R.A. Heacock and G.L. Mattok- The Chemistry of the Aminochromes Part V: Rearrangements in the Prescence of Sodium Hydroxide and Zinc Acetate

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T H E C H E M I S T R Y O F T H E A M I N O C H R O M E S

P ART V . RE ARRANGE M E NT S IN T HE P RE SE NCE OF S ODIUM HYDROXIDE

AND ZINC ACETATE1* * 3

R. -4. HEACOCKND G. L. R~AT TOK

Th e Psychiatvic Research Un it , Univers i ty Hospi tal , Sask atoon, Saskatchewan

Received September 10, 1962

ABSTRACT

The rate s of rearrangement of severa l aminochromes have been measured in: (I) water,(2 ) aqueous sodium hydroxide, and (3) aqueous zinc acetate. Th e rates were found to be firstorder with respect to aminochrome concentration in each reaction medium, and to zincacetat e concentration. However, no simple kinetic relationship between the rate of rearrange-ment and alkali concentration was detected. The rate increased very rapidly with increasingalkali concentration.

Mechanisms for these rearrangements are suggested, based on the influence of substituentsin the I-. 2-, and 3-positions of t he aminochr ome molecule on the kin etic and the rmodvnam icfeaturesof the reaction.

INTRODUCTION

The ease with which ,the red solutions obtained on oxidation of the catecholamines

could be decolorized was recognized long before the structures of the compounds involved

were established (see ref. 1 for references). As a resu lt of studies on the oxidatiosl of

3,4-dihydroxyphenylalanine (DOPA) carried out over 30 years ago, Raper proposed

what was essentially the correct explanation of the changes that occurred, namely t ha t

the oxidation of DOPA (I : R1 = R3 = H ; Rs = COOH) resulted in the initial formation

of an an~inochrome,~.e. a 2,3-dihydroindole-5,6-quinoneerivative (11: R1 = R3 = H ;

R z = COOH),t which subsequently underwent a spontaneous internal oxidation-

reduction process, forming the colorless 5,6-dihydroxyindole (111: R1 = R z = R 3 = H).

The rat e of decolor izatioi~ f the intermediate pigment could be increased by the act ion

of either base or acid. In the lat ter case, however, the rearrangement product was not

5,6-dihydroxyindole, but 5,6-dihydroxyindole-2-carboxylic cid (111; R1 = R 3 = H ;

R2= COOH) ( 3 ) . This general picture has subsequently been confirmed spectroscopic-

ally, manometrically, and paper chromatographically (4-6).

Solutions of adrenaline (I : R1 = CH3; RZ= H ; Rs = OH) and certain related cate-

cholamines with a hydroxyl group in the P-position that have usldergone oxidation in

'T hi s inves t igat ion was supported b y grants from the Gooernment of Saskatc hewan (D epartme nt of P ubl icHealth) and the Department of Nat iona l Heal th and We lfare (Ottawa) .

2Presented in part a t the 45th A nn ua l Conference of the Chemical Ins t i tute of Can ada, Edmo nton , Alber ta,M a y , 1 9 6 2.

3P ar t I V : C an . J . C hem . 38 , 51 6 ( 1960 ) .*T he ter m "aminoch rome" as a geneval na me for the highly colored cyclic oxida tion products of the catechol-

amines was not introduced unt i l 1951 by Sobotka and Aust in (2 ) .tT h e chemical and physical properties of these com pou nds suggest that the switterionic for m of the molecule,

as shown above, makes the majo r contr ibut ion to the aminochrome s tructure (cf . ref . 1) .

Cana dian Journal of Chemist ry. Volume 41 (1963)

13 9



140 CANADIAN J OURNAL O F CHEMISTRY. VOL 41 , 1963

alkaline media exhibited a transient but intense yellow-green fluorescence (see ref. 1 for

references). Th e fluorescent derivative of adrenal ine was, in fac t, 5,6-dihjdroxy-N-

methylindoxyl" (i.e, adrenolut in; IV), first isolated and charac terized by Lund in 1949

(7, 8) and obtained by the alkaline rearrangement of the initially formed aminochrome

(i.e. adrenochrome; 11: R1 = CH3;Rz = H ; R 3= OH ). Rearrangement of aminochromes

to 5,6-dihydroxyindole or 5,6-dihydroxyindoxyl derivatives is catalyzed by certain

metallic ions, part icularly Zn* and A13+ (9, 10).

Although speculative mechanisms, notably those of T rau tne r and Bradley (11),

Sobotka, Barsel, and Chanley (12), and Bu'Lock and Harley-R/Iason (13). have been

advanced t o explain certain aspects of the manne r by which the rearrangement of the

aminochromes to 5,6-dihydroxy-indole or -indoxy1 derivatives occurs, none is based 011

a systematic physico-organic chemical investigation.

A number of reports of an essentially qual itat ive natu re dealing with the stabi lity of

adrenochrome solutions has appeared in the lit erature, and these have been summarized

previously (1). Zainbotti and lI or et studied the effects of pH and temperature on the

stab ility of adrenochrome solutions in phosphate buffer polarographically and mano-

-metrically and reported tha t, in the relatively limited range studied, the decolnposition

of adrenochroine follows first-order kinetics and th at t he rate of disappearance of amino-

chrome varied linearly with the pH a t 37" and exponentially with temperature a t pH

= 7.38 (1-4-16).

I t appeared t o the author s th at a systematic stud y of the kinetic and thermodynalnic

features of the rearrangement of a number of different aminochromes would enable a

more satisfactory explanation of t he mechanisms of these reactions to be formulated .

Aminoch~omes

Adrenochrome (17), iV-isopropylnoradrenochrome (181, and adrenochrome methyl and ethyl ethers (18)

were prepared as pure crystalline solids by the methods described in the literature. Holvever, in the cases of

epinochrome, 2-methyladrenochrome, N-ethyl-2-methylnoradrenochrome, and noradrenochrome, where it

was eithe r not possible to isolate a pure sample of the aminochrome or where only limited quanti ties of the

relevant catecholamines were available, th e aminochrome was prepared in aqueous solution by oxidation

of t he appr opri ate catecholamine hydrochloride (25 mg in 3 ml water) with freshly prepared silver oxide

(2X 0.2 g) (finally filtering the oxidation mixtu re thro ugh a small Dowex-1 (Cl-) (200/400 mesh) resin bed

t o ensure complete removal of colloidal an d ionic silver (cf. ref. 17). The rate s of rearran gement obtained for

adrenochrome prepared in this way showed satisfactory agreement with those determined using crystalline

adrenochrome. Solutions of noradrenochrome prepared in this manner were not entirely satisfactory, since

th e visible absorption spectra of these solutions frequently showed a shift in X,,,accompanied by an increase

in th e intensity of absorption a t this wavelength. This phenomenon is possibly due to th e relatibely slow

cyclization of the initially formed "noradrenaline quinone" (i.e. 1-(a-hydroxy-0-aminoethy1)-3,4-benzo-

quinone) t o noradrenochroine (cf. refs. 19, 20). However, it is not unreasonable to assume that the ratesobtained represent the relative order of react ivity of this c on~p ound .

Kinetic ~WeasurementsTh e rearrangements of the var ious atninochromes were studied in three react ion med ia: (a) water, (b )

aqueous sodium hydroxide, (c) aqueous zinc acetat e. Th e reactions were followed by measuring the decrease

in absorbance a t A (ca. 480-495 m,u) with ti me using a Beckmann DK -2 spectrophot ometer equi pped with

*Often ornzulated in the enolic form, i.e. as 3,6,G-trilzydro?cy-N-1~zethylindole.



HEACOCK AK D MATTOK: AMINOCHROMES 1 41

a temperatu re-regu lated cel l ho lder . (The absorp t ion max ima and min ima o f the an~inochro~nessed areg iven in Tab le I . ) Th e in i t ia l concen trat ions of t he reagen ts ar e g iven in Tab le 11. In a l l cases the so lu t ions

T A B L E I

Absorp tion spectra o f some ami~lo chrom esn water(in the range 250-650 mM)

Absorp t ion Absorp t ionm a x i ~ n a m l n i m a

R I Rg R , ( w ) ( m ~ )

of th e reagen ts were p reheated to the react ion tem peratu re in the cell ho lder. Th e react ion mix tu res \ rerep repared by th e admix tu re of 2 ml of the aminochrome solution with 1 ml of th e cataly st solution, carebeing taken to ensure rap id an d complete mix ing of t he reagen ts .

There was a good l inear re la t ionsh ip between th e aminochrom e concen trat ion an& the absorban ce a tx

Th e Reaction of Adrenochronze ;l[ethyl E ther w ith Zinc Acetate-4 satu rated so lu tion of z inc acetate (1 .5 ml) was add ed to a so lu t ion o f ad renochrome m ethy l e th er

(73 mg) in water- (2 .2 ml) . The react ion mix tu re was lef t to s tan d fo r 1 h o u r an d th e d a rk b lu e p rec ip it a t ewhich fo rmed was f i l tered o ff, washed wi th water a nd eth er , and d r ied in a i r . Th e weigh t of the d ry p recip i ta tewas 60.2 mg. Th e aqueou s filtrate, which was initially yellow b ut which quickly becam e blue-green in color,gave, af ter s tand ing fo r an hour , on the add i t ion o f more z inc-acetate so lu t io~ l 3 ml) a b lue p recip i ta te ,which was f i l tered , washe dwith water an d eth er , and d r ied in ak . The weigh t o f th is d ry res idue was 29 .8 rng .

The aqueous f i l t ra te (30 ml) was ex traeted wi th e th er ( 3 x 1 0 ml) . Concen trat ion of the d r ied (XasSO*)ether ex tract af fo rded a whi te crysta l l ine res idue (5.5 mg-).A paper ch romatograph ic examinat ion of th isres idue ind icated that i t was p robab ly 5,6-dihydroxy-A-methylindole (i.e. 111: K1 = C H 3 ; R 2 = R 3 = H(cf . ref. 21 )) . Assuming t ha t th is w as in fa ct the p roduct , the exp ected y ield o f a complex composed of onezinc a tom and one aminochrom e un i t wou ld be 90 .4 mg , and t ha t fo r 1 :2 complex , 78 .9 mg . Th e to ta l weigh tof com plex obtained wa s 85.7 mg.

Analyses of sev eral different samples of thes e produc ts for carbon, hyd rogen , nitrogen, an d zinc wereinconclusive. (Found: C, 47.57, 4'i.38, 43.20, 43.19, 42.52, 49.53, 51.06;H , 5.32, 4 .08, 4 .07, 3 .83, 4 .16, 4 .61,4 .70 ; N, 5.96, 5 .90, 4 .07, 5 .63; Zn, 12.57, 12.57Gjo.) T he calcu lated com position of 1 :l zinc/aminoc hromecomplex would be C, 46.41; H, 4 .29; N, 5 .42 ; Zn , 25 .28%; and that fo r a 1 :2 z inc/an~inochrome omplexwould be C, 53.16; H, 4 .91 ; N, . 20 ; Zn , 14 .47%. I t i s therefo re d i f f icu lt to s ay wheth er the exper imen tal lydetermined percen tage composi tion of th e con ~p le x uppo rts a 1 : l o r a 1 :2 complex .

I t i s in teres t ing to no te th at th e averages of th e exper imen tal values ( i .e . C , 46 .35 ; H , 4 .69 ;N, . 39 ; Z n ,12.577;) fit th e calculated comp osition of a hydr ate d 1:2 comp lex (4 molecules of wa ter) (i.e. C:oHzeNnOlaZnrequires C, 46.21; H, 5 . 0 4 ; X, 5.39; Zn, 12.587;).

S ince these p roducts are inso lub le in the usual reagen ts , i t was no t possib le to pur i fy them fu r ther byrecrystallization.

In view of th e formatio n of insoluble precipita tes in this case, the reac tion was n ot followed spectroscopic-al ly beyond approx im ately 1 0% react ion , s ince c loud ing of the cell wal ls th at resu l ted wou ld h ave g ivenanomalous resu lts .

R E S U L T S

Th e rearrangemeilts of adrenochrome and it s inethyl ether were first order with respect

to aminochro~ne once~ltratiolln all three reaction ~ ne di a see Figs. 1,2 , 3 , and 4 ) . 111 the



142 C A N A D I A N J O U R N A L OF C H E M I S T R Y . VOL 41, 1963

4 + LOG AMINoCHROME&.~

FIG. 1. Rearrangement of: adrenochrome (A ), a t 28.g0, and adrenochrome methyl ether ( 0 ) , at30.2', in water. First -order plots ( k l (for adrenochrome) = l.10X10-4 min-I; kl (for adrenochrome methylether) = 0.96X min-I).

FIG.2. Rearrangement of: adrenochrome ( A ), a t 29.7', 4.5X10-5 N NaOH, and adrenochromemethyl ether ( O ) , t 42.6', 8.5X10-6 N NaOH, in the presence of sodium hydroxide. Order with respect toaininochrome concentration. (A = adrenochrome; AM E = adrenochrome methyl ether.)

4+LOG [A]

0.2 0.3 0.4

0 SLOPE: 0'95

0.9 -LT"_I

+N

3

0.6 0.8 1'0 12

4 + LOG [ZA]

0 SLOPE. 1.03I 0 S L n l . D . 9 5

FIG.3. Rearrangement of adrenoch rome in th e presence of zinc ace tat e, a t 28.8'. Order in: adreno-chrome (A) , zinc acetate 9.4X1OP4 Af , and zinc acetate (O) , adrenochrome 2.0X10-4 M. (A4 adreno-chrome; ZA = zinc acetate.)

FIG. 4. Rearrangement of adreno chrome methy l eth er in the presence of zinc ace tat e, at 42.6'. Order in:adrenochroine methyl ether ( 0 ) and zinc acetate (0).AME = adrenochrome methyl ether; ZA = zincacetate.)

presence of zinc acetate the rearrangements also obeyed first-order kinetics with respect

to zinc aceta te. Rearrangements in the presence of sodium hydroxide, whilst being first

order with respect to aminochrome concentration, did not show any simple dependency on



HEACOCK AND MATTOK: AMINOCHROMES

I

FIG.5 . Effect of sodium hydroxide concentrati on on the rate of rearrangement of: (A ) adrenochrome,a t 29 .7" , initial concentration of adrenochrome 1.90X10-4 M, an d (B ) adrenochrome methyl ether, a t42.6", initial concentratio n of adrenochrom e methyl ethe r 1.91 X10-4 AM.

alkali concentration (see Fig. 5). Th e rate of rearrangement in the presence of sodium

hydroxide increased rapidly with alkali concentration.

With the exception of exper iments which were carried out t o determine th e order of

the reaction, they were all performed with standardized zinc aceta te and sodium hydroxide

concentrations. Th e first-order rate constants were calculated by the method of initial

slopes to avoid errors due t o any secondary reactions.

Th e rates of rearrangement, a t 35', of some aminochromes are given ill Table 11. When

the substituent on carbon atom 3 only is varied the sequence of reactivity is : H > OH

> OCH3 > OCzHS. Further, when the substituent on the nitrogen atom only is varied

the sequence of re activ ity is i-C3H7> CH3 > H. Variation of t he substi tuent on Cz

from EI t o C H3 had little effect on the rat e of reaction (see Table 11). These generaliza-

tions are true for rearrangements in water, alkali, and zinc acetate solution. An incidental

observation is that OH- is abou t 10 times better a catalys t for the rearrangement than

Zn2+ (on a molar basis). I t is also of inte rest t o note t ha t solu tions of noradrenochrome

are not as unstable a s they are generally considered to be.

Th e effect of temperature in the range 30-50' on the rates of some of these reactions

was also investigated, and the thermodynamic functions (at 35') for these rearrange-

ments are given in Table 111. In each of the three reaction media, th e activa tion energy

decreases as the rate of rearrangement increases. In general, the en tropy term is fairly

constant . However, with epinochrome, which carries two hydrogen atoms on C3, the

entropy term is co~ ~s is tent ly ore favorable than for adrenochrome. Although th is

difference is small, it is probably significant.



C A N A D I A N JOURXAL OF CHEMISTRY. VOL 41 . 1963

T A B L E I1

Rea rran gem ent of sever al amiriochromes in variou s reaction media

( R a t e c o n s t an t s a t 35')

0 \ ~ - _ C H R 3I IC H R z

k l X l o 4 (mill-l) in:

Aminochrome" RI Rz R3 Hz 0 NaO H* Zi l (OAc)?*

E p in o ch ro m e C H 3 H H 1 4 . 6 7 2 . 1 1 26Adrenochrome CH3 H O H 2 . 0 4 22.4 1 3 . 4Adrenochrome methy l e ther CI-13 H O C H , 1 . 2 6 1 5 . 3 1 0 . 4Adrenochrome ethy l e ther C H I H OC,H, 0 . 7 6 1 0 . 2 9 . 7 7N-1soprop)-lnoradre~lochrome i-C3H7 H O H 3 .7 2 4 1 .7 1 9 .5Noradrenochromet H H O H 1 . 4 8 1 2 .3 1 1 .92-Methy ladrenochron le CH C H I O H 1 8 0 1 7 .3 1 6 .3A'-Ethyl-2-methyli~oradre~~ochromeC2Hs C H , O H 1 .SO 1 9 .3 1 8 .8

*Initial concentrations of reagents: NaOH = 8.5OX10-5 M , Zn(0Ac)z = 9.5OX10-4.If, aminochrome = 2.05X10-4M.?See experimental section dealing with preparation of aminochromes.

TABLE I1 1

Rearra ngem ent o f aminochro tnes in ( i ) water , ( i i) aqueous sod ium hydrox ide, and ( ii i) aqueous z inc aceta te

( T h e r m o d ~ a m ic f u ~ l ct i o n s t 35')

-S u b s t i t u en t s I I 'a t e r N aO H (1.5X10-5 Jf) Z n (0 X c)z (9 5 X 3 1)-- -R I R 3 E,,,* AS*? AFc* E,,, AS* AF* E,,, AS* AF*

*Eexpand AF' in kcal/mole.?AS* in e.u.

D IS C U S S IO N

Reurrungements in Watev and Alkali

The overall reaction consists of relnoval of protons from the 2- and 3-positions in the

five-membered ring of the aminochrome molecule (11) and the addition of a proton to

each of the Cg- and C6-carbonyl oxygen atoins on t he o-benzoquinone ring. Th e primary

reaction center il~ustherefore be either C2 or Ca. The following lines of evidence suggest

th at the primary reaction center is, in fact, C3 : (i) I n th e cases investigated, substituents

in th e 3-position had a marked effect on the reaction rate s, whilst those in th e 2-position

had little effect; (ii) the entropy te rm for epiilochrome (11: R1 = CH3;Re = R 3 = H)

is slightly more favorable for rearrangement than for the other aminochromes. This would

be expected if t he rate-determining process is reinoval of a proton from carbon 3.



HEACOCK AXD MATTOK: AMINOCHROMES 145

The reaction in water is first order with respect to aminochrome concentration. ('This

is the case for at least 40% reaction.) In aqueous alkali, the rearrangement is also first

order with respect t o amillochrome; however, the order with respect t o sodium hydroxide

concentration is not simple, indicating that alkali probably plays a multiple role in the

reaction.

Th e rate-controlling process would then be th e loss of a proton from the three position,

resulting in a transition stat e involving one ami noc hro ~l~ eolecule.

Th e two carbonyl groups in o-quinonoid struc tures tend to promote electromeric changes

in opposite directions, resulting in the high reactivity associated with these structures,

which have a tendency to revert t o structures in which the tension of the opposed electro-

ineric effects has been relieved (22). The tendency of the Cs-carbonyl group to polarize

effectively lowers the electron densi ty on C3, by the series of electromeric changes as

shown below, thus facilitat ing the removal of t he proton from the 3-position. Electron-

attr acting substitueilts a t C 3 will diminish the supply of electrons available for th e

eler tro~neri c hifts, resulting in th e polarizatioil of the C6-carbonyl group. Th e rat e of

rea_rra~lgemeilt ill therefore decrease with an increase in electron-attracting capacity of

the C3-subst ituent (R3), and this is, in fact , observed for the following series of co~npounds:

epinochroine (R3 = H) > adrenochrome (R3= OH) > adrenochrome methyl ether

(R3= OCHB) > adreilochrorne ethyl ether (Ra = OC2H5).

The rate-determining stage is then followed by a second series of electronic shifts in

the pyrrole moiety of t he molecule, resulting in the loss of a proton from Cz andthe forma-

tion of a fully aromatic structure.

Electron-donating groups on the nitrogen atom will promote fnrther polarization of the

CG-carbonyl group, resulting in an increase in t h e already high contribut ion of the zwit-

terionic form of the aminochrome molecule to the ground-st ate resonance hybrid. Th is

results in a raising of the ground-state free energy of the molecule. Th e observed sequence

of reactivity for th e N-subs tituted arninochromes is: N-i-C3H, > N-CH3> N-H.

This would be expected 011 the basis of the inductive effects of these groups. This effect

is also probably associated with th e observed shift towards longer wavelengths of the

iilain absoi-ptioil peak (see Table I ) of the N-substi tuted aminochrornes with increasing

electron-donating capac ity of the N-substi tuent.

Th e rapid increase in the rat e of rearrangement of the aminochromes with increasing

alkali co~lcen tration ndicates t ha t t he catalys t does not play a single role in the reaction,

but presumably assists several processes simultaneously. The hydroxyl ions will act as

proton scavengers, and the presence of alkali will also tend to stabilize th e enolate anion

of the tr a~ls itio n tate. Fur thermore, interaction of the hydroxyl ions with the qu atern ary

nitrogen center will localize the positive charge of the zwitterionic system and thus

destabilize the molecule by limiting the possibilities for resonance.

Rearrangements in the Puesence of Zinc Acetate

Several of t he observed kinetic features of these rearrangements are si ~n il ar o those in

the alkali-catalyzed and u ~lcat alyzed earrangements. Th e same sequence of reactivity

for substituents in the I-, 2-, and 3-positions is observed. The thermodynamic aspects of



146 CANADIAN JOURNAL OF CHEMISTRY. VOL. 41. 1963

the rearrangements are similar. However, there are some important differences. Firstly,

there is a good first-order dependency with respect to the zinc acetate co~lcentration,

whilst there is no simple relationship to alkali concentration. Secondly, rearrangement

of the various aminochromes in the presence of sodium hydroxide leads t o analogous

products in every case. However, when zinc aceta te is the catal yst , rearrangement of the

aminochro~neswith R3= H or OH leads to the formation of the same products a s with

alkali, whereas when R 3 = 0-alkyl (i.e, the aminochrome ethers) these aminochromes

react with zinc acetate solution to form an insoluble dark blue precipitate (cf. ref. 21),

which forms relatively slowly. The composition of these precipitates is uncertain. Analysis

of the product derived from adrenochrome methyl ether did not confirm either a 1 :l or

1:2 zinc/aminochrome compositioll but suggested a hydrated 1:2 complex. I t was in ~po s-

sible to obtain a pure sample of this material, since it is probable th at t he product is

contaminated with insoluble melanitic Inaterials which are formed a t the same time as

the complex. Insoluble precipitates were never obtained initially in the cases where

R 3= H or OH.

Bu'Lock and Harley-Allason have suggested, by analogy with the products formed

during the oxidation of catechol in the presence of zinc ace tat e, tha t the rearrangement of

aminochromes in the presence of zinc acetat e proceeds via an in termediate co~nposed f

one zinc unit a nd two aminochrome units (13). Our results do no t rule out the formation

of such a complex as th e final product with the aminochrome ethers, bu t, t he transition

st at e for the zinc ion catalyzed rearrangement must , from the kinetic dat a, involve only

one zinc ion and one aminochrome molecule.-

The birnolecular process required to form a 1 1 conlplex is more likely than the three-

body collision necessary for the formation of the 1:2 complex proposed by Bu'Lock and

Harley-Mason. Further , it is difficult to rationalize the pronounced effect of the C3-

subs tituent, in the case of the aminochrome ethers, on the solubility and stability of this

complex.

