LABORATORY COURSE I N AROMATIC .CHEMISTRY BASED ON SEQUENCE SYNTHESES MANUEL M. BAIZER Brooklyn College, Brooklyn, New York
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work carefully. He has generally had to consult references other than his own text and laboratory manual; he may even have had the new experience of consulting original papers. He has very likelv encountered reaction types which would otherwise not have come within his ken in an undergraduate lahoratory. One incidental but important experience that is an outgrowth of the "sequence synthesis" is the practice of paying more than usual attention to the properties of intermediates so that they may be properly stored until needed. Many of the advantages of interest and selfdisciplinc that accrue to a student from carrying through a "sequence synthesis" can be gained from a laboratory course in aromatic chemistry in which all the preparations are part of a small number of major sequences. The starting material for each of these sequences in this plan is benzene, so that in effect all aromatic products are totally synthesized from the parent hydrocarbon. (One need not approach any more closely the popular starting materials, "coal, air and water.") A variety of undergraduate laboratory courses in aromatic chemistry can be devised in which the preparative experiments are based on sequence syntheses. They must all be designed, however, to include sanplings of the cornmoil aromatic reaction types (such as Friedel-Crafts reaction, nitration, etc.) and to afford practical instruction in a number of standard manipulative skills (e. g., vacuum distillation, recrystallization, use of mechanical stirring, etc.). The scheme proposed below has the virtue of requiring possihly the least modification of currently
OF THE features of the laboratory course in aromatic chemistry which students a t this college find most attractive is the "sequence synthesis" assignment. Beginning with the fourth or fifth laboratory period, t,he student undertakes, in addition to his regnlarly scheduled experiments, a series of syntheses in which the product of the first reaction is the starting material for t.he second reaction, etc. The'"sequence synthesis" runs to the end of the semester. Allocation of time for this work is arranged by the student himself so that it does not interfere with his other preparations. The product chosen as the final objective of the exbended synthesis derives interest not only from the fact that it is relatively difficult to prepare but generally also because it finds application in one of the several branches of Applied Chemistry. The following are typical sequences that have been fonnd suitable for inclusion in our course:
--
( I ) Ht:nzyl chloride --t benzyl cyanide p-nitl.ophenyhcetic p-bromoph$nylacid --r p-aminophenylacetic acid scetieseid (2) Sitrobenzene hydraeohonzene + henzidine + Congo Red (3) Tolueno saccharin (1) Phenol --t ooumarin (5) p-Sitrotoluene + esters oi p-aminobenzoic aeid
-
In contrast to the usual one-step "prep" these syntheses are lengthy projects. The student is stimulated to exert his best efforts in order t,hat a t the end of the semester he may, with pride, present a ponderable sample of a chemical which he has literally wrested from a maze of products and by-products that threatened to engulf him. He has had to think of timing his
,
t
IiUitrobenzene
r I
4 Quinaline
1X X I I Reneonitrile
I
4 .kcetanilid
I
Benzaldchyde XVII Sie?tinic acid
-m-Dinitrobenzene 4 11,'. ( X X I ' m-Phenyl$ned~nminc Benzidine 13cneddehyde
I
.
Sulfanilamide 1VI ---------........ prontos,lt : ........... -'
XIS
111
~he*nol
Salicylaldehyde XI Coumarin
1knzoic
Cinnamic acid Benzylaloohol ''x XIV xid Benzoin
,
4 xv
Bend XVI B~nzilioacid
L-Phenylhydrazine
,[
Diphenjlmethanr
7 svrrr .%nisolr
4 xx
Diphenylaeet~cacid
X6
+
JUNE, 1948
337
accepted course plans, since a large number of the syutheses present.ed in widely used lahoratory manuals derive from either nitrobeuzene or henzaldehyde. A listing of these experiments is presented below giving experiment number, name of the reaction illustrated, and reference to detailed direct,ions which can .be adapted to the requirements of this course: . . --
Erperimenl .Vumber I ; 1: 11; I1 I11 IV
V
VI
VII VIII IX X XI; XI' XI1 XI11 XIV XV XVI ICVII SVIII XIX XX XXI XXII SXIII
Reaction Illustralion Nitrat,ion Reduction of -NO1 to -N& Diszotisation and hydrolysis Acetylation of -NH2 Chlorosulfonationand ammonolysis Diaaotiaation and coupling; formation of anaso dye Chloromethylation Friedel-Crafts reaction Controlled sidechain oxidation Canniaaaro reaction Perkin resetion Reimer-Tiemsnn resetion Skraup synthesis Benzoin condensation Oxidation of a secondary alcohol Benzilic acid rearrangement Side-chain oxidation; decarboxylation Formation of a phenolic ether Reduction of a, diazonium compound Reduction of a secondary alcohol Controlled reduction of -NO2; hen& dine rearrangement Sandmeyer reaction Stephen reaction
Reference (id (14 (le) (4)
4)
(6)
(If) (6,; 6b) (19) (Ih; )' (84 (li)
(IA
,
(Ik) (11) (9%)
(94 (Im) (10) (9c)
-
(8b) ( 1 1 ~l;i b )
Obviously more experiments are included here than can be performed by each student in a one-semester course affording four hours of laboratory work per week. The instructor will have to make adjustments in the outline to accommodate it to his requirements. He may wish to cut short one or more of the sequence branches; he may, in order to include as many types of synthesis as possible, reduce some to test-tube scale; he may have a portion of the class work on one sequence while another follows a different but closely related sequence.' This last procedure has much to recommend it, for it introduces additional elements of variety and interest into the laboratory and permits a student to observe the techniques and practices involved in experiments which he has not the opportunity to perform himself. A laboratory course based on sequence syntheses allows for interesting variations in the scale of operations. Here, too, the instructor will wish to exercise his own discretion and preference. He may give the student (or class) one bottle of benzene a t the beginning of the semester and announce that no additional starting material or other aromatic compound will be ~upplied.~The student will therefore start For example, onehalf the class may prepare aniline while the other prepares m-phenylenediamine. The same division of work applies to the preparation of oinnamic acid and of coumarin. a In case of accident or other unusul circumstance this decree will have to be interpreted liberslly.
