

observed; however the analogous formation of the 1-amino

anionic sigma complex of 4-bromoisoquinoline and amide ion

is reported elsewhere in this dissertation.








Several reports have appeared describing the results

of electron transfer to halopyridines. Loss of halide ion

follows the electron transfer, and the pyridyl radical is

formed.3133 This process is analogous to the first propa-

gation step in equation 7 showing loss of halide ion from

the initially formed radical anion to give the 4-isoquinolyl

radical. The exact structure of the 4-isoquinolyl radical

is unknown, but since the 2-, 3-, and 4-pyridyl radicals are

a radicals,31,32 it is reasonable to assume that the 4-iso-

quinolyl radical is also a a radical. It has also been

reported that halopyridines can be polarographically reduced

to pyridine.33

Equations 9, 11, and 12 are analogous to those proposed

by Bunnett and Wamser for the reduction of aryl iodides in

alkaline methanol via a radical chain process.2 An important

difference between this work and the work being discussed

here is that the deiodination of aryl iodides requires

initiation by an external radical source while the reductive

debromination of 4-bromoisoquinoline proceeds spontaneously

on heating.

Radical abstraction of halogen by *CH2OH to give an

aryl radical was ruled out by Bunnett and Wamser2 because

this mechanism does not account for their observation that

sodium methoxide is required. However, radical abstraction

of halogen by the radical anion of formaldehyde, equation 13,

seems to us to be a viable alternative route.








Bromine abstraction by -CH20- in the case of 4-bromo-

isoquinoline is a possibility which must be considered

seriously. Thus, substituent effect studies on free-radical

abstraction of iodine from aromatic34 and aliphatic iodides35

show that the carbon atom from which the halogen is being

removed has anionic character in the transition state. Con-

sider now the polar transition state, III, for debromination

of the isoquinoline. The likely sense of polarization is

shown. This involves the generation of the 4-isoquinolyl

anion. The 4-isoquinolyl anion is known to form when iso-

quinoline is deprotonated by base, and the annular nitrogen

atom provides considerable inductive stabilization of the

negative charge.36 In the debromination reaction by -CH20-,

the indicated polarization produces a formaldehyde-like

structure. It seems likely with this polarization that *CH20O

will be more reactive than *CH20H. The latter will give rise

to a protonated formaldehyde-like structure in the transition

state and is less favored energetically.

Br- CH2=O
Br 'CH20 ..-




III


Either methanol or methoxide ion could serve as the

hydrogen atom donor to the 4-isoquinolyl radical, equations

9 and 10. Methoxide ion is expected to be a better donor

than methanol. (No comparison of these two donors appears to









have been published.) There are numerous reports that

electron-donating substituents on the hydrogen atom donor
37
facilitate this transfer. In the present case this sense

of polarization of the transition state, IV, for hydrogen

atom transfer is particularly favorable. Again, a 4-iso-

quinolyl anion-like structure is produced and the oxide ion

(from 'CH)20) is expected to stabilize the transition state

more than the hydroxy group (from 'CH20H). Oxide ion is a
38
better electron donor than the hydroxy group. The relative

amount of hydrogen atom donation from the two donors cannot

be gauged from the present study. The more reactive donor

is present in lower concentration (typically about 1 M)
39
relative to methanol (20 M for the neat material at 1650).

If methanol is a hydrogen atom donor, the hydrogen atom
4 0
should come largely from the methyl group.

H-CH20O- H CH2=0




IV


There is a possibility that isoquinoline forms by hydride

transfer from methoxide ion to the 4-isoquinolyl radical,

equation 8. A radical anion forms in this case. When this

radical anion donates an electron to 4-bromoisoquinoline,

product is formed and the chain is continued. Such a sequence

seems to be unprecedented, however.









The termination steps in the proposed mechanism are

obscure. However, since a good mass balance is observed for

the reaction, it is likely that the radical chain is long

and that the initiation and termination steps have little

effect upon the stoichiometry of the reaction.

The formaldehyde formed in Scheme I most likely reacts

under the reaction conditions to give methylformate. The

methylformate subsequently reacts with hydroxide ion formed

from methoxide ion and residual water to give the format

ion which was detected in the nmr spectra (equations 17

through 19).

2CH20 HCO2CH3 (17)

CH30- + H20 CH3OH + OH" (18)

HCO2CH3 + OH" HCO2- + CH31OH (19)

Furthermore the proposed mechanism requires that 0.5

mole of format ion be produced per mole of isoquinoline.

The experimental observation was exactly that. The format

ion to isoquinoline ratio was 0.5. No methylformate was

observed in the reaction mixtures. It was shown that the

nmr signals of methylformate overlap with the methanol and

aromatic mass proton signals of the reaction mixtures. More-

over, methylformate reacts so quickly with hydroxide ion to

give format ion and methanol that a sufficient concentration

for detection by nmr is never present.

The reductive dehalogenation reactions carried out with

DMSO as a cosolvent may proceed by a different mechanism.

This may involve the dimsyl anion. This mechanism is described








in equations 20 through 22 and has been reported for the

reductive dehalogenation of aryl halides and bromothio-

phenes.41-45 Briefly, this mechanism involves formation of

the dimsyl anion by deprotonation of DMSO, nucleophilic

displacement on halogen by the dimsyl anion forming a halo-

methyl sulfoxide and an aryl anion, and then proton abstrac-

tion from the alcohol solvent by the aryl anion. This

mechanism does not involve format ion formation as does

the radical chain process.

CH1sO + CHsSOCH3 CII301{ + CHsSOCH2- (20)

CHIISOCH2- + ArX Ar- + CH3SOCH2X (21)

Ar- + CH30H ArH + CHa30 (22)

Extension of reductive dehalogenation to other bases

and substrates.-Reductive dehalogenation appears to be a

common reaction for hetaryl halides in which the halogen is

meta to the annular nitrogen. (When the halogen is ortho

or para to the annular nitrogen the nucleophilic substitution

reaction is especially favored, and substitution occurs

instead of reduction.) The reduction of 4-chloroisoquinoline

in methanolic sodium methoxide shows that the reaction is

not limited to a brominated isoquinoline and the reduction

of 3-bromoquinoline and 3-iodopyridine shows that other

halogenated heterocyclic ring systems undergo the reaction.

