R. M. Letcher Universlly of Hong Kong Honq Kona
I I I
An Undergraduate Organic Laboratory Project Involving Independent Synthesis of Novel Flavones
Objectives in the synthetic organic laboratory vary, hut common general objectives include giving students the opportunity to carry out reactions which are studied in the lecture course, and to produce compounds which themselves have interest value. The traditional approach to laboratory organization, in which all students prepare the same compound in a laboratory period, is still very much in vogue ( I ) , but such a uniform approach does, in our experience, tend to create a lack of enthusiasm among some students, often leading to sample trading and plagiarism (2). An alternative, the group project, also has the serious drawback that all too often one student does most of the work ( 3 ) .In order to develop initiative, stimulate interest, and ensure that all students benefit from the exercise, independent synthetic activity is necessary, but this is an ideal seldom realized due to its problematic nature and excessive demand on instructor time (4. 5 ) . In the experiment described here, the independent synthesis approach is ensured by providing each student with different starting materials to prepare different flavones, with additional motivation derived from the fact that many of the flavones are new comoounds not oreviouslv described in the litt.mulre. Since a11 studtmts use rhe same yenernl pniredure, hned un thv "Orcanir Ssnrhesis" tfil tlavone ~ r e ~ a r . , t i < m . which works satisfactoril; for a very wide variety of suhstituents, many different flavones can he synthesized without truitr,~limand u irh the minimum 01'instruc1~1r i~ttcnriun.'l.hc 1n:lr n l l qtudcnts are pruvidtld ulirh exprrimenr a l c cniurc5 ~ very nearly equal opportunity and experience. By contrast, research or library search oriented synthetic projects (5, 7,8, 9 ) for undergraduates so often have the disadvantage of unequal time requirements to produce a successful conclusion, and the fact that some students have readily workable projects which develop confidence, while others fail, causing frustration. This five stage convergent synthesis includes a number of topics from the lecture course: rearrangement reactions (Fries and Baker Venkataraman), aldol chemistry, esterification, structure elucidation employing physical methods, and with flavones themselves heing studied in the natural products course (biosynthesis, degradation etc.). Further features include the literature search which provides a realistic situation, and the class project aspect, in which students compare the pooled spectral data of their flavones to ascertain if any diagnostic features are apparent. In this way, students not only benefit from their own ex~eriencebut also from the trends r e ~ i & d I,\ their poolcd rrwlts. .\s each student prepares a differrnr n m w u n t l , rewrr writ~nrih rlearlv an ~ndividual matter, with students Geing encouraged to report their ohservations and any changes adopted in the experimental procedure. The experiment which involves basic organic techniques suitable forkhe second level organic courses, requires no more than four 4-hr sessions for completion. Finally, since the chemicals required are inexpensive, and the apparatus simple, the experiment may he adopted easily by universities and colleges in the less affluent parts of the world.
phenols employed for compound (I) have included: phenol, 4-methyl-, 4-chloro-, 4-bromo-, 2,4-dichloro- and 2,4-dibromophenol. The Fries Rearrangement (I1 111) of the phenyl acetates follows. To obtain only one product it is necessary that all ~ h e n v acetates l contain a oara-suhstituent. Generallv vields bf 86% were recorded, the products heing low melting solids. VI) were Yields from the henzoylation steps (111 V generally good (70-80%) with the products heing crystalline. The henzoic acids (IV) used to produce the henzoyl chlorides (V) included: 2-bromo-, 4-bromo-, 2-chloro-, 4-chloro-, 2.4dichloro- 4-methoxy-, 4-nitro- and 3,4,5-trimethoxyhenzoic acid. Both the fourth step (VI VII) the Baker Venkataraman rearrangement, and the final cyclization (VII VIII) to give the flavone, occur in fair togood yield. Purification of the flavones is achieved readily through crystallization. Some of the new flavones prepared include 4'-chloro-&methyl-; 4',6-dichloro-; 4'-bromo-6-chloro-; 6-hromo-4'-chloro-; 2'hromo-6-chloro-; 2',4'-dichloro-; 4',6,8-trichloro-; and 4'chloro-6.8-dihromoflavone.
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The Project Aspect
After recording ir, uv, nmr, and mass spectra, students were encouraged to tabulate their data for each flavone on the notice hoard, from which common diagnostic features could be
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Journal of Chemical Education
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Reaction Sequence (see Scheme)
The first step (I 11) involves acetylation of a phenol and purification of the product by reduced pressure distillation. If necessary this fairly trivial step may be deleted saving some 4 hr, by supplying the phenyl acetates to the students. Typical
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(i) A ~ ~ O i P y r i d i n e(iv) Pyridine (ii) AICI, (u) KOH/Pyridine (iii) SOCI, (vi) H,SO./AeOH
deduced. T h e absorption frequency of t h e flavone carhonyl a t 1640-1660 cm-I a n d t h e chemical shift (6 value 6.6-6.8 p p m ) for H-3, showed very little variation. T h e u v spectra of t h e flavones proved particularly interesting: all flavones showed t w o ahsorptions ( a t a b o u t 260 a n d 300 nm), with t h e flavones having n o s u h s t ~ t u e nat t t h e 2'-position exhibiting stronger absorption at t h e higher wavelength, a n d those possessing a 2'-suhstituent showing a stronger absorbance for t h e s h o r t e r wavelength. S t u d e n t s were asked t o c o m m e n t on t h e reason for this. T h e mass spectra of t h e flavones showed s t r o n e ~ e a k for s t h e retro-Diels Alder fragmentation which i n a p p r o p r i a t e cases could b e used for ascertaining whether t h e various suhstituents were present in ring A or B. T h o s e flavones containing halogen(s) exhibited excellent examples of isotope clusters for t h e molecular ion a n d also for s o m e fragment ions, which students were asked to interpret. Finally s t u d e n t s were asked to find o u t whether their particular flavone h a d been described in t h e literature, by consulting Beilstein a n d t h e Chemical Abstracts Formula Indices.
The resulting benmyl chloride (V) is used immediately. A mixture of the benzoyl chloride (V) and the 2-hydrouy-acetophenone (111) (0.07 moles) dissolved in dry pyridine (15 cm") is left fur 20 min before pouring into 0.5 M-hydrochloric acid (350 em") containing crushed ice (100 g). After filtering, the product is recrystallized from methanol-water yielding the benzoate (VI). If the normally colorless benzoate is contaminated by s dark colored gummy material, purification hy boiling the methanol solution in c h a r a d before filtering is reeommended.
Orlho-Hydroxydibenzoylmethane ( V11) (6)
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Experimental Phenyl a c e t a t e s (10 The phenol (I) (0.1 mules) dissolved in acetic anhydride (30 em") and dry pyridine (1 cm'), is refluxed for 1% hr. After cooling, the mixture is poured into 2% aqueous hydrochloric arid (100 em9 and extracted with ether (200 c m l and 50 em'). The eomhined ethereal layers are washed with excess 2%aqueous sodium hydroxide and dried (anhydrous NazC0:J. After evaporating off the ether, the acetate (11) is finally distilled under reduced pressure (appmx. 150' a t 20 mm). 2-Hydroxy-acetophenones (110 Working in the h m s hood, a mixture of aluminum trichlaride (0.2 moles) and the phenyl acetate (0.1 mdesi (11) contained in a 250 cm" rnund-bottomed flask set up for reflux, is gently heated on an oil bath, with occasional swirling until the bath temperature reaches 120'. The reaction is maintained at this temperature for 15 min lwfore cadin% and adding ice and 2 M hydruehlaric acid (200 cm:'). The resulting solid is filtered and crystelliad from lightpetnrleum "idding (111).
Orlho-Benzoyloxy-acetophenones( Vo The substituted benmic acid (IV) (0.1 moles), excess thionyl chloride, and one drop of pyridine or DMF is refluxed fur 1 hr before distilling off the excess thinnyl chloride using a water vacuum pump. Dly henzene (5 rm" is added and then removed under reduced pressure. This should be repeated several times to remove all traces of thionyl chloride.
moles) is rapidly pulverized using a preheated pestle and mortar, before slowly adding to the pyridine solution. Constant swirling is maintained for 15 min a t 50°, before cooling and adding 10% soetic acid (fin cm3). The resulting yellow precipitate of ortho-hydroxydibenaoylmethane (VII) is filtered, dried, and used directly for thenext step. Favone ( VIIiJ ( 6 ) T o the ortho-hydrorydibeneoylmethane (VII) (0.025 moles) in glacial acetic acid (30 em" contained in a 100cm%round-bottomed flask is added with swirling, eonc. sulfuric acid (0.025 moles), before heating under reflux on a boiling water bath for 1 hr, with occasional shaking. The mixture is then poured onto crushed ice (160 g), the flavone (VIII) washed with water (ahout 300 cm" until the washings are neutral, dried, and crystallized [suggested snlventz:light petroleum (b.p. 60-8O0)]. Physical properties and spectra of the new flavones will be provided upon request to the author. Literature Cited 111 Recent examples include: Einten. R. M.. Ponder.J. W.. and Lenai, R. s.. J. CHEM. RDUT..S4.:IR2(197i):VanVerfh..J.E..and 1llmer.S.W.,.J.CHEM.EDLTC.,54,381 11977): Carmher. C. R.. .I.CHRM. EDUC.. 55. 61 (197R);Schstr. P. F.. J. CHEM. EDIIC.. i 5 , G R 119781. (2) Hiprrmllh, Ill. 1:. L.. Hintnn..l..Ni,rmnrd. R..nnd Rnymund.C ...ICHRM. RDUC..S2.
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ICthe benzoate (VI)proves insoluble under these conditions, warm the mixture a t a higher temperature (up to i s 0 ) andlor add more wridine.
Volume 57, Number 3. March 1980 I 221
