AN INVESTIGATION OF THE DAKIN REACTION. A Thesis Submitted for the Degree of MASTER -OF SCIENCE. In the UNIVERSITY of NEV/ SOUTH WALES. by KENNETH EDGAR WHICHELLO ; inOVTlEJnVUliJ i fi n I lJN.ll/ERSlTy OF 2?9S3 2 6. FEB, 75 iiBmy A-CKNOWLEDG M E N T. The author would like to record his appreciation of the helpful advice and valuable assistance given by Dr. G-. ¥. K. Cavill and Dr. R. J. L. Martin. He also v/ishes to express his thanks to Dr. A. Bryson for the loan of equipmento AN INVESTIGATION OF THE DAKIN REACTION, CONTENTS. PAGE NO 1. SUMMARY. 1 11. INTRODUCTION. 3 111. EXAMINATION OF REACTION PRODUCTS. 9 A. Introduction. 9 B. The Yield and Purity of Reaction Products. 10 C. Paper Chromatographic Analysis of Reaction Products. 14 D. Conclusions. 15 IV. KINETIC INVESTIGATION. 16 A. Discussion of Experimental Results. 16 B. Equilibria in the System. 24 C. Mathematical Treatment of Results <, 27 V. GENERAL DISCUSSION AND CONCLUSIONS. 34" VI. EXPERIMENTAL. 36 A. Preparation of Hydroxybenzaldehydes and fielated 36 Compounds. B. Determination of Yield and Purity of Products. 43 C. Chromatography - Development of Solvent System and Spot Tests. 49 D. Kinetic Experiments. 57 E. Analytical Methods. 62 F. pH Measurements 67 Vll. APPENDICES. 71 1. List of Compounds subjected to the Dakin Reaction (from the Literature). 71 2. List of Graphs and Tables. 76 Vlll. REFERENCES. ^/^^c^sm OF f/fjy Kensington 1. SUMMARY, V^ ^ -•-^^/-'aRARV During this investigation of the Dakin reaction, the yield and purity of products from the alkaline hydrogen peroxide oxid- ation of ortho- and para-hy.droxybenzaldehydes, of ortho- and para-hydroxyacetophenones andof 2-chloro-4-hydroxy- and 2-hydroxy- 4-chloro'benzaldehydes yWere examined. The latter two compounds had not been subjected previously to the Dakin reaction and were found to behave normally. A paper chromatographic method was developed for separating and identifying phenolic substances possibly present in reaction products. The reaction was completed rapidly with each of the above compounds except £-hydroxyacetophenone. Dimers and other free radical products could not be detected by the chromatographic tests; this indicated that a free radical mechanism was unlikely, A kinetic investigation, using initial rates of reaction, indicated that the rate was first order with respect to both 4 salicylaldehyde and hydrogen peroxide concentrations, in the absence of excess sodium hydroxide. However, in the presence of excess sodium hydroxide the initial rates were inversely prop- ortional to the excess hydroxyl ion added. Since the Dakin reaction normally occurs very rapidly most of the kinetic runs were made using excess alkali. It was found that the use of total concentrations of react- ants, for the calculation of the rate constant, was unsatisfact- ory and pH measurements were used to calculate the constants for the various ionic equilibria involved in the system. On the basis of a plausible mechanism attempts were made to relate initial rates to functions of the concentrations of the molecular and ionic species present in the system. This was only partly successful as none of the likely functions adequately described the reaction. It is possible that a satisfactory interpretation cannot be obtained from the existing kinetic data because the equilibrium constant for the reaction:- 0" 0" /H G-OH 0 A OOH is not known. It is probable that in the first stage of the reaction this equilibrium is rapidly established and the resulting complex then decomposes to form catechol and formic acid. It is believed that this rearrangement proceeds through the phenolic form, rather than the phenoxide form of the complex, because of the retarding effect of hydroxyl ion, since:- 0" OH G-OH H OOH G-OH A 'OOH oC OH- 11. INTRODUCTION. The Dakin reaction, which was first reported in 1909, involves the oxidation of ortho- and para-hydroxybenzaldehydes and acetophenones with alkaline hydrogen peroxide; dihydroxy- "benzenes are formed and the carbonyl or ketonic side chain is oxidised to formic or acetic acid respectively. Thus with salicylaldehyde, catechol is formed whilst with^-hydroxybenz- aldehyde, hydroquinone is obtained. The overall reaction is summarised in the following equation for salicylaldehyde:- ^ONa ^OH r^-CHO ^ „ . if^OH + HgOg u + HCOONa Interesting features of this reaction are that it often gives the pure product in quantitative yield, it is rapidly completed in alkaline solution but does not proceed in neutral or slightly acid aqueous solutions, no salicylic acid is formed, and the meta-hydroxy compounds do not react. Dakin investigated the reaction using various hydroxy- benzaldehydes and acetophenones. Additional substituents included hydroxyl, methoxyl, nitro, chloro and bromo groupso The yields and rates of reaction did not appear to depend on the nature of the substituents and a list of compounds which have been subjected to the Dakin reaction is given in Appendix 1. Other peroxy reagents, such as