B. E. Norcross,' O. and M. Weinstein State University of New York
at Binghamton, 13901
1 I I
The Hantmh Pyridine Synthesis A factorial design experiment for the introductory organic laboratory
W e have for some time been responding to concerns such as those reccntly expressed in THIS JOURNAL (I) about the nature of the laboratory experience in the beginning organic chemistry course. These concerns have prompted us to search for experiments which can provide a challenge to different levels of students, may illustrate some "different" chemistry, and provide an opportunity for open-ended extension for the more motivated or slcilled students. The synthesis described here has hcen uscd in various forms with four classes with an average enrollment of about eighty. Each class is divided into laboratory sections of fifteen to twenty-two students. Originally the experiment was run in one 3-hr period. Two compounds, one yellow and one colorless, were prepared and purified by recrystallization, and their physical properties and spectra were determined. We have since modified the experiment to give the class some experience in the factorial design of the first step (2). This new experiment also presents the student with the individual problem of selecting the oxidizing agent and conditions for the second reaction. Some statistical analysis is also possible. Syntheses of related compounds which show some surprising reactivities provide an opportunity to lead some advanced students into detailed mechanistic considerations. Background
Few organic laboratory manuals provide model syntheses of common hcterocyclic compounds. The
Hantzsch synthesis (5), developed in 1882, provides access to a series of generally crystalline, substit,uted, 1,4-dihydropyridines (4). Not only are these compounds of interest because they are nitrogen heterocyclics, but also because they have served as model compounds for the NAD-NADH biological redox system (5). Thus this synthesis can lead into a consideration of some biochemistry and model enzyme studies. The reactions (Fig. 1) proceed wit,h moderate to good yields even when badly handled. The infrared, ultraviolet, and nuclear magnetic resonance spectra of the two products provide ample opportunity for the firstorder spectral analyses so appropriate for this level of student. In general, R==H and the factorial portion of the reaction sequence, the synthesis of 2,6-dimethyl3,5-dicarboethoxy-l,4-dihydropyridine,is carried out with varying proportions of aqueous formaldehyde and/or aqueous ammonia with n constant quantity of ethyl acetoacetate. Heating. periods were varied from . 1.5 to 60 min. The substituent R may be changed wit.h little modificat,ion in~ the~ exnerimental urocedure 16) ~ ~ , . for certain substituents.~ The interesting fact that oxidation of the dihydropyridines in which R = methylor phenyl (10) produces a 4-substituted pyridine (114, while oxidation of the dihydropyridine in which R = benzyl produces the 4-unsubstituted pyridine (IIb) ( 6 ) , provides intellectual stimulation, as well as some possible (and probably beneficial) self-doubt in the validit,y of one's experimental work in even the sophisticated and blase undergraduate.
To whom inquiries should be addressed. address: Department of Chemistry, Kenyon College, Gamhier, Ohio 43022. 3 Rome difficuliy has beell observed wit,h this original Hmtaschtype reaction system in the synthesis of difierent molecules for which the required aldehyde may powess e-hydrogens. Hawever, numerous specific molecules with widely varying subst,itw tion (including the "no-substitution" case, 1,bdihydropyridine (7)) have heen synthesized under conditions ranging from mild, modeled after biological (aqueous media and valying pH values) systems (a), to strongly forcing conditions ( 9 ) .
' Present
,.
OXIDIZINGAGENT
II. Figure 1. wnthetir.
694
/
=b
Stoichiarnetric equations for the two-step Hanbxh pyridine
Journal of Chemical Education
Equip a. 100-ml mund-bottom flask in a. mantle or steam cone with a short reflux condenser. Add, in order, through the condenser, the following reagents:' 2.8 ml of aqueous formaldehyde (370/,), 10.0 ml of ethyl acetoacetate, and 12.4 ml of concentrated aqueous ammonia. Rinse the sides of the condenser into the flask with 3.8 ml of ethanol. Swirl the mixture, and note the exothermic reaction. Heat at reflux for 30 min." At the end of the reaction period, cool the reaction mixture thoroughly in an ice bath. Filter the resulting slurry on a Biichner funnel. Carefully rinse the filter cake with l(t15 ml of well-chilled ethanol, divided into several portions. Recrystallize the product from a minimum amount of hot ethanol. Typical yields of yellow crystals, mp 183-184'C, are in the range of 4 4 g. A second crop of less pure material may he obtained by adding water to the mother liquors and washings obtained above, and recrystallizing the material so precipitated.