his sequences with relatively large-scale laboratory "prepsn-which, incidentally, utilize inexpensive materials-and in the course of the semester he will gain experience in the use of progressively smaller quantities of material and appropriately scaled apparatus. His manipulative skill will be increasingwith practice while at the same time his need for exercizing' that skill will be continuously sharpened by the knowledge that small losses of product become ever more important on a percentage basis and that only the intelligent application of the laboratory arts will assure him of achieving the final product of a sequence. If a student occasionally succeeds in obtaining only disappointing yields, he may have to conclude his sequences by experiments on a semi-micro scale. It, is not to be inferred, of course, that instruction in semimicro techniques is offered as a reward for poor success in ~ynthesis. The instructor may wish to include one or more small-scale syntheses a t the end of the semester as an integral part of the program, and with this purpose in mind he will suitably calculate the quantity of starting material he dispenses a t the start. Alternatively, the instructor may desire that all t,he preparations be made on approximately the same scale. In that case the student (or class) prepares each chemical in the sequences chosen but not the total quantity that is required for the subsequent step. The balance is supplied from stock, and the student will readily adjust to the idea that if he had scaled up earlier experiments he would indeed have prepared all his compounds from one sample of benzene. The suggestions presented in this paper apply only to the preparative aspects of a laboratory course in aromatic chemistry. It is assumed that the course includes.numerous test-tube experiments which illustrate qualitatively characteristic reactions of the various aromatic types. No recommendation is made concerning the genesis of the aromatic reagents which may be needed for these tests. The author intends to prepare a syllabus of experiments and to have his students a t this college assay the success of a sequence synthesis course. It is hoped that instructors elsewhere will be inclined to initiate similar plans and to report their findings. It is a pleasure to acknowledge the friendly interest of Professors Louis Sattler and Elise Tobin of this department in this project. CITED (I) ROBERTSON, G. R., "Laboratory Practice oi Organic Chemistry," Revised edition. Maomillan Co., New York, 1943. (a) p. 242; ( b ) p. 250; (c) p. 262; ( d ) p. 251; (e) p. 324; (fl p. 300; ( g ) p. 279; (h) p. 282; ( i )p. 331; ( j ) p. 280; (k)p. 281; (1) p. 281; ( m ) p. 276. (2) A ~ H., S.~ H. M~ ~ ~ E AND~~ N.~W., ~K ~ ~ rtpraC. ~ ~, ~ tice of Organic Chemistry," MoGraw-Hill Book Co., Inc., New York, 1940. (a) p. 225; (b) p. 101. (3) WILLIUS, R. J., AND R. Q. BREWWER,"Laboratory Manual of Organic Chemistry,'' Van Nostrand Co., Xew York, 1934, p. 119. (4) RICHTER, G. H., "Laboratory Manual of Elementary Or(Cmtinued o n page 541)
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JUNE, 1948
LABORATORY COURSE IN AROMATIC CHEMISTRY BASED ON SEQUENCE SYNTHESES (Continued from page 337) ganic Chemistry," John Wiley & Sons, Inc., New York, 1940, p. 104. (5) F u s o ~AND MCKEEVER,"Organic Reactions" (Adams, Editor-in-chief), John Wiley & Sons, Ino., New York, 1942, Val. I, p. 67. F., "EnzyklopBdie der Technisohon Chemie," (6) (a) ULLMANN, 2nd ed., Urban and Sohwarzenberg, Berlin and Vienna, 1928, Volume 11, p. 207; ( b ) LORGES,Rev. chirn. ind., 34, 52 (1925). (7) COHEN,J. B.,"Practical Organic Chemistry," 4lacmillan Co., London. 1930, p. 221.
L.,A N D H. WIELIND,"Lahomtory Methods (8) GATTERMAAN, of Organic Chemistry," iVIacmillan Co., New York, 1932. (a) p. 226: (b) p. 193. (9) FISHER, H. L., "hboratory Manual of Orgsnio Chenlistry," 4th ed., John Wiley & Sons, Ino., New York, 1938. (a) p. 215; (b) p. 193; (e) p. 180. R E. C. CAUDLE,"Organio (10) MARVEL,C. S., F. D. H ~ G E AND Syntheses" (Gilman-Blatt, Eds.), 2nd ed., John Wiley & Sons, Inc., New York, 1941, Coll. Vol. I, p. 224. (11) (a) STEPEEN,H., J. Chem. SOC.,1925, 1876; (b) J. W. Williams. J . A m . Chm,r.Soe.. 61, 2249 (1939).
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