sodium peroxide, sodium perbenzoate and sodium persulphate (Caro's acid in alkaline solution) were reported by Dakin to be just as effective as alkaline hydrogen peroxide. On the other hand he noted that potassium permanganate, dichromate and ferricyanide, lead dioxide, manganese peroxide, silver oxide, benzoyl peroxide and air, (v/ith and v/ithout benzaldehyde) , did not give the Dakin reaction. Other alkalis can be used instead of sodium hydroxide; potassium hydroxide and ammonia were used success- I fully by Dakin and' tetramethylammonium hydroxide by Baker et.al, (1953). Dakin's first explanation of the reaction involved the formation of a "super-peroxidewhich decomposed to catechol and formic acid:- ^H ^H /H OH ifr^HO + „H2O ^ 2 If^-OH OOH '•J +HCOOH He felt that this v;as inadequate and, to explain the non- reactivity of the meta compounds, he suggested, in agreement with Hantsch (1906), that the ortho- and para- aldehydes existed partly as quinonoid salts in alkaline solutiono If the yellow quinonoid intermediate were the reactive form it would also explain the lack of reaction in neutral or slightly acid solutions which a,re colourless. Dakin's suggested mechanism was:- 0 OH E « /H C + NaOH ONa + > Intermediate H fOH HCOONa HCOONa -a 0"" V/acek and Eppin^er (1940) suggested that the attack v;as not initially at the carbonyl "but at the hydroxyl group, v/ith the formation of a "super-peroxide" which rearranged. The basic argument was a proposed similarity betv/een the reaction of o-aminobenzaldehyde"with Caro's acid, in faintly alkaline solution" (Bamberger, 1903) and the Dakin reaction. However the yield of o~aminophenol in the former reaction was small (31?S), and other products, o-aminophenyl formate and anthranil, were formed. Their proposed scheme was:~ 1 1 ! N o ^(r^^^ if^OCHO ll^-OH + HgOg- + H2O (+H.0)—>• 1 , + HCOOH V/hilst Caro' s acid sometimes gives catechol, v/ith salicyl- aldehyde (Dakin, 1909), the reaction mechanism in faintly alk8,line solution may not be the same as with alkaline hydrogen peroxide; Baker and Brown (1948), and Forest and Petrow (1950), have reported the formation of gentisic and protocatechuic aldehydes • from salicylaldehyde by alkaline persulphateOKidation. The postulated formate intermediate^^was obtained' by a normal Baeyer-Villiger reaction (Wacek and Bezard, 1941) via the peracetic oxidation of salicylaldehyde, and was found to hydrolyse rapidly to catechol. Several formates of this type were isolated and all gave the corresponding dihydroxybenzenes. However the suggested mechanism does not answer the question of what are the primary reactive species, nor does it give a satisfactory explanation of the method of conversion of the carbonyl to a hydroxyl group. Spath (1940) obtained small yieldvS of raethoxyphenols from methoxybenzaldehydes by prolonged "boiling with peroxide in ether, but, as the corresponding acids were also formed, the mechanism does not seem to be the same as for the Dakin reaction. No further studies have been made of the mechanism of the Dakin reaction but it has been used in preparative work (see Appendix l)o It is also discussed in several reviews(eog. Swern, 1949; Leffler,.1949; Johnson, 1950 and Bayer, 1954) where it has been suggested that it maj^be ionic. Bunton (1948,1949) found, in the oxidation of o^r-diketones with alkaline peroxide, that the hydroperoxide ion was the reactive species (Bunton and Mintoff,1949) and he suggested a similar mechanism for the Dakin reaction. He also agreed with Dakin that the quinonoid form of the aldehyde v/as probably the .reactive entity. Whilst the presence of a quinonoid structure is a simple way of explaining the non-reactivity of the meta compounds, the oxidation in acetic acid, which gives catechol, (V/acek et.^. 1940,1941) must be taken into account. Here, however, the reagent is probably peracetic acid and there are differences between this reagent and alkaline peroxide as the former gives m~hydroxybenzoic acid with m-hydroxybenzaldehy,de, (ibid), whilst the latter does not react (Dakin,1909). It could be supposed that the mechanism is comparable with that for Fenton's reaction, for which a free radical path has been demonstrated (Boeseken and Soesman,1933; Mertz and Waters, 1951). However, in this C8.se the yields are much lower and many side reactions occur, (Fenton,1894; Fenton and Jackson,1899); also Fenton's reaction gives 2,3-dihydroxy'bensaldehyde with salicylaldehyde (Somner,1902)o Again,the Elbs persulphate oxidation (Elbs,1893; Baker and Savage,1938) is a similar reaction but, in contrast to the Dakin reaction, the meta-hydroxy compounds also react, and a hydro?-cyl group is added to the ring. For example, salicyl- aldehyde gives 2,5-dihydroxybenzaldehyde (Forest and Petrov;, 195o). It has been fairly conclusively established that the Elbs persulphate oxidation goes by a free radical path (Desai and Sethna,1941; Sethna,1951) although some later v/ork by Levitt (1953,1954) favours an ionic mechanism.