A more highly substituted isoquinoline such as 4-bromo-3-

methylisoquinoline is also reduced under these conditions.

It seems likely that these reduction reactions proceed by

the same kind of mechanism considered for 4-bromoisoquinoline.









t-Butyl alcohol is a poor hydrogen atom donor because

it has no alpha hydrogens. That t-butoxide was able to

effect the reduction of 4-bromoisoquinoline via a radical

chain process was a mild surprise. In fact, Bergstrom's

observation that 4-bromoisoquinoline is reduced to isoquino-

line by t-butoxide in about 50 percent yield (isolated as the

picrate)' is confirmed by our analysis of reaction mixtures

by nmr. Furthermore the rate of formation of isoquinoline in

these mixtures is retarded by two different radical traps

(azoxybenzene and l,l-diphenylethylene), demonstrating that

the reaction pathway involves a radical chain. An upfield

shift of the hydroxyl peak also suggested that t-butoxide ion

was consumed in the course of this reaction. It is not clear

what serves as the hydrogen atom donor in this solvent. It

should be noted that decomposition products are present in

the reaction mixture as evidenced by the dark color. Perhaps

the hydrogen atom comes from degraded material.

Related Investigations.-Although little has been reported

to date on the mechanism of base catalyzed reductive dehalo-

genation of hetaryl halides, there have been several related

reports on other systems. Some of these have already been

mentioned when they were directly applicable; others deserve

comment at this point.

The reductive debromination of hexabromobenzene in the

presence of methoxide ion has been reported. A radical

mechanism for the protodebromination of hexabromobenzene to

give penta- and tetrabromobenzenes was quickly dismissed








because no biphenyls were detected when benzene was added to

the reaction mixture, and the carbanion mechanism previously

reported by Bunnett46 was postulated. Hydrazine hydrate reacts

with hexabromobenzene in ethanol to replace two adjacent

bromine atoms with hydrogen via an unknown mechanism.4

6- and 8-Bronoquinolines were reported to undergo

reductive dehalogenation with sodium methoxide at 1250 in

48 and 71 percent isolated yields respectively. An ionic

mechanism was suggested for these reactions in which meth-

oxide ion addition to C-2 was followed by a proton adding at

C-6 or C-8. Loss of positive bromine and methoxide ion then

gave quinoline, equation 23. Little evidence was given to

support this mechanism, and it is possible that the reactions

proceed via a radical chain process.48 By comparison, treat-

ment of 7-bromoquinoline with sodium methoxide resulted in

formation of 7-methoxyisoquinoline.49 These observations

follow the emerging pattern that substitution is favored when

the negative charge of the initial anionic sigma complex can

be delocalized onto the annular nitrogen, e.g. 7-bromoquino-

line, but when this is not possible, reduction occurs

instead.




Br
Br Br -Br+ H
_ONrH CH H3 (23)
OCH
OCH3














CIIAI'l I R 3

ALKOXIDE ION PROM'IOT.D IniCIlIOPlIT. IC
SUBSTTITTION O0: liTARYL IALIDES


Results

Products and product ratios from the reaction of 4-bromo-

isoquinoline with mixtures of sodium methoxide nd sodium

thiophlienoxide.-4- Bromoisoquinol inc underwent simultaneous

reduction and substitution when heated in a methanolic solu-

tion of sodium methoxide and sodium thiophenoxide at 165.

Reactions were generally carried out in sealed nmr tubes, and

the reaction mixtures were analyzed directly by nmr with

t-butyl alcohol often serving as an internal standard. The

identity of the products v;as confirmed by tlc and glpc. The

time required for the reaction to proceed to completion was

dependent upon the methoxide ion concentration. For example,

a reaction mixture 0.36 M in 4-bromoisoquinoline, 0.62 M in

sodium methoxide, and 0.75 M in sodium thiophc-,oxide required

between 45 and 85 minutes at 1650 to go to >95 percent comple-

tion. (The reaction mixture was not examined between these

two times.) Another reaction mixture 0.40 M in 4-bromoiso-

quinoline, 1.9 M in sodium methoxide, and 0.79 M in sodium

thiophenoxide required less than 10 minutes at 1650 to go to

>95 percent completion. The only substantial difference in

these two reaction mixtures is the sodium methoxide concentra-

52








tion. There is little or no degradation of products under

the reaction condition-, and the 'mass balance is high. A

control run was conducted to verify the stability of 4-phenyl-

thioisoquinoline under the reaction conditions. This compound

is stable in 2 M sodium methoxide and methanol heated at 1650

for 320 minutes. After 1441 minutes at 165, a typical

reaction mixture with sodium isobutyrate as an internal area

standard was analyzed by nmr, and the analysis showed a

combined product yield of 92 percent. Another reaction mix-

ture heated at 1470 for 90 minutes with t-butyl alcohol as

an internal area standard was analyzed by nmr and the analysis

showed a combined product yield of 105 percent. A small

amount of degradation (<5 percent) may have occurred in the

reaction mixture heated for 1441 minutes at 165, but this is

an unusually long reaction time for the experiments analyzed

by nmr, and generally the nmr analyses are valid to 5 percent.

The above results and others obtained at 165 are tabu-

lated in Table 7 in order of decreasing sodium methoxide to

sodium thiophenoxide ratio. In the presence of the more

nucleophilic thiophenoxide ion and without added inhibitor,

very little 4-methoxyisoquinoline was produced, and it could

not generally be detected in the nmr spectrum. Therefore,

Table 7 only lists the isoquinoline to 4-phenylthioisoquino-

line product ratios. Considering the first five entries in

Table 7, for which there is initially a sodium methoxide to

4-bromoisoquinoline molar ratio of greater than or nearly

equal to 2, it is apparent that the isoquinoline to










Table 7. Product Ratios for the Reaction of 4- romoisoquinoline with Sodium
Methoxide and Sodium Thiophenoxide.


[Substrate]o


0.57

0.40

0.44

0.56

0.36

1.2

0.52

0.60


[NaOCII3] a [NaSC6iI5] a [NaOCI13]a
rNaSC6alla


2.0

1.9

1.2

1.5

0.62

0.67

0.98

1.5


0.69

0.79

0.67

1.5

0.75

1.1

0.98

1.6


2.9

2.4

1.9

1.0

0.83

0.60

1.0

0.94


[NaOCIl3]f
[NaSC6Hs]




33.0

,2.3

1.8

'0.98

0.77

0

,l.0

<0.87


T,OC %Isoquinoline
% 4-Phenylthioiso-
quinoline


165

165

165

165

165

165

147

143


1.7

1.7

1.2

0.71

0.66

0.49

0.62

0.80


aReactions were carried out in sealed nmr tubes. Concentrations are corrected for
thermal expansion.

Subscripts refer to initial and final concentrations; the final values are
calculated values.









4-phenylthioisoquinoline ratio decreases as the initial

concentration ratio of sodium methoxide to sodium thiophen-

oxide decreases. The former ranges from 1.7 to 0.66 as the

latter ranges from 2.9 to 0.83. Those reactions in which

there is less than a 1.5:1 molar ratio of sodium methoxide

to 4-bromoisoquinoline could give an unusually low product

ratio due to complete consumption of methoxide ion in the

reduction process. In the experiment listed with less than

a stoichiometric concentration of sodium methoxide, the

product ratio is 0.49.

The final pair of reactions listed in Table 7 were

conducted at temperatures lower than 1650. The effect of

temperature on the product ratio is not certain, but it

appears that lowering the reaction temperature lowers the

reduction-substitution product ratio. Comparison of the

last entry at 143 with an earlier entry of nearly the same

concentrations shows that the product ratio dropped from 1.0

to 0.80 with the 22 degree temperature change.

As shown in Table 8, various additives had an effect

upon the product ratio. Each of the radical inhibitors

known to be effective in suppressing the reduction of 4-

bromoisoquinoline decreased the product ratio so as to

favor phenylthio substitution product. For the first three

entries in Table 8, the product ratio from the control run

in the absence of inhibitor is 1.0, and in each case the

inhibited reaction gives a product ratio two-thirds or one-

half that of the control run. At the lower temperatures










Table 8. Product Ratios for the Reaction of 4-Bromoisoquinoline with Sodium
Methoxide and Sodium Thiophenoxide in the Presence of Inhibitors.a


[Substrate]o [NaOCH3]o [NaSCsHs]o [NaOCH3]o
[NaSC6Hss]



0.56 1.4 1.5 0.93


0.56


0.56


0.52


0.60


1.4


1.4


0.98


1.5


1.5


1.5


0.98


1.6


0.93


0.93


1.0


0.94


T,C % Isoquinolineb
% 4-Phenylthio-
isoquinoline


165 0.7 (1.0)


0.5


0.5


0.44


0.2


(1.0)


(1.0)


(0.62)


(0.80)


Inhibitor




0.02 M 3-Car-
bamoyl-2,2,5,5,-
tetramethyl
3-pyolin-l-
yloxy radical

0.06 Mc
CuC12

0.2 M Nitro-
benzene

0.2 M Azoben-
zene

0.4 M Azoxy-
benzene


aReactions were carried out in sealed nmr tubes. Concentrations are corrected for
thermal expansion.
bProduct ratio in the absence of inhibitor is indicated in parentheses.

cThis would be the concentration if all the CuC12 dissolved.








(1470 and 1430), 0.2 M azobenzene reduces the product ratio

by one-third, and 0.4 M azoxybenzene reduces the product

ratio by three-fourths.

The product ratios which are listed in Tables 7 and 8

were taken near the end of the reactions. In the absence of

inhibitors, these ratios adequately describe the course of

the reaction and do not undergo gross variations with time.

From Figures 8 and 9, the product ratios can be obtained at

four different times during the reaction. Assuming a 2:1

stoichiometric relationship between methoxide ion consumed

and isoquinoline formed and a 1:1 relationship between

thiophenoxide ion and 4-phenylthioisoquinoline, Table 9 can

be constructed. By the time a significant variation in the

methoxide to thiophenoxide ion ratio occurs, the reaction

is 90 percent complete, and there is no large effect on the

product ratio. In fact, within an acceptable range the

product ratio is a constant 616 percent throughout the

reaction. This sort of analysis is generally true for all

the reaction mixtures studied where the sodium methoxide and

sodium thiophenoxide are initially present in excess over

4-bromoisoquinoline. Compare the initial and final ion

ratio given in Table 7.

However the product ratios in the presence of inhibitors

are not nearly as constant with time as those in the absence

of inhibitors. As will be seen, this has a bearing on the

significance of a small change in the final product ratio

caused by the presence of the inhibitor. In Figures 8 and 9










Table 9. Product and Reactant'Ratios at Various Times for the Reaction of 0.52 M
4-Bromoisoquinoline with 0.98 M Sodium Methoxide and 0.98 M Sodium
Thiophenoxide at 1470


% 4-Bromoisoquinoline


[NaOCHi3]
[NaSC61,5]


0.99

1.0

0.88

0.75


Isoguinoline
1 4-Phenylthioisoquinol ien


0.55

0.60

0.67

0.62


Minutes









the same reaction as discussed in the previous paragraph is

followed in the presence of 0.2 M azobenzene (Table 10).

During the first 70 minutes, there is complete inhibition of

isoquinoline formation (and presumably much of 4-phenyl-

thioisoquinoline formation which occurs via a radical

process), but the concentration of 4-phenylthioisoquinoline

formed by direct aromatic nucleophilic substitution is

increasing. When the inhibition period is largely over,

there still remains 75 percent of unreacted 4-bromoisoquino-

line. The final portion of the reaction proceeds normally,

and the large effect of the inhibitor on the final product

ratio is masked by the large contribution of the normal

process to the final observed product ratio.