From the kinetic da ta , there will be a pr imary interact ion between one Z1l2+ ion and

one aminochrome molecule. Presumably, the zinc ion approaches the dicarbonyl function

of the benzoquinone moiety. The polarization of the Cs-carbonyl group will assist this

approach. The proximity of the ZnL+ on t o the Cs-carbonyl will induce polarization in

this group, thus providing the driving force for the same electromeric shifts, resulting

in the removal of th e C3-proton ,as proposed for the hydroxyl ion catalyzed rearrangement.

The C2-proton is removed by the second series of shifts a s described previously.

The mechanisms of rearrangement of the amiilochromes in the presence of alkali or

zinc acetate therefore differ mainly in the method by which the two catalysts bring ab out

the same electronic changes in the aminochrome molecule. This is in accord with the fact

th at , apa rt from catalytic aspects, the same general kinetic features are observed for the

two types of rearrangement .

ACKNOWLEDGMENTS

Th e authors wish to express their thanks to Burrough-Wellcome and Co. (C anada ) Ltd .,

for a generous gift of epinine hydrochloride and t o Mrs. B. D. Scott for the preparation

of samples of 3,4-dihydroxyephedrine hydrochloride and N-ethyl-3,4-dihydroxynor-

ephedrine hydrochloride.

REFERENCES

1. R. A. HEACOCK.Chem. Rev. 59, 181 (1959).2. H . SOBOTKAnd J. AUSTIN. J. Am. Chem. Soc. 73, 3077 (1951).3. H. S. RAPER. Biochem. J. 21, 89 (1927).



HEACOCK A S D MATTOK: AMISOCHROMES

4. H. S. MASON. J. Biol. Chem. 172, 83 (1947).5 . H. S. R~IASONnd C. \%'RIGHT. J. Biol. Chem. 180, 235 (1949).6. S. BOUCHILLOUXnd A. KOD TA. Bull. Soc. Chim. Biol. 42, 65 (1960).7. A . LEWD. Acta Pharmacol. ~ox ic ol . . 75 (1949).

8. A. 1 , ~ s ~ .cta Pharmacol. Toxicol. 5: 121'11949).P. FISCHER, G. DEROUAUX,. LAMBOT,and‘^. LECOMTE.Bull. Soc. Chim. Belges, 59, '72 (1950).J. HARLEY-MASONnd J . D. BU'LOCK. Nature, 166, 1036 (1950).E. M . TRAUTKERnd T. R. BRADLEY.Australian J . Biol. Sci. 4B , 303 (1951).H. SOBOTKA,. BARSEL, nd J. D. CHANLEY. Fortsch r. Chem. Org. Naturstoffe, 14, 217 (1957).J . D. BU'LOCKnd J. HARLEY-MASON.. Che m. Soc. 2248 (1951).V. ZAUBOTTInd V. MORET. Arch. Sci. Biol. (Bologna). 33. 522 11949).1'. ZA~ IBOTT I and V. RIORET. Arch. Sci. Biol. (Boloina),34, 272 (1950).V. I O R E T . iorn. Biochim. 3, 210 (1954).R. A. HEACOCK,. NERENBERG,nd A. N. PAYZA. Can. J. Chem. 36, 853 (1958).R. A. HEACOCKnd B. D. SCOTT. Can. J. Chem. 38, 516 (1960).A. KODJA nd S. BOUCHILLOCX. ompt. Ren d. Soc. Biol. 153, 1407 (1959).A. K o ~ r xnd S. BOCCHILLOUX. iochim. B i o ~ h ~ s .cta. 41. 345 11960).

21. R. A. HEACOCK. Chem. I nd. (Londo n), 752 (1'959).22. J. R. JOHXSOW. n Organic chemistry. Val. 11. Edited by H. Gilman. John \I7iley & Sons Inc., New

York. 1957. p. 1922.

R.A. Heacock and G.L. Mattok- The Chemistry of the Aminochromes Part V: Rearrangements in the Prescence of Sodium Hydroxide and Zinc Acetate

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