To 1.0 g of the dihydmpyridine obtained above, dissolved in 10 ml of hot glacial acetic aeid, is added, in very mall portions, 1.0 g of sodium nitrite' (use the hood). The solution is swirled until all evidence of brown gas disappears (completion of oxidation is signalled by the fading of the yellow color due to the dihydropyridine). The above solution is poured into 40 ml of ice water in a separatory funnel. The resulting slurry is extracted with three 30-ml wrtions of ether. The combined ether extracts are further extracted with four 20-ml portions of dilute hydrochlorio acid (where is the pyridine?). The combined acid extracts are carefully neutralized with a solution of sodium carbonate. The resulting suspension is filtered and the white needles are air dried. Typical yields are in the range of 0.6-0.7 g of material melting at 70.5-71.0DC. Recrystallization from methanol-water or ethanal-water yields long white needles of sharp melting point (71.2-71.5'C, sealed evacuated capillary). Results
Different variables in the experiment have been suhjected to study. A typical result is shown in Figure 2, where trends in average yields are apparent for various quantities of aqueous ammonia with a constant volume of aqueous formaldehyde and ethyl acetoacetate. Similar results have been observed by varying the relative amounts of formaldehyde while keeping the relative proportions of the other reagents constant. The differing yields ohtained by students performing the reaction with the same proportions of reagents and heating periods permit the introduction of statistical analysis into the organic lab-an endeavor ordinarily 4 If the reaction is to he run as a factorial experiment, each student. is given a card listing the reagent quantities and heating period to use. The yield of that particular reaction is then reported by turning the card back to the instructor. When all (or most) of the reactions have been completed, the collected yields are summarized and redistributed to the class for data reduction by the individual student aocarding to m y of several standard p r o c e d u r ~( 2 ) . Other oxidants used in this solvent system, in order of decreasing student average yields, have been: iodine, bromine on carbon, chromic anhydride-sulfuric aeid, potassium permanganate, and potsssium ferricyanide (requires some modification of solvent by addition of water to twoid a heterogeneous, hut workable, system).
Figure 2. Average yields of 2.6-dimelhyl-3,5-dicorboe~oxy-l,4-dihydmpyridine os o function of quantity of aqueous ommonia ond period of heating.
considered first appropriate for the physical chemistry laboratory. Pooling data collected over a period of several years helps to provide enough points to make such an analysis worthwhile and meaningful. We have found the experiment generates enthusiasm in most of the students. The various oxidizing agents pose small, but immediate problems, the solutions of which require thoughtful observation of the progress of the reactions. The extension of the experiment to different 4-substituted compounds and their oxidation products can provide real challenge and an encounter with the unexpected for the top students. Literature Cited
(1) SILBERMAN, R., AND MCCONNELL, J., J. CAEM.EDUC.,45, 267 (1968); FIFE, W. K., J. CAEM.EDUC.,45,416 (1968); SMITH,R. B., J . CHEW.Enuc., 46, 273 (1969). E. J., JR., J. CAEM.EDUC., (2) SMITH,R. B., AND BILLINGHAM, 45, 113 (1968). HANTZBCH, A,, Ann., 215, 1, 72 (1882); Ber., 18, 1744 (1885); Be?., 19, 289 (1886). MosHEn. H. S. in "Heterocvelic Comoounds." Vol. I. (Editor: ELDERFIELD, R. C.) John Wiley & Sons, Inc., New York, 1950, p. 462ff; CAMPBELL, N. in "Chemistry of Carbon Compounds," Vol. IV, (Editor Ronn, E. H.), Elsevier Publishing Co., New York, 1957, p. 495ff; BRODY,F., AND RULY,P. R. in "Heterooyclic Compounds-Pyridine and Derivatives," Part One, (Editw: KLINGSBERG. E.). Interscience (division of John Wilev & Snna. Inn.). ~ e i ~ o r 1960. k . n.'500ff. ~oRcRoHs,B. E., KLI~EDIN~;, P. E., JR., AND WESF HEIMER, F. H., J. Am. Chem. SOC., 84, 797 (1962), and K. A., AND references cited therein; SCHELLENBERG, WEