8/11/2019 Grob Acie Rev.1967

1/15

ANGEWANDTE

CHEMIE

Middle and unsaturated

groups

fragments

V O L U M E 6 . N U M B E R

J A N U A R Y

1 9 6 7

P A G E S 1-106

NucleoJugal

groups and fragments

I. Definition

RC=CR

RzC=NR

RC=N

RzC=O

CO2

Nz

c = o

Heterolytic Fragmentation. A Class of Organic Reactions

-B;

--I

-SO,R

-0COR

-OH28

- N R ~

-SR2a

--NSN

B Y

C . A.

GROB

AND P. W. SCHIESS 1 1

Heterolytic fragnientation is a widespread but neglected class of organic reactions. It

involves the regulated cleavage of molecules Containing certain combinations of atoms such

us

carbon, oxygen, nitrogen, sulfirr, phosphorus, silicon, boron and halogens. Fragmentation

reuctions are useful in degradation and structure Pbcidation, some are also of preparative

value. A knowledge of the structural and electronic requirements makes it possible to

predict and influence the course

of

reactions. From a theoretical viewpoint the recognition

ojheterolytic fragmentation has lead to the classification and correlation of a large number

of apparently diverse reactions. Selected cases are reviewed in this article.

On the basis of mechanistic principles most reactions in

organic chemistry can be reduced to a relatively small

number of reaction classes. Those most extensively

studied and therefore known in greatest detail are

substitution, addition, elimination and rearrangement.

In this manner

a

vast number of chemical transforma-

tions has been correlated, a development which has

deeply influenced teaching and research.

About ten years ago

a

further reaction class was defined

and termed fragmentation, since it involves the cleavage

of

a

molecule symbolized by a-b-c-d-X into three

fragments a-b, c= d and Xrll. The letters a,b,c, and d

denote a sequence

of

atoms such as

C ,0 N, S,

P, or

B.

However, fragmentation also occurs with compounds

containing metal atoms

21.

In heterolytic fragmentation,

[ * ]

Prof. Dr. C.

A. Grob

and

Doz.

Dr. P.

W.

Schiess

lnstitu t fur Organische Chemie de r Universitst

St. Johanns-Ring 19

4056 Base1 (Switzerland)

~ -

[l] C. A.

Groh and

PV.

Baumann, Helv. chim. Acta

38,

594 (1955);

C.

A.

Groh, Experientia

13,

126 (1957); Theoretica l Organic

Chemistry Report on the Kekule Symposium, Butterworth,

London 1958, p. 114; C. A. Groh and F. Ostermayer, Helv. chim.

Acta 45, 1119 (1962).

121 The cleavage of carbonium ions into a smaller cationic frag-

ment and an olefin in acco rdan ce with R3C-C-C-X

--z

R@+

C=C was first recognized as a possible secondary reaction of

carbonium ions by

F .

C. Whifmore and E.

E.

Stahlv, J. Amer.

Chem. SOC.55, 4153 (1933); 67, 2158 (1945). V. I . Muksimov,

Tetrahedron 21, 687 (1965), has recerBtly attempted to interpret

fragmentations as cases of o,o-conjugation as defined by A. N .

Nesmeyanov,

Vestnik Moskovskogo Univ. Ser. I1 132, 5 (1950).

This term is evidently intended to describe the electromeric

participation of a

B

bond

p

to an unsaturated center which is

formed in the transition state. It would therefore correspond to

hyperconjugation, which does not necessarily lead

to

fragmenta-

tion, i.e. cleavage of a CT bond.

which is by far the most common type in solution, X

leaves with the electron pair by which it was originally

attached to the rest of the molecule,

i.e.

as

a

nucleo-

fuge 131. X thereby becomes more negative by one

charge unit and is converted into a nucleofugal frag-

ment. This

is

usually

a n

anion such as

a

halide, carbox-

ylate and sulfonate

ion. Neutral nucleofugal fragments

derive from diazonium-, oxonium-, ammonium- and

sulfonium-groups (Scheme 1).

Elecr rofigul

groups and fragments

a-b or

a-b-

HO-CRz-

RO-CRz -

HOOC-

R2N-CR2-

R3C-

RCO-

0

R:C-CRz-

HzN-NH-

O=CRI

8

RO=CR2

co

@

RzN=CRz

R3C3

8

RC; 0

RzC=CR2

HN-NH

HN=N- NZ

r

d-

_ _ _ _

-CR~-CRZ-

-CR=CR-

-CRz-NR-

-CR=N-

-CRz-O-

-co-0-

-N=N-

-co-

The electron deficiency on atom d

c=d -X

R~C=CRZ -CI

I

.esulting

from

the

departure

of

X

leads to heterolytic cleavage of the

bond between b and c, with formation of an unsaturated

fragment c-d and

a

fragment a-b. The latter leaves

without the bonding electron pair, i.e. as an electro-

X

Angew.

Chem.

internal.Edit

VoI. 6 1967)

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fugeL31, becoming one unit

of

charge more positive in

the process. Electrofugal fragments are therefore fre-

quently cations.

Typical electrofugal fragments are carbonyl compounds

(often formed as their conjugate acids), carbon dioxide,

imonium-, carbonium-, and acylium-ions, olefins, di-

imine, and nitrogen (Scheme

1).

Silicon, phosphorus,

boron derivatives, and organometal ions also act as

electrofugal fragments. The ease with which an electro-

fugal fragment a-b is formed will depend

on

the

stabilization of the incipient positive charge on b due to

the inductive or conjugative effect of a. This structural

unit is frequently a hydroxyl, amino, alkyl, or aryl

group. The displacement of electrons from a towards b,

i.e.

a+b or a-b

promotes the release of the unsaturated fragment c=d.

Unsaturated fragments frequently encountered are ole-

fins,

acetylenes, imines, and nitriles. Less common are

carbonyl compounds, carbon dioxide, carbon monoxide

and nitrogen (Scheme 1).At present more than sixty

fragmentable systems are known which differ only with

respect to the groups a-b and c-d. By taking into

account variations

of

the nucleofugal group X, a far

greater number of cases can be cited from the literature.

Since new examples a re constantly being found,

a

system

of classification is urgently needed. The system adopted

in this review is based

on

the nature

of

the three frag-

ments in the following order:

1.

middle-, 2. electro-

fugal- and

3.

nucleofugal-fragment.

Fragmentation reactions 141 can also be classified ac-

cording to mechanistic criteria, since, like elimination

reactions 157, they can proceed by three basic mechanisms

These differ in the order in which the fragments are

released. Thus one-step and two-step processes can be

distinguished depending

on

whether a-b and

X

depart

simultaneously from c-d or whether a-b

or

X depart

successively 5a3. In this review of a selected number of

fragmentation reactions, questions related to mecha-

nism will be considered only insofar as they

are

essential

[3]

Whereas the terms nucleophile and electrophile refer to the

role of reagents in bond formation the complementary terms

nucleofuge and electrofuge refer

to

bond cleavage, specifically

to the partitioning of the electrons which formed the original

bond. T he term leaving group is inadequate, since in fragmenta-

tion two different kinds of leaving group are involved:

J. Mathieu,

A. Allais, and

J .

Valls, Angew. Chem. 72, 71 (1960).

[4] According to the above definition, heterolytic fragmentation

is a generalization of heterolytic elimination. An elimination

involves the removal of a nucleofugal group X and an electro-

fugal atom, usually

a

proton, from the P-position, whereas in

fragmentation the electrofugal fragment

is

a group of atoms. If

the chain a-b-c-d=X contains a double bond between d and X,

the group X does not leave the molecule on heterolysis of the

b-c bond. The molecule then breaks down into only two frag-

ments. Reactions of this type, such as the retroaldol reaction

eO-C-C-C=O --f O=C + C=C-Oe, are 1,2-eliminations

where a resonance stabilized nucleofugal group is liberated. They

are therefore not considered in the present review.

[5] C. K . Ingold: Structure and Mechanism in Organic Chemistry.

Cornell University Press, Cornell 1953, p. 419.

[5a]

Mechanistic and stereochemical aspects of heterolytic

fragmentation will be discussed in a later article.

to the understanding of the particular reaction. More-

over, homolytic fragmentation and the fragmentation

patterns resulting from electron impact and detected

by mass spectrometry will not be discussed, since

different principles are involved in these cases.

11.

Olefin-Forming Fragmentations

(a -b

-C

-

C -X)

a)

H-0-C-C-C-X

In many olefir-forming systems, the electron-donating

part is a hydroxyl group or an alkoxide oxygen atom.

In these cases the electrofugal fragment is a carbonyl

compound. Probably one of the earliest examples is the

acid-catalysed fragmentation

of

tetramethyl-2,4-pen-

tanediol

I )

into acetone and dimethyl-2-butene

6 1

-

3

- H 2 0 O=C(CH3)2 + ( C H B ) ~ C = C ( C H ~ ) ~

In unsymmetrical 1,3-diols, the nucleofugal fragment is

usually formed from the hydroxyl group on the more

highly substituted carbon atom, as is shown by the

exclusive formation of benzaldehyde and 1,l-diphenyl-

ethylene when 1,1,3-triphenyl-l,3-propanediol

2)

is

heated with acid. This suggests that the fragmentation

proceeds via the more stable tertiary carbonium ion

(3) [71:

However,fragmentation canalso occur

via

the diazonium

salt

5)

as in the deamination

of

y-aminoalcohols

4 )

with nitrous acid

181.

The yields vary, and depend on the

substituents

R

and on stereochemical factors.

-

R 2 C = 0 + CH,=CRz + Nz + Ha

[61 A. Slawjanow, J. Russ. Phys. Chem. SOC.39, 140 (1907);

Chem. Abstr. I, 2077 (1907).

171

J. English

and F. V .

Brutcher,

J.

Amer. chem. SOC.74, 4279

(1952).

IS] J .

English and A.D.BIiss, J. Amer. chem. SOC. 8,4057 (1956);

R .

R. Burford, F . R. Hewgill, and

P . R .

Jefferies, J. chem. SOC.

(London) 1957,2931.

2

Angew. Chem. internat. Edit. 1 VoI.

6 1967)

J No. I

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In this as in many other cases, fragmentation is ac-

companied by substitution and elimination.

Many fragmentations, such as that of the bicyclic

y-hydroxytosylate (6), are brought about by a strong

base, c.g. potassium t-butoxide~ 1 ;he reacting substrate

is therefore the anion (7).

w

OH

Kw0

6 KOTos

In such cases the fragmentation is also of preparative

use, since it permits the stereospecific synthesis of

medium-sized unsaturated rings that are otherwise

difficult to obtain.

The reverse of this fragmentation, i . e . the condensation of an

olefin with an aldehyde

or

ketone in the presence

of

an acid,

is possible in many cases

1101.

(When form aldehy de is used a s

the carbonyl component, this is known as the Prins reaction).

b) O=C-C-C-X

Aldehydes and ketones bearing

a

nucleofugal group in

the P position can be cleaved in to acids an d olefins by

treatment with alkali. This reaction is observed in

particular when the usual 1,2-elimination of HX with

formation

of

the a,@-unsaturated arbonyl compound

is

difficult or prevented by structural factors. Thus it has

been shown that, on treatment with sodium hydroxide,

3-bromo-2,2-dimethyl-1-phenyl-l-propane[ 8a)=

Br]

(w-bromopivalophenone) or the trimethylammonium

iodide [ 8b),

X = N(CH3)310]

breaki down

via

the adduct (9) into benzoic acid and isobutene

1111.

This

Another example is 3-mesyl-~-glucose,whose hemi-

acetal form (10) is cleaved by sodium hydroxide into

the enol I I ) , the precursor of 2-deoxy-~-ribose121,

and formic acid 1121.

CH,OH

.i NaoH

2 3 4

5 1

HOCH=CH-CHOH-CH(OCI)-:H~OH

11)

HOCHz-(CHOH)Z-CHz-CHO

+

HCOOH

121

C) -N =C-C-C-X

Imines (Schiff bases) containing a nucleofugal group in

the P-position also become fragmentable after addition

of

a

nucleophile. Thus the 3H-indole derivative

13)

reacts with sodium hydroxide t o fo rm the unsaturated

nine-membered lactam

14) 1131.

(131 114)

Fragmentation occurs as an undesirable side reaction in

the preparation of unsaturated aldehydes by aldol

condensation of an acetaldimine with ketones. For

example, on treatment with acid, the P-hydroxyaldimine

is an example of

a

compound tha t becomes fragmentable

only after a n active electrofugal group has been formed

by the addition

of a

nucleophile.

[9]

P .

S. Wharton and G. A. Hiegel, J. org. Chemistry

30,

3254

(1965); E. J . Corey, R . B. Mitra, and H . Uda, J. Amer. chem. SOC.

86, 485 (1964).

[lo] Cf.,

e.g . ,

H.

Stetrer,

J .

Gartner, and

P. Tacke ,

Angew. Chem.

77, 171

(1965); Angew. Chem. internat. Edit. 4, 153 (1965).

[111

F. Nerdel, H. Goetz, and

M.

Wolf l ,Liebigs Ann. Chem. 632,

65 (1960);

F.

Nerdel,

D .

Frank,

and H . J .

Lengert,

Chem. Ber.

98,

728 1965).

15)

not only undergoes hydrolysis and dehydration to

16), but also suffers fragmentation with formation of

cyclohexylformamide and a-methylstyrene

[141.

The

common reactive substrate

is

undoubtedly the product

resulting from the addit ion of water 17).

I121

D .

C. Smith, J.

chem. SOC. London) 1957,

2690;

E.

Hard-

egger et a l . , Helv. chim. Acta 40, 815 (1957).

1131 M. F.

Bartlett,

D .

F. Dickel, and W.

I.

Taylor,

J

Amer. chern.

SOC. 0, 126 (1958).

[14] G. Wittig and H.D.Frommeld, Chem.Ber. 97, 3548 (1964).

Angew. Chem. in terna t .

Edit.

Yol. 6

1967)

N o . I

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d)

H-0-CO-C-C-X

Many $-halocarboxylic acids undergo decarboxylation

to an olefin when their salts are heated in solution. One

of the earliest examples is the formation of styrene

from 3-bromo-3-phenyl propionic acid 18) in aqueous

soda [151.

Na~O-CO-CI- IZ-C I -CGH, COP

+

CHz=CH-C&

1 8 ) B r + N a B r

The sodium salt of the erythro form of dibromohydro-

cinnamic acid

(19)

is stereospecifically decarboxylat-

ed in a non-polar solvent such as acetone t o cis-bromo-

styrene [161.

C OoNa@

In P-hydroxycarboxylic acids decarboxylation competes

successfully with the elimination of water to form the

cc,P-unsaturated acid. Whereas 3-hydroxy-3-(p-methoxy-

pheny1)propionic acid ( 2 0 ) is dehydrated

to

the

cinnamic acid derivative in strongly acidic solution, the

main reaction in weakly acidic solution is decarboxyla-

tion t o p-methoxystyrene. In th is case the reactive

substra te is presumably

(21),

which contains an internal

hydrogen bond [171.

The p-amino acids

( 2 2 ) ,

R2

=

OH

or alkyl, which can

be obtained by

a

Mannich reaction from malonic acid

- C,H,N

- OOC-CH=CHAr COZ

An interesting variant of these reactions

is

the Darzen

reaction. a,P-Epoxy acids (glycidic acids) such as

(25)

are readily decarboxylated to t he aldehyde with one less

carbon atom [2*1. In this case the nucleofugal oxygen

atom of the epoxide group remains attached to the

unsatura ted fragment, so that th e primary product is an

enol

(26),

the precursor of the aldehyde

(27).

In principle, any carboxylic acid having

a

carbonium

ion center in the P-position can undergo decarboxyla-

tion, as is shown by the acid-catalysed fragmentation

of the R,@- and P,y-unsaturated acids

( 2 8 )

and (29)

1211.

In both cases the olefinic double bond is protonated to

form the P-carbonium ion ( 3 0 ) .

( 2 9 ) CHz

-

Ha/- co,

9CBH5

CHz=C,

CH3

The same is true

of

the decarboxylation

of

salts

of

x,p-

unsaturated acids such as 31) with bromine

[221 to

the

and P-keto acids 1181, undergo spontaneous decarboxyla-

tion

to

form =$-unsaturated carbonyl compounds.

Arylethylenedicarboxylic

cids ( 2 3 ) also readily undergo

decarboxylation when hea ted with pyridine. Thereactive

substrate in this case is the zwitterion ( 2 4 ) which

contains the nucleofugal pyridinium group to the

carboxyl group

1193.

1151 R . Firfig and F. Binder,

Liebigs Ann. Chem.

195,

131 (1879).

[16]

S. J .

Cris to land W. P. Norris, J. Amer. chem. SOC.

75,

632,

2645 (1953);

E. Grovenstein and

D .

E. Lee, ibid.

75, 2639 (1953).

[17]

D.

S Noyce, P.

A.

King, and G. L .

Woo,

J. org. Chemistry

26, 632 (1961).

[18]

H .

Hellmann, F. Lingens, and

K .

Teiehmann,

Angew. Chem.

70,

247 (1958);

C Szantay and J. Rohaly,

Chem.

Ber. 96, 1788

(1963).

[19] E. J . Corey and G . Fraenkel,

J.

Amer. chem. SOC.

75,

1168

(1953).

bromo olefin, which

monium ion ( 3 2 ) .

a

0-oc,

Br2

,C =CHAr

-

presumably proceeds

via a

bro-

0-oc,

g

C- CHAr

-

C = C H A r

A; 32) A;:

e) R-0-C-C-C-X

The role of the electron-donating atom

a

of the electro-

fugal group a-b can occasionally be assumed by a n

ether oxygen atom. Thus when the tosylate 33) is

heated with dimethyl sulfoxide, very little of the ex-

[20]

M . S .

Newman and B.

J.

Magerlein, Org. Reactions 5, 413

1211

W .

S.

Johnson and W. E. Heinz, J. Amer. chem. SOC. 71,

2913 (1949).

[22]

J.

D . Berman and C. C. Price, J. Amer. chem. SOC. 79, 5474

(1957).

(1949).

4

Angew. Chem. internat. E dit .

1 Vol.

6 1967)

No.

I

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pected aldehyde is formed; instead fragmentation to the

oxonium salt 34) yields benzophenone and 3-buten-

1-01

231.

DMS e

ArzC=O-CH2-CHz-CH=CHz

341

-

OTosO

A r

=

C6H,

A r 2 C = 0 + H O - C H ~ - C H ~ - C H = C H Z

f ) RZN-C-C-C-X

The most thoroughly studied fragmentation reactions

include those of y-amino halides and sulfonates

[241.

Several cleavages of this type have been observed in

alkaloids [251. They also occur, accompanied by side

reactions, with acyclic y-amino halides. For example,

the solvolysis of

N- 3-chloro-3-methylbutyl)dimethyl-

amine 35) in 80 % aqueous ethanol leads t o t he frag-

mentation product isobutylene (36) in about

40

yield, together with the amino olefin, the alcohol, and

the azetidinium salt 1263.

f 6)

(CH3)2N=CHz

+

CH2=C(CH3)2

i C H ~ ) ~ N - C H Z - C H ~ - C = C H Z

CH3

Y H

( H 2 0 )

( C H ~ ) Z N - C H ~ - C H ~ - $ - C ~-

+ ( C H ~ ) ~ N - C H ~ - C H ~ - C ( C H ~ ) Z O H

35) CH3

Under solvolytic conditions, cyclic y-amino halides such

as 4-chloro-1-methylpiperidine [ 37), X = Cl] [271 and

4-bromoquinuclidine

39)

[281, as well as N-niethyl-5~-

tosyloxy-trans-decahydroquinoline

40)

[291,

undergo

quantitative fragmentation to imonium salts or their

hydrolysis produc ts,

i.e.

amino olefins, aldehydes, and

ketones.

The reverse of this reaction,

i.e.

the Mannich olefin

condensation, proceeds particularly readily when it

leads to ring closure, as in the reaction

(38)

37),

X =-= OH.

[23] R. K . Hi l l and S . Barcza, J.

org.

Chemistry

27,

317 (1962);

cf., eg., R. F. Ziircher and J . Kalvoda, Helv. chim. Acta 44, 198

(1961).

[24] Cf. C. A . Grob et al . , Helv. chim. Acta 45, 1119 (1962) and

later publications on fragmentation reactions.

I251 H .

S. Mosher, R. Forker,

H. R .

Williams, and

T. S.

Oakwood ,

J. Amer. chem. SOC.

74,

4627 (1952); M . F. Bartlett , E. Schlit t ler,

R .

Sklar, W . I .Taylor,

R .

L.

S.

Amai, and E . Wenkert, J. Amer.

chem. SOC.82, 3793 (1960).

[26] C. A . Grob , F. Osfermeyer , nd W . Raudenbusch, Helv. chim.

Acta 45, 1672 (1962).

[271

R .

D'Arcy , C. A. Grob, T. Kaffenberger, and

V .

Krasnobajew,

Helv. chim. Acta

49,

185 (1966).

[28]

P .

Brenneisen, C. A. Grob ,

R .

A . Jackson, and M . O h t a , Helv.

chi,. Acta

48,

146 1965).

[29]

C. A . G r o b , H .

R .

Kiefer, H. Lutz,

and H .

Wilkens,

Tetra-

hedron Letters 1964. 2901.

i 3 9 )

gTos

g ) R3C-C-C-X

The fragmentation

of

propanol derivatives containing a

tertiary

y-C

atom should yield relatively stable

carbonium ions

R3C@ R

alkyl or aryl) in addition

to

olefins. However, experience has shown tha t the electro-

fugal activity of ordinary carbonium

ions

is not suffi-

cient for cleavage. Thus no fragmentation could be

observed in th e solvolysis either of

cis-

and

trans-3,3,5-

trimethylcyclohexyltosylate

41) 1301

or of 2-chloro-

pentamethylpentane 42) 1311- In this last case further

reaction of the intermediate carbonium ion

43)

leads

only to the olefin

( 4 4 ) .

However, if the carbonium ion

43) is repeatedly reformed by protonation of the olefin

44),

he thermodynamically more favorable fragmenta-

tion to the t-butyl cation and dimethyl-2-butene takes

place

[ )I] .

Fragmentatio n can also occur in strained compounds [301, as

is

shown

by

the formation

of

j3-terpineol 48) and limonene

49)

on

treatment of a-pinene 45)

[*I

with acidL3zl and

on

deamination of endo-bornylamine 46) with nitrous acid 1331.

In

both cases fragmentation leads to the formation of the

carbonium ion 47), the precursor of

48)

and 49).

1301 C. A . G r o b, W. Schwarz, and H .

P.

Fischer, Helv. chim. Acta

47,

1385 (1964).

1311 V.J. Shiner and G . F. Meier, f.org.Chemistry 3 1 , 1 3 7 1966).

[*I This type of fragmentation

is

not initiated by the withdrawal

of a nucleofuge, but by the addition of an electrophile to a doubl e

bond.

[32]

G. W agner, Ber. dtsch. chem.

Ges.

27,

1944 (1894);

G. Val-

kanas

and

N . Iconomou, Helv.

chim. Acta 46, 1089 (1963).

[33]

W . Hi ickel and F. Nerdel, Liebigs Ann. Chem.

528.51

(1937);

W. Hiickel

and

J. Scheef, ibid . 664,

19 (1963).

Angew. Chem. in terna t . Edit. Vol. 6 1967) No. I

5

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h

48)

A special case is that of 2-methyl-3-tropyl-2-propanolSO),

which undergoes fragmentation with perchloric acid to for m

the very stable tropylium ion (51) and isobutene [341.

h)

-eC-C-C-C-X

This class includes fragmentations induced by the

formation of

a

carbanion center

on

the &carbon atom.

The cleavage

of

1,4-dihalides by zinc or an alkali metal

possibly follows this path [351. In the reaction of cis- and

trans-l,4-dibromocyclohexane 52)

with zinc, which

yields 1,5-hexadiene exclusively, the fragmentable

substrate might be the organozinc compound 53).

However,

a

reaction pathway via the 1,4-diradical

5 4 )

is not excluded since, like other l,Cdiradicals, it could

undergo homolysis t o form the hexadiene.

B r BPZn- Br

B r Br

(S.?j f 53)

54)

Another example is provided by the fragmentation of trans-

8-bromocamphor hydrazone (55) to limonene in the Wolff-

Kishner reduction

[361. If, as is generally assumed[371, the

carbanion

(56)

occurs as an intermediate in this reaction,

this represents a heterolytic five-center fragmentation. How-

ever a seven-center mechanism as indicated in (57) cannot

be ruled

out,

4. 4 9 ) 1 5 7 )

The decomposition of the five-membered cyclic ylides 59) 1381

and (61)

1391,

which result from the action

of

phenyl-lithium

[34]

K. Conrow, J. Amer. chem. SOC. 1,

5461 1959).

1351 C.A.Grob and W.Baumann,Helv. chim. Acta 38,

594 1955).

[36]

D .

M. Gustavson and W. F. Erman, J. org. Chemistry 30,

1665 1965).

1371

W. Seiberf,

Chem. Ber.

81,

266 1948).

1381 G. Wittig and W.Tochtermann,Chem. Ber.

94, 1692 1961);

F.

Weygand and H.

Daniel,

bid.

94, 1688 1961);

Liebigs Ann.

Chem. 671, 11 1964);H . Daniel, ibid.673, 92 1964).

1391 F.

Weygandand H.

Daniel,

Chem. Ber.

94,3145 1961).

on

the ammonium

58)

and sulfonium

(60)

ions respectively,

may be regarded as fragmentations.

In

the first case di-

methylvinylamine is formed in addition to ethylene, while

methyl vinyl sulfide is formed in the second case. Since the

nucleofugal group

X

remains attached to the atom a as in

62), only two fragments are formed 1401.

i) H-N-N-C-C-X

or

eN-N-C-C-X

It has recently been found that diimine

HN=NH

can

assume the ro le of th e electrofuge in an olefin-forming

fragmentation. Thus the treatment of chloroacetyl

hydrazide (63) with aqueous sodium hydroxide leads to

the formation of acetic acid besides nitrogen and

hydrazine, the secondary products of ketene and di-

imine

[411.

The recently described conversion of 1,2-O,O-cyclo-

hexylidene- 5

0

mesyl - D

-

glucofuranuronyl hydrazide

64)

into the 5-deoxy compound

(66)

by treatment with

hydrazine can be explained by

a

similar base-induced

fragmentation to diimine and the sugar ketene 65) ,

which is the precursor of the deoxy acid hydrazide

(66) 1421.

HZNNH-CO-CHR-OMes HN=NH + O=C=CHR

6 4 ) 1 6 5 )

k) HN =N-C-C-X or 9N =N-C-C-X

It has long been known that the Wolff-Kishner reduc-

tion of aldehydes and ketones containing a nucleofugal

group u

to

the carbonyl group yields olefins instead

of

saturated compounds 431. Suitable nucleofugal groups

are

a

halogen atom,

a

hydroxyl, amino, even an epoxy

[40]

For other examples, cf.

P . S.

Wharton, G. A .

Hiegel ,

and

R. S. Ramaswami, J. org. Chemistry

29, 2441 1964).

L41]

R. Buyle, Helv. chim. Acta

47, 2449 1964).

[42]

H.

Paulsen

and D. Stoye, Chem. Ber.

99, 908 1966).

[43]N.

J . Leonard and S. Gelfand,J. Amer. chem. SOC.

77, 3272

1955).

6

Angew.

Chem. internat. Edit.

Vol.

6 (1967) 1

No.

I

8/11/2019 Grob Acie Rev.1967

7/15

group or a cyclopropane ringt45). The base-induced

formation

of

nitrogen and olefin can be formulated as a

fragmentation of the tautomer

(68) of

the hydrazone

(67). The electrofugal activity

of

nitrogen is so high

that this reaction proceeds even with notoriously poor

nucleofugal groups such as

OH

and

NR2.

1)

H-0-P-C-C-X

P-Halophosphonic acids such as

69)

behave in the

same manner as the corresponding carboxylic acids.

Relatively stable in aqueous solution, they react rapidly

in alkaline media with liberation of olefin and meta-

phosphate

[46

471.

m)

R3Si-C-C-X

P-Haloalkylsilanes such as

(70)

undergo base-induced

cleavage to silanols and olefins [481.

(C2H5)3Si-CH2-CH2-Cl a C2H:,)sSiOH

+

CH2=CH2

-

8/11/2019 Grob Acie Rev.1967

8/15

P-Halogenated cr.,P-unsaturated carbonyl compounds

are systems that become fragmentable only upon

addition of

a

nucleophile. Thus in the presence of

aqueous sodium hydroxide,substituted 3-chloroacroleins

(7.5) decompose into formic acid and alkynesL541. The

reactive substrate is assumed to be the anion

of

the

aldehyde hydrate (76).

C ) HO-P-C= C-X

An example of this class of reactions

is

the formation

of phenylacetylene from the salt

of

P-bromo-c-phenyl-

vinylphosphonic acid (77). The electrofugal fragment

in this case is metaphosphoric acid 1551.

O C H

I t 1 6

O - P - C = C H B ~ + 1 - 1 ~ 0 ~C,H,-C=CEI + E rO

6 H

1 7 7 )

d) "OCO-O-C~H~

Alkyne-forming fragmentations include, at least for-

mally, certain reactions used in the preparation of ben-

zync

(79).

Thus this unstable compound is formed by

mild decarboxylation of diazotized anthranilic acid

(78) [561 or of

diphenyliodonium-o-carboxylate 80) [571.

Both of these compounds contain combinations of very

active electrofugal and nucleofugal groups. Whether

benzyne is to be regarded as an acetylene derivative,

however, is

a

matter of opinion.

IV. Imine-Forming Fragmentations

(a -b -C

-N

-X a nd a -b -N -C -X)

In the reactions discussed

so

far, the nucleofugal group

X was attached to

a

carbon atom. In the following sub-

classes, however, the group X

is

attached to a hetero-

atom such as nitrogen or oxygen.

In

these cases nucleophilic substitution no longer

competes with fragmentation. Another difference is

that cationic centers form much less readily on nitrogen

or

oxygen than on carbon. On the other hand, rearrange-

ment involving

a

1,2-shift of

a

group in the 6 position

often competes with fragmentation in these systems.

a) HO-C-C-N-X

The P-hydroxy-N-chloro amine (81) obtainable from

veratramine, undergoes fragmentation with bases to

form the imine

(82),

which is hydrolysed

to

the aldehyde

(83) [581.

A similar acid-catalysed cleavageof N,N'-dimethy1-N'-

2-hydroxy-2-phenylethy1)hydrazinium ion 84) - to

benzaldehyde and forniimine or its hydrolysis products

has recently been formulated as

a

fragmentation

[591.

b)

N-C-C-N-X

Benzoylation

of

the N-oxide of

1,4-diazabicyclo[2.2.2]-

octane 85) followed by hydrolysis yields piperazine and

formaldehyde. This reaction may be regarded as

a

fragmentation of the ammonium salt (86) to the

bisimonium salt (87) [601.

C ) HO-CO-C-N-X

This class includes the

oxidative decarboxylation of

oc-amino acids with halogenating agents such a s hypo-

chlorite or N-bromosuccinimide

(NBS)

[GI]. N-halo-

I541 K. Bodendorf

and R .

Mayer,

Chem. Ber.

98, 3554 (1965).

[ 5 5 ] Cf. 1461 and E.

Bergmann

and A .

Bondi,

Ber. dtsch. chem.

Ges.

66,

278 (1933).

[561 M. Stiles and R. G. Miller,

J.

Amer. chem. Soc. 82, 3802

(1960);

M. Stiles,

R . G.

Miiier,

and U.

Burckardt, ibid. 85,

1792

(1963); L. Friedtran

and F.

M. Logullo, ibid. 85, 1549 (1963).

[57]

E.

LeGqf;

J . Arner. chern.

SOC. 84, 3786 (1962).

[ 5 8 ] R.

W.

Franck and W. S. Johnson, Tetrahedron Letters 1963,

545; T.

Masamune, M.Takarugi,

and Y .

Mori, ibid. 1968, 489.

[59] W.

H .

Urry, P. Szecsi, C. Ikoku,

and

D .

W.

Moore,

J.

Amer.

chem. Soc. 86, 2224 (1964)

[60]

R

Huisgen and W. Kolbeck, Tetrahedron Letters 1965, 783.

[61] Cf. A. Schunbrrg

and

R. Moubociier,

Chem. Reviews

50, 261

(1952).

A n g e w . Cltem. internat. Ed it.

Vol . 6 1967) / No.

8/11/2019 Grob Acie Rev.1967

9/15

amino acids

(88)

may be assumed as intermediates,

though fragmentation of the acyl hypobromite (89)

cannot be ruled out.

NBS

(3 ,

p

HOOC-YH-NH2 0-CO-YH-NH-Br

K It

88)

-H B r

3

/7u

-

0 2 RCH=NH

-

2N-$H-CO-O-Br

-

Rr j

R 1891

N-Arenesulfonylamino acids (90) also undergo frag-

mentation when heated in pyridine [621.

eO-CO-CHR-NH-SO2Ar + CO2 + RCH=NH + ArS0z0

90)

d)

N-C-N-C-X

In the imine-forming fragmentations described above,

the electrofugal group is attached to the carbon atom

and t he nucleofugal group to t he nitrogen atom. How-

ever, cases are also known in which the positions of

these two groups on the middle group a re reversed. Fo r

example, the decomposition of the allophanyl chloride

(91)

into the diisocyanate (92) in the presence of tri-

ethylamine involves the formation of an N=C double

bond. This reaction evidently is induced by the attack

of the base on the H atom attached t o nitrogen

[633.

H

co-c1

V. Fragmentations Leading to Cyanic Acids

(a

-b -CO -N -X)

In the Hofmann, Curtius, or Lossen degradation

of

amides, the release of the nucleofugal group from the

nitrogen atom is normally accompanied by migration

of the group R to form an isocyanate (route a):

K-N=C=O

R-CO-NH2 - - R-CO-N-X

X

= Halogen, -NF, 0CO R

R @ g = C = O

However, if R is an active electrofugal group, frag-

mentation can compete with the rearrangement. Such

groups are present in amides of a-hydroxy, a-keto,

a-amino, and cc-halo acids. Thus in the Hofmann

degradation of a-hydroxy carbonamides (93), the ex-

pected rearrangement product a-hydroxy isocyanate

[62]

R. H . Wiley and

R.

P. Davis , J Amer. chem.

SOC.

76,

3496

(1954).

[63] A . A . R. Savigh, J .

N .

Tilley,

and

H. Ulrich,J.

org. Chemistry

29, 3344 (1964).

(94) could not be detected [641, suggesting that direct

fragmentation to the aldehyde and the cyanate ion has

taken place in accordance with (93).

n

H- v- CHR- CO- N- Br RCHO + NCO +

H B r

(93)

Y

RCH-NCO

(94 )

The formation of carboxylic acids and cyanate ions

in

the Hofmann degradation of a-keto carbonamides

9 5 )

in aqueous alkali solution [651can also be formulated as

a

fragmentation as in

(96).

+ N C O

95) 1 96)

Azides of N-tosyl-or-amino acids (97) are relatively

stable in neutral solution. When alkali is added, how-

ever, they decompose to form an aldehyde, p-toluene-

sulfonamide, cyana te ion, and nitrogen indicating

a

fragmentation in accordance with (98).

( 9 7 ) 198)

The formation

of

geminal dibromides

(101)

and cyanate

ion in the Hofmann degradation of or-bromo carbon-

amides

99)

has been explained by an intramolecular

mechanism

(100)

[671.

I n

any case, the hypothetical

rearrangement product

(102)

is stable under the con-

ditions of the reaction, and therefore does not occur as

an intermediate.

K H

-

N-C

=o

I

Br

I l 02 )

VI.

Nitrile-Forming Fragmentations

(a-b-C =N-X and a-b-N =C-X )

If the hydroxyl group of a ketoxime

[ 103),

X = OH] is

converted into a more active nucleofugal group by

protonation, esterification, or etherification,

a

Beck-

mann rearrangement (route a) generally takes place

(681.

[64]

C. L. Stevens, T. K . Mukherjee, and

V . J .

Truynelis, J Amer.

chem.

SOC. 78, 2264 (1956).

[65]

C. L .

Arcus

and

B .

S .

Prydul,

J. chem. SOC. London)

1954,

4018.

[66]

A .

F .

Beechum,

J.

Amer. chem.

Soc.

79, 3257, 3262 (1957).

1671

D . A . Burr and

R. N .

Huszoldine,

J.

chem. SOC. London)

1957,

30.

[68] Cf. L. G. Donaruma and W. Z . Heldt, Org. Reactions 1 1 , 1

(1

960).

Angew. Chem . in ternat . Ed i t .

Vol. 6

1967)

J N o . I

9

8/11/2019 Grob Acie Rev.1967

10/15

The group

R

that is

t r a n s

to

X

migrates to form a

nitrilium ion

104),

which reacts further with water to

form the amide

1691.

However, if R is an active electro-

fugal group it may be wholly or partially removed, with

simultaneous formation

of a

nitrile (route b). Processes

of this type are frequently referred to as second orde r

Beckmann reactions. A more appropria te term would

be Beckrnann fragmentation

1701.

This reaction occurs particularly with a-amino,

a-

hydroxy, a-alkoxy, a-0x0, a-imino, and a-carboxy

ketoxime derivatives. A number of electrofugally sub-

stituted ketoximes are listed in Scheme

2,

togethe r with

products resulting from Beckmann fragmentation and

subsequent hydrolysis. Classes

a

to

h are substantiated

by several examples in the literature.

Scheme

2.

Examples of Beckmann fragmentations.

R

\

,C-N,

R@[a]

+

RCEN

+ X e

-

a

b

C

d

e

f

g

h

1

k

R-

I

R2N-C-

HO-k-

R o d -

R-CO-

R-C(0H)-

[c]

Y

RN=C-

HOOC-

R3C-

RzC-C-

RS-C-

I

R@

R~N %c