When a 9:1 (V:V) DMSO and methanol solution of 0.40 M

4-bromoisoquinoline, 0.38 M sodium methoxide, and 0.78 M

sodium thiophenoxide was heated at 1000, the product ratio

was 0.42. This is close to the value 0.49 obtained for a

.reaction mixture heated at 1650 with a similar base to

nucleophile ratio (Table 7). If the data in Table 7 are

correct, then a 650 reduction in temperature should lead to

a considerable enhancement in the amount of substitution

product. Since this is not observed, it may be concluded

tentatively that the DMSO facilitated the formation of

reduction product.

Kinetics of the reaction of 4-bromoisoquinoline with

sodium methoxide and sodium thiophenoxide.-Data for the

rate of disappearance of 4-bromoisoquinoline, and for the










Table 10. Product Ratios at Various Times for the Reaction of 0.52 M 4-Bromoisoquinoline
with 0.98 M Sodium Methoxide and 0.98 M Sodium Thiophenoxide in the Presence
of 0.2 M Azobenzene at 1470.


% Isoquinoline


% 4-Phenylthio-
isoquinoline


% Isoquinoline
% 4-Phenylthio-
isoquinoline


0

0

0.20

0.24

0.32

0.36

0.38


Minutes









rate of appearance of isoquinoline and 4-phenylthioisoquino-

line were obtained in the presence and absence of inhibitors

using nmr. Figure 7 shows a typical plot for the rate of

disappearance of 1.2 M 4-bromoisoquinoline at 1650 in a

methanolic solution of 0.67 M sodium methoxide and 1.1 M

sodium thiophenoxide. Note the inflection point early in

the reaction; this is indicative of initial inhibition of

a radical process. Under these conditions the reaction is

93 percent complete within one hour and gives 58 percent

4-phenylthioisoquinoline, 30 percent isoquinoline, and ~5

percent 4-methoxyisoquinoline.

The effect of 0.02 M azobenzene on the course of the

reaction is shown in Figures 8 and 9. The disappearance of

4-bromoisoquinoline and the appearance of isoquinoline are

plotted in Figure 8 in the absence and presence of azobenzene

at 147. The concentrations of all other reactants are the

same in both runs. (The results are not unlike those obtained

in the reduction of 4-bromoisoquinoline by methoxide ion in

the absence of sodium thiophenoxide.) In the absence of

inhibitor, the 4-bromoisoquinoline is totally consumed in

120 minutes; whereas with 0.2 M azobenzene present 20 percent

of the 4-bromoisoquinoline remains unreacted even after 370

minutes. The rate of formation of isoquinoline is also much

slower in the presence of azobenzene.

Figure 9 shows the effect of the inhibitor on the rate

of formation of 4-phenylthioisoquinoline in identical reaction

mixtures but with and without 0.2 M azobenzene. During the














100

r 90
-H

0 80


o 70

60
0
50

o 40

30
o

a. 20

10



0 10 20 30 40 50 60 70 80 90

Minutes

Figure 7. Disappearance of 1.2 M 4-Bromoisoquinoline in 0.67 M Sodium
Methoxide and 1.1 M Sodium Thiophenoxide at 1650.














90

80 -

u 70-

60
60 -
CB
so A
m 50

40
4 40
u 30

20

10 B A
0 r -- a I I I I I

50 100 150 200 250 300 350

Figure 8. Rates of Disappearance of 0.52 M 4-Bromoisoquinoline (6) and
Appearance of Isoquinoline (A) in 0.98 M Sodium Methoxide and
0.98 Sodium Thiophenoxide at 1470 with (A) and without (B)
0.2 M Azobenzene.





































50 100 150 200 250 300 350
Minutes


Rates of Appearance of 4-Phenylthioisoquinoline from 0.52 M
4-Bromoisoquinoline in 0.98 M Sodium Methoxide and 0.98 M
Sodium Thiopenoxide at 1470 in the Absence (0) and Presence
(0) of n0.2 M Azobenzene and Rates of Appearance of 4-Phenyl-
thioisoquinoline from 0.52 M 4-Bromoisoquinoline and 0.98 M
Sodium Thiophenoxide at 1470 in the Absence (A) and Presence
(A) of r0.3 M Azobenzene.


Figure 9.








first 40 minutes of the reaction, 11 percent of the substi-

tution product is formed in each of the reaction mixtures.

Then the formation of 4-phenylthioisoquinoline rapidly

increases in the reaction mixture containing no azobenzene

and rises to 65 percent after 90 minutes. In the same time

only 25 percent 4-phenylthioisoquinoline has been formed in

the presence of 0.2 M azobenzene. In other words, about five

times more substitution product is formed between 40 and 90

minutes in the mixture free of azobenzene. After 90 minutes

the reaction mixture with no inhibitor is 90 percent complete,

while the inhibited reaction is only 25 percent complete.

When an 0.2 M azobenzene and 0.72 M sodium methoxide

methanolic solution was heated at 1650 for 1 hour, there was

no change in either the methoxide ion concentration or the

azobenzene concentration. Analysis was done by nmr with

t-butyl alcohol as the internal area standard. Furthermore,

methanolic solutions of sodium thiophenoxide (0.84 M) and

sodium methoxide (0.87 M) were heated for 1060 minutes in

the presence and absence of azobenzene (~0.3 M). Again

analysis by nmr showed no significant change in the concen-

tration of any of the reagents. Azobenzene does not react

with either sodium methoxide or sodium thiophenoxide under

the reaction conditions.

The dependence of the rate of formation of the phenylthio

substitution product on the concentration of sodium methoxide

is shown in Figure 10. Two runs identical in 4-bromoiso-

quinoline (1.2 M) and sodium thiophenoxide (1.1 M) concen-







































50 100 150 200 250 300
Minutes


Rates of Appearance of 4-Phenylthioisoquinoline from 1.2 M
4-Bromoisoquinoline in 1.1 M Sodium Thiophenoxide at 1650
in the Presence of 0.67 M Sodium Methoxide (e) and in
the Absence of Sodium Methoxide (0).


0.75


0.50






0.25






0


Figure 10.









trations, but one containing sodium methoxide (0.67 M) were

heated at 165. Rates for the first 10 minutes are about the

same, but then the rate of formation of 4-phenylthioisoquino-

line increases markedly in the methoxide ion promoted

reaction. After about 80 minutes the maximum amount of

4-phenylthioisoquinoline (59 percent) has been formed in the

run containing added sodium methoxide, but in the absence

of sodium methoxide after 80 minutes only -30 percent of

the maximum has formed, and the maximum conversion to substi-

tution product has not been reached even after 350 minutes.

Results similar to those obtained at 147 with azo-

benzene were obtained using much lower concentrations of

azoxybenzene at 143. These results are shown in Figure 11.

When present in only 0.03 M concentration, azoxybenzene is

an effective inhibitor of both the reduction and substitution

reactions. In one hour in the absence of azoxybenzene,

4-bromoisoquinoline was converted completely to isoquinoline

and 4-phenylthioisoquinoline; whereas the inhibited reaction

mixture with identical initial reactant concentrations

contained 75 percent 4-bromoisoquinoline after one hour, and

even after 460 minutes 15 percent of the starting material

remained. This is the most dramatic inhibition observed in

any reaction mixture, with only a 0.03 M concentration of

inhibitor extending the time required for complete reaction

by more than 7-fold.

A solution of 0.60 M 4-bromoisoquinoline and 1.2 M

sodium thiophenoxide was prepared and divided between two





































100 200 300 400
Minutes

Relative Rates of Reaction of 0.60 M 4-Bromoisoquinoline in
1.5 M Sodium Methoxide and 1.6 M Sodium Thiophenoxide at 1430
in the Presence (B) and Absence (A) of 0.03 M Azoxybenzene.
(4-Bromoisoquinoline, 0; isoquinoline, A; 4-Phenylthioiso-
quinoline, 0).


Figure 11.








nmr tubes, one containing azoxybenzene (-0.2 M). The reac-

tions were followed at 1750 rather than the usual 1650 for

convenience. Analyses at two different points in the reaction

showed that less 4-phenylthioisoquinoline had been found in

the tube containing azoxybenzene. The final analysis showed

that after 120 minutes there was 53 percent product in the

tube containing azoxybenzene compared to 72 percent product

in the tube with no inhibitor. It appears that there may be

slight inhibition of autocatalysis by sodium thiophenoxide.

However, it is clear that this is not a gross effect, and if

there is autocatalysis by sodium thiophenoxide it is insigni-

ficant compared to methoxide ion catalysis.

The concurrent reduction-substitution reaction of 4-

bromoisoquinoline with methoxide and thiophenoxide ions was

studied under pseudo-first-order conditions by glpc. The

results of these studies are presented in Table 11, and they

show the same general trend in product ratios as those studies

conducted by nmr. Throughout any one of the four runs the

reduction to substitution ratio remains constant to within

20 percent of the mean value. However, redetermination of

the product ratio 6 months later in one run gave a larger

uncertainty, 30 percent of the mean value. The total

amount of isoquinoline and 4-phenylthioisoquinoline products

found at completion varies from 38 to 72 percent. This is

far below the expected 100 percent for reasons which are

unclear. Perhaps this low mass balance is due to the

formation of the anion of 4-hydroxyisoquinoline which is











Table 11. Kinetic Results for'Concurrent Pseudo-first-order Reaction of
4-Bromoisoquinoline with Sodium Methoxide and Sodium Thiophenoxide
at 1650


Initial Concentrations


[Substrate]o

[NaOCH3]0

[NaSC611slo



[Substrate]o

[NaOCH3]o

[NaSC61Hs]o


= 0.014

= 0.39

= 0.95



= 0.015

= 0.8

= 0.8


Minutes % Substitution % Reduction


60

186

300


Not determined


% Reduction
% Substitution



0.087

0.083


0.076



0.21

0.15

0.16

0.15

0.19











Table 11. Continued.


Initial Concentrations






[Substrate]o = 0.015

[NaOCH3]o = 1.7

[NaSC6Hslo = 0.79


Minutes % Substitution




Ab B

20 26 32

40 37 33

80 50 38

120 44 39


% Reduction




A B

14 20

12 18

22 21

25 26


% Reduction
% Substitution



A B

0.54 0.62

0.32 0.55

0.44 0.55

0.56 0.67


[Substratejo = 0.015

[NaOC3H]o = 0.90

[NaSC6IHslo = 0.27


9.8

20

29

27

27


5.4

10

14

11

11


0.55

0.50

0.48

0.41

0.41


aReactions carried out using aliquots in sealed tubes. Analysis done by glpc. All
concentrations are corrected for thermal expansion.










Table 11. Continued.


A and B represent analyses carried out on two different glpc columns. A analyses
were conducted some 6 months after the B analyses.








not measured by glpc. This anion arises from the cleavage of

4-methoxyisoquinoline. Hence the studies were discontinued.

An independent check on the product ratios from nmr

analysis of reaction mixtures containing substrate in the

0.5 M concentration range was made using glpc. The glpc

product ratios are in good agreement with those obtained

by nmr on the same reaction mixtures. Also the glpc

studies confirm the nmr product identifications.

Alkoxide ion promoted substitution of 4-bromoisoquino-

line by negatively charged ions other than thiophenoxide ion.-

Attempts were made to extend the alkoxide ion promoted sub-

stitution reaction of 4-bromoisoquinoline to include other

negatively charged ions which would result in the formation

of carbon-carbon, carbon-nitrogen, or carbon-oxygen bonds.

The lithium and sodium salts of 2-nitropropane were generated

in situ in a methoxide solution with excess 2-nitropropane.

When 4-bromoisoquinoline was heated for two consecutive

periods of 30 minutes each at 1000 and 1650 in these solu-

ions, no reaction was observed. When the lithium salt of

2-nitropropane was isolated and then dissolved in DMSO or

DMF, no reaction with 4-bromoisoquinoline (or 3-iodopyridine)

could be detected when heated at temperatures of 1000 or less

for several hours. The presence of excess alkoxide ion in

these reaction mixtures did not promote substitution at 1000

and gave the usual isoquinoline and 4-methoxyisoquinoline

products at 1650. Use of a mixed solvent system consisting

of DMSO and methanol resulted in no substitution reaction








between 4-bromoisoquinoline and the lithium salt of 2-nitro-
propane in the presence of lithium methoxide. The mixture
was heated at 1000 for over an hour. No substitution reac-
tion involving 4-bromoisoquinoline and either the sodium
salt of acetonitrile or piperidine in excess methoxide ion
and DMSO was observed at 1000; rather, reduction to iso-
quinoline occurred.
However 4-bromoisoquinoline did appear to undergo meth-
oxide ion promoted substitution with negatively charged
sulfur nucleophiles other than thiophenoxide ion. These
included sodium me-thylmercaptide-, sodium p-chlorothiophen-
oxide, and the sodium salt of 4-thiopyridone. The study of
the reaction of 4-bromoisoquinoline with the sodium salt of
4-thiopyridone was impractical because of formation of large
amounts of 4-methoxypyridine which presumably arose from
nucleophilic substitution of the initially formed 4-(4-thio-
pyridyl)-isoquinoline by methoxide ion to give 4-methoxy-
pyridine and 4-isoquinolylmercaptide ion, equation 24.


SS- OCH3




WON
S CH + (24)





The reaction of 4-bromoisoquinoline with sodium methyl-
mercaptide at 1650 was complicated by the cleavage of the
methyl-sulfur bond in the 4-methylthioisoquinoline product.









As a result the reaction could not be followed for long

periods of time. No attempt was made to establish the

mechanism of this cleavage reaction. The results obtained

from those reactions observed for a short period of time

are given in Table 12. Considering the first entry, in the

presence of nearly equimolar amounts of sodium methoxide

and sodium methylmercaptide, it can be seen that the reaction

is complete within 5 minutes to give 65 percent substitution

by methylmercaptide ion and 35 percent reduction. For the

second entry where there is no sodium methoxide, the reaction

is only 55 percent complete after 5 minutes and gives no

reduction. It appears that sodium methoxide accelerates

both the overall reaction and the formation of 4-methyl-

thioisoquinoline, and that methoxide ion is essential to

the reduction process. Finally, a reaction mixture contain-

ing no methoxide ion and the same concentration of sodium

methylmercaptide as that for the second entry but with added

0.5 M azoxybenzene gives less substitution product in the

same amount of time (36 percent compared to 55 percent). It

appears that the inhibitor has slowed down the formation of

product via autocatalysis by methylmercaptide ion. However,

on the basis of only one observation, the relatively small

difference is of questionable significance.

The problem of cleavage of 4-methylthioisoquinoline was

partially overcome by lowering the reaction temperature to

1270. At this temperature less cleavage occurred, and

correction could be made for the small amount which did occur.











Table 12. Reactions of ,d.4 M 4-Bromoisoquinoline with
and/or Sodium Mothylmercaptide at 1650.


[NaSCH3I]b


Minutes Additive


Sodium Methoxide


Products


None


None


"0.5 M
Azoxybenzene


65% 4-Methylthioisoquinoline
35% Isoquinoline

55% 4-Methylthioisoquinoline
45% 4-Bromoisoquinoline

36% 4-Methylthioisoquinoline
64% 4-Bromoisoquinol i ne


aReactions were carried out in sealed nmr tubes.

concentrations (mol/1) are corrected for thermal expansion. Concentrations are
approximate due to the difficulty of introducing an accurately known weight of
gaseous methylmercaptan.


[NaOCH3] b


,2.0


,2.1


s2.0


"2.0


~_ ~CL_~C~__ __~









The results of the usual control and inhibited runs are

presented in Figure 12. A 0.47 M solution of 4-bromoiso-

quinoline in methanol with ~2.2 M sodium methylmercaptide

and ~2.1 sodium methoxide was divided between two nmr tubes,

one containing -0.1 M azoxybenzene, and heated at 1270. The

presence of inhibitor slows the formation of both isoquino-

line and 4-methylthioisoquinoline. The inhibition is not

as dramatic as in reactions involving thiophenoxide ion.

The reaction of 4-bromoisoquinoline (0.51 M) with

sodium y-chlorothiophenoxide (0.98 M) and sodium methoxide

(0.98 M) at 1470 is followed in Figure 13. In this exper-

iment no products were isolated, rather it was assumed that

the usual substitution reaction took place, and the new peaks

appearing in the nmr spectrum were from this product. A

typical inhibition was observed in the presence of 0.4 M

azoxybenzene. Thus, over 60 percent substitution product

was formed in 100 minutes in the run without inhibitor, but

in the presence of azoxybenzene only 15 percent product was

formed in the same time.

An attempt was also made to observe substitution by a

non-charged sulfur nucleophile, methyl disulfide, in the

presence of sodium methoxide. This failed when the methoxide

ion apparently reacted quickly with the methyl disulfide,

and the 4-bromoisoquinoline remained unreacted.

Reaction of other heterocycles with sodium thiophenoxide

and sodium methoxide mixtures.-Three compounds other than

4-bromoisoquinoline were studied briefly for alkoxide promoted














90

80

70 -
U
60 6 -

Sso A
0

40

U 30
B
20 A

10


25 50 75 100 125
Minutes

Figure 12. Appearance of 4-Methylthioisoquinoline (0,9) and Isoquino-
line (A,A) from 0.47 M 4-Bromoisoquinoline in u2.2 M
Sodium Methoxide at 1270 with (A) and without (B) u0.1 M O
Azoxybenzene.






































200 300 400 500


Minutes


Rates of Appearance of 4-(4-Chlorophenylthio)-isoquinoline from
0.51 M 4-Bromoisoquinoline in 0.98 M Sodium 4-Chlorothiophenoxide
and 0.98 M Sodium Methoxide at 1470 with (B) and without (A) ,0.4M
Azoxybenzene.


Figure 13.









substitution by thiophenoxide ion. 3-Bromoquinoline (0.47 M)

underwent reaction with sodium methoxide (1.7 M) and sodium

thiophenoxide (0.87 M) at 165 in 30 minutes to give an nmr

spectrum quite different from that of starting material.

This was a complicated spectrum, presumably consisting of

a mixture of 3-phenylthioquinoline and quinoline. 4-Bromo-

3-methylisoquinoline (0.44 M) underwent reaction with sodium

methoxide (1.4 M) and sodium thiophenoxide (0.63 M) at 165

in 1 hour to give a 3:1 mixture of 3-methylisoquinoline and

another compound presumed to be the 4-phenylthio substitution

product. 3-lodopyridine (0.33 M) underwent partial reaction

at 1000 in 60 minutes with sodium thiophenoxide (0.71 M),

sodium methoxide (1.2 M), and ABIN to give a product which

is presumed to be the 3-phenylthio substitution product.

Clearly, such reactions are worthy of future studies.


Discussion

A proposed mechanism for the reaction of 4-bromoisoquino-

line with mixtures of sodium methoxide and sodium thiophen-

oxide.-There are several key observations from experiments

involving the simultaneous reduction and substitution

reactions of 4-bromoisoquinoline with mixtures of methoxide

and thiophenoxide ions which must be accommodated by any

proposed mechanism. These observations are: A short initial

induction period is observed in the rate of appearance of

4-phenylthioisoquinoline; methoxide ion accelerates the rate

of formation of 4-phenylthioisoquinoline; known radical

inhibitors change the product ratio of isoquinoline to









4-phenylthioisoquinoline in favor of the substitution product;

known radical inhibitors slow the rate of formation of

4-phenylthioisoquinoline; an increase in the initial meth-

oxide ion to thiophenoxide ion ratio is reflected by an

increase in the reduction to substitution product ratio.

In the absence of added sodium methoxide, 4-phenyl-

thioisoquinoline is formed from 4-bromoisoquinoline and thio-

phenoxide ion in methanol. This reaction apparently proceeds

by the "classical" ionic aromatic nucleophilic substitution

mechanism, hereafter referred to as the ionic mechanism.

Second-order rate plots for this reaction at 1470 and 1650

are linear through 80 percent conversion of 4-bromoisoquino-

line; there is no evidence of an induction period, and azo-

benzene has no significant influence on the rate (1470).

Note, however, that a question has been raised recently

whether electron transfer may be involved in "classical"

substitution reactions at an aromatic carbon.50 In any case,

the present study is concerned with the nature of the rate

acceleration brought about by added methoxide ion. The

present results should not be confused in any way with the

rate acceleration brought about by added base in substitution

reactions at an aromatic carbon involving amine nucleophiles.s5

The rate acceleration in these ionic reactions involves

kinetic general base catalysis and is entirely different

in mechanism from that considered here.

In the presence of sodium methoxide, 4-phenylthioiso-

quinoline is formed from 4-bromoisoquinoline and thiophenoxide









ion by a pathway which must involve radical intermediates.

Evidence to support this is found in the induction period

for the formation of the substitution product, Figures 9

and 10. As the results in these figures show, the initial

rates of substitution in mixtures with and without methoxide

ion are essentially the same, indicating the operation of

the ionic substitution reaction as the major pathway to

substitution product during the early portion of the reaction.

But after this period, there is a considerable divergence in

rates, that reaction mixture containing methoxide ion form-

ing 4-phenylthioisoquinoline at a considerably faster rate.

A rough measure of the rate acceleration brought about

by methoxide ion may be gained by estimating the rate of

appearance of the substitution product by drawing a tangent

to the illustrated concentration-time curves. A tangent

should be selected early in the accelerated portion of the

rate in order to minimize differences in concentrations

between the runs with and without methoxide ion. About a

10-fold acceleration is produced by an initial 0.98 M con-

centration of sodium methoxide at 1470 (Figure 9) and about

a 6-fold acceleration is produced by 0.67 M sodium methoxide

at 1650 (Figure 10). The smaller acceleration probably

largely reflects the lower concentration of methoxide ion.

The temperature and initial concentration of 4-bromoisoquino-

line are not the same. Clearly the effect of added methoxide

ion is significantly large and must be associated with a

second mechanism of substitution.








The effect of various added inhibitors on the isoquino-

line to 4-phenylthioisoquinoline product ratio is given in

Table 8, and in each case the effect of the added inhibitor

is to lower the product ratio by increasing the amount of

substitution product. This result is consistent with a

mechanism in which isoquinoline arises by a radical chain

process and 4-phenylthioisoquinoline is formed by direct

nucleophilic substitution. It is also consistent with a

mechanism in which isoquinoline arises by a radical chain

process and the 4-phenylthioisoquinoline arises by multiple

paths, one of which may be a radical chain reaction.

To distinguish between the two mechanisms of substitu-

tion suggested in the preceding paragraph, it is necessary to

observe the rate of formation of 4-phenylthioisoquinoline in

the presence and absence of inhibitors. Figure 9 shows that

the rate of formation of 4-phenylthioisoquinoline in the

presence of methoxide ion is decreased by the presence of

-0.2 M azobenzene. As shown earlier, the inhibitor also

decreases the rate of formation of the reduction product.

The inhibitor thus decreases the rates of formation of the

reduction and substitution products, the reduction reaction

being affected more. This is taken to mean that 4-phenyl-

thioisoquinoline arises in part by a radical chain process

which is influenced by the inhibitor and in part by a purely

ionic pathway which is insensitive to the inhibitor.

The maximum amount of substitution product which arises

by the ionic mechanism may be estimated as follows: At 90









minutes, Figure 9, the reaction containing methoxide ion is

essentially complete and 65 percent of the 4-bromoisoquino-

line is converted to 4-phenylthioisoquinoline, the remainder

being largely isoquinoline. At the same time the reaction

without methoxide ion has given rise to only 16 percent

4-phenylthioisoquinoline. Hence, no more than 16/65 or 25

percent of the substitution product in the methoxide ion

promoted reaction arose by the ionic mechanism. This is a

maximum value because it does not consider that the faster

reaction with methoxide ion will have less 4-bromoisoquino-

line available for the ionic pathway after the initial

induction period, and so less substitution product will

form by the ionic route. A similar consideration of the

results in Figure 10 indicates a maximum of about 47 per-

cent 4-phenylthioisoquinoline arose by the ionic route.

This value is lower than the earlier value probably because

the methoxide ion concentration is lower (0.67 versus 0.98 M).

The minimum amount of substitution product formed by

the ionic mechanism may be estimated by considering the

amount of substitution product present at the end of the

induction period, assuming that substitution product

essentially arises by the ionic route during the induction

period. This amounts to about 15 percent in both cases.

Note the shorter induction period in the reaction at the

higher temperature.









Azobenzene (-0.2 M) was used to inhibit the methoxide

ion promoted substitution reaction, Figure 9. Although the

inhibition is effective, the rate of formation of 4-phenyl-

thioisoquinoline in the presence of this inhibitor and meth-

oxide ion still is faster than the rate of formation of the

substitution product by the ionic mechanism. Azobenzene is

known to accept electrons readily. 1',2-s4 This retardation

by azobenzene must represent true inhibition of the reaction.

It cannot be due to some kind of reaction between thiophen-

oxide ion and azobenzene which lowers the concentration of

thiophenoxide ion and thereby lowers the rate of substitution.

A control run, Figure 9, involving 4-bromoisoquinoline and

thiophenoxide ion shows that the rate of the ionic substitu-

tion reaction is not changed by the presence of 0.3 M azo-

benzene. Still another control shows that methoxide ion

and azobenzene do not react under the conditions of the

substitution reaction.

The fact that proven radical inhibitors affect the rate

of formation of 4-phenylthioisoquinoline is strong evidence

for a radical chain mechanism of substitution. Furthermore,

it is certainly reasonable that this radical chain process

be similar to that described for the reduction of 4-bromo-

isoquinoline by sodium methoxide. Such a mechanism with the

4-isoquinoyl radical as a common intermediate leading to

both reduction and substitution is consistent with all the

experimental data.









The additional propagation steps necessary for a radical

chain process of substitution are given in equations 25 and

26. The key reaction in equation 25 has ample precedent.

It has been shown that g-nitrophenyl radicals can be trapped

by various anions,55 and that thiophenoxide ion efficiently

traps p-nitrocumyl radicals in DMF or DMSO.56

Isoq- + C6 1sS + [lsoqSC611I5 (25)

[IsoqSC61Hs] + IsoqBr [IsoqBrj + IsoqSCsHs (26)


Examination of Table 7 shows that the sodium methoxide

to sodium thiophenoxide ratio remains almost constant for

all but one of the reaction mixtures studied, the exception

being the mixture having excess substrate. There is a

decrease in the ratio as the reaction proceeds. But

assuming a stoichiometry such that 1.5 moles of methoxide

ion is consumed for every mole of isoquinoline formed and

that one mole of thiophenoxide ion is consumed for every

mole of 4-phenylthioisoquinoline formed, the methoxide to

thiophenoxide ion ratio never changes by more than 7 percent.

Likewise, thiophenoxide ion is initially present in excess

over 4-bromoisoquinoline and no more than 30 percent is

consumed. All but one of the initial concentrations at 1650

are within 10 percent of 0.73 M. Based on the above con-

siderations both the base to nucleophile ratio and the nuc-

leophile concentration may be assumed to be constant for a

semi-quantitative interpretation of the data.









On the basis of the data presented in this chapter and

in Chapter 2, a radical chain process is the favored mechanism

for both reduction and formation of a major portion of the

phenylthio substitution product. In both processes the 4-

isoquinolyl radical may be the key intermediate, and it is

reasonable to assume that this species is the common inter-

mediate in the simultaneous reduction and substitution reac-

tions. Consequently, a kinetic scheme may be constructed to

show how the product ratio depends on the concentration of

methanol, methoxide and thiopenoxide ions, assuming they all

compete for the 4-isoquinolyl radical. Assume that reduc-

tion occurs by hydrogen atom abstraction from methanol with

rate constant k2 and by hydrogen atom abstraction from meth-

oxide ion with rate constant ki; assume that radical sub-

stitution occurs by reaction with thiophenoxide ion with

rate constant ka. The product ratio is then given by equa-

tion 27. Certainly the methanol concentration is constant

%IsoqH kl[CH30-] + k2IC1130H] (27)
%IsoqSCIIH k3[C6HsS-] k3[CeHsS-]

throughout the reaction and is 20 M at 1650. Since the

thiophenoxide ion concentration is also roughly constant for

most of the runs, equation 26 assumes the form of a linear

equation where the intercept is k2 [CH30H]/k3 [C6H5S ] and

the slope kl/k3. The least squares line plotted from the

first five entries (1650) in Table 7 is presented in Figure

14; the slope is 0.560.15, and the intercept is 0.180.30.

The correlation coefficient is 0.978. The indicated uncertainty





































0.5 1.0 1.5 2.0 2.5 3.0
[C1 3ONa]

[C HsSNa]


Product Ratios Versus Base Ratios in the Competition Reaction
of 4-Bromoisoquinoline with Sodium Methoxide and Thiophenoxide
at 1650.


2.0

1.8

1.6

1.4

1.2

1.0

0.80

0.60

0.40

0.20

0


Figure 14.




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