The Synthesis of 2-acetyl-1,4=naphthoquinone A Multi-step Synthesis

Ivan R. Green University of the Western Cape, Private Bag X17, Bellville 7530, South Africa

Although 2-acetyl-1,4-naphthoquinone is by no means a comnlicated comnound in terms of its structure. a search of

PATHWAY A

the literature is rather revealing in that it shows that no simple one or two sten svnthesis exists from readilv available starting materials. ~ h k main objective of the synthetic exercise pre- sented here is to demonstrate that in choosing a pathway for the successful synthesis of any desired compound thi fol- lowing factors, among others, play an important role in de- termining the eventual choice of a particular reaction se- quence: (1) the availabilitv of stsrtine materials.

(11) Y - H

(111) Y = N 0 2

(IV) Y-NU2

(v) Y=Nb$HCI

(VI) V-NHAc

(VII) R - H

(VIII) R.OH

121 the numher of51eps and thedegreeofsophistiration in trrmsaf appnratuannd technique of the reactions invulved,

13) thp yields t ~ f each itepand huw thesecan heoptimlaed effectively hy an understanding of whether the reactions are rate or equi- librium-controlled processes (This fador will naturally determine the overall yield as well.), and

(4) the cost of reagents employed.

PATHWAY B

The Experiments Since two maior reaction nathwavs toward the svnthesis of

the title compo;nd have bekn deveioped at our ut;iversity, it was found that bv dividinr thr class into two sections, each

(X) Y= OH

(XI) Y- OAC

tollowing a rhasen pathway, a meaningful basis of comparison o f the rrlati\,e merits of the two pathways rould he made.

Pathway A This involves Friedel Crafts acylation of the cheap starting

material 1-naphthol (I) to produce 2-acetyl-1-naphthol(I1) which in turn is nitrated to give 2-acetyl-4-nitro-1-naphthol- (111) in good yield. Conversion of this latter compound into 2-acetvl-1.4-nanhthoouinone(VII) can he achieved in one of

Table 1. Summary of Results Obtained tor the Synthesis of 2- Acetyl-1,4-NaphthoquInone(VII)

Pathway Group Number otSteps % Yield

A 1 4 5* A 2 5 18 B 1 4 25 B 2 4 47

, . two different ways so that students following pathway A should he divided into two smaller erouos. each chmsina one method (or even attempting bothj in order to compare the resnective results. Gn.up I. to f<dl<,w the method ofcram ( I j which initially involvesa large scale ramlyii~ hydrogenation ofthe nirrugrwrpof1IIIj into the 'We found mat considerable quantities of compoum IVIIII were formed dwlng the

penultimate oxidatiw step. aminophenol (IV). Group 2: to follow the method of Spruit (2) which employs a zinc and hydrochloric acid reduction of the nitro group in (111) to produce the aminohydrochloride (V).

Table 2. Summary of Results for the Formation of 2-Acetyl-4- Pathway B

Starting from the more expensive reagent 1,4-naphtho- quinone(IX), the intermediate acetoxypbenol(XII), can he synthesized by two different routes, each involving different techniques. Once again students following pathway B should he divided into smaller groups, each following one method.

Amino-1-Naphthol Hydrochloride (V) and 4 -~ce tox~-2-~ce t~ l - l - Naphthol(XI1)

Palhway OIDup % Yield of (V) % Yield of (Xli)

A 1 65 A 2 61 B 1 45 B 2 68 Croup I . tofdlw the method of Kurovawa (3) whereby a sarurnrrd

sulutiun of bunmtrifluuride i n acetic anhydride is used roncylare and acetylate simuitancously 1.4-dihydroxynn~~hthn1enetXJ to the syn- thon(XI1). Group 2: to follow the method of Read and Ruiz (4) employing a Fries rearrangement of 1,4-diacetoxynaphthalene(X1) into the syn- thon(XI1).

level of competence of the students so that as more data be- comes available from year to year, the relative merits of the

Both erouos now follow the same nrocedure in convertinz two pathways can be reassessed on an annual basis. the synr i ;on (~ l~) into the title compound IVIIj. An objective compariwn between pathways A and H is valid since in all the reactions involved, the products formed arc- the wsult of the euuilibrium-controlled vrocrssrs. Nodoubt the vieldsauoted

Some typical results are presented in Tables 1 and 2 which serve to indicate that the method of Read and Hui7. ( 4 ) would be the one uf rhoire albeit the most expensive. Very often in small scille syntheses une is more concerned with obtaining a high yield of final product than hy the expense incurrid i;~ahles 1, 2, and 3 can he improved, depending upon the

698 Journal of Chemical Education

Table 3. Results of Synthesis of Compounds IV-XIII

Compound Yield in gram % Yield m.p. 'C Lit. Ref. Lit. m.p. 'C

IV 5.0 72 124-125 1 126-127 V 5.0 61 - 5 - VI 4.5 74 210-212 6 212 VII 2.3 62 82-83 1 80-81 VII 1.8 72 82-83 4 82-83 VII 0.2 5 81-82 2 64 Vlll 1.1 51 131-132 2 131-132

X 5.0 99 195-196 2 195 XI1 5.0 66 101-103 3' 101 XI1 4.0 74 100-101 4 102-103 Xlll 3.2 95 212-214 4 214-216

' CAUIION: S B E ~ BF* IS a wlwnous pas, the whole opnatlnn otrslvratlngthe scetlc anhydride must be done In a fume cupboard.

Experimental

Since very few modifications t o the original literature were found to he necessary, only those syntheses where innovations have been introduced will be presented. T h e scales in the other preparations, our results, and literature references a re pre- sented in tabular form.

2-Acetyl- I-naphthol (11) To a mixture of 10.5 g crushed anhydrous zinc chloride in 14 ml

acetic anhydride in a 100-ml round bottomed flask add 14.4 g 1- naphthol and heat the resultingmixture in an oil bath at 145-150°C under reflux for 30 min. Allow the mixture to cool slightly and then pour it into 800 ml water and stir vigorously until the oil solidifies. Pulverize the brown solid and filter it from the solution. Wash the filter cake with 1% aqueous hydrochloric acid and recrystallize the product from 96% ethanol. Yield: ahout 13 g (70%) of olive green crystals mp 101-102'.

2-Acetyl-4-nitro- I-naphthol (111)

Slowly add a solution of 3.5 ml fuming nitric acid of density 1.50 (CAUTION: This is a highly corrosive and extremely dangerous acid that fumes when it comesinto contact with air and thus the synthesis should he performed in a fume cupboard. It is advisable to have a container of saturated asueous sodium bicarbonate nearbyto neutralize any accidentalspill.) in 20 ml glacial acetic acid toa stirred solutionof 9.3g2-aeetyl-1-naphthol in 95 mlglacialacetic

acid at 35'C in a 500 ml Erlenmeyer flask. Keep the temperature constant by external cooling. Soon a thick yellow precipitate will form. After the addition (20 mid. cool the mixture and add 40 ml water with ~ ~~ ~ . ~

.firring. I.'iirer tlw prfcipif~I(. and *,fish with wnwr. Yield: nhout 8.6 g AO$ t. h ptlrr p r ~ d u r r cnn hr ohtn~ncd hy rerrysrnllmtiun from glacial acetic acid and appears as yellow needles with mp 156-15IPC. The crude product is sufficiently pure for further reaction.

CAUTION: All nitro compounds are poisonous and must be handled carefully. If any of the nitrophenol comes into contact with the skin i t should he removed immediately by washing with ethanol and then with soap and water.

Stir vigorously a mixture of 5.5 g 1,4-naphthoquinone, 4.5 g zinc dust, 1 g sodium acetate in 35 ml acetic anhydride and heat to 90°C for 1 hr. During this time the color of the solution changes from yellow to almost colorless. Treat the hot solution with 20 ml of glacial acetic acid, bring to a boil, and filter. Pour the filtrate into 500 ml water and stir until the oil solidifies into white crystals. Filter the product and recrystallize from 90% ethanol. Yield: about 7.8 g (92%) mp 127- 128°C.

General Caution about Quinones

Some of these compounds and derivatives thereof have very important medicinal value on the one hand, b u t on t h e other hand c a n he toxic. Thus, a n y contact w i t h the derivat ives heinpr synthesized should he avoided. In the e v e n t of cont&< s t u d e n t s should w a s h their h a n d s w i t h ethanol fol lowed by s o a p and water .

Financial support from the Council for Scientific a n d In- dustrial Research # is gratefully acknowledged.

Literature Cited

(11 Cram, O.J.,J Amor. Chem.Soc.71.3953 (1949). (2) Spruit,C. J.P.,Rrc Trov Chim.66.655 (19471. (31 Kumsswa. E.,Bull. Chem. Soe. Jnpan.34.3W (1961). (4) Read, G., and Ruis, V. M . . J Chem. Soc Perkin 1.235 (1973). (51 Friedlaender, P., Chsm. Barichfs, 28,1946 (1895). (61 Torrey, H. A,. and Cardarelli. E. J., il Amer Chem Soc.;32.1477 (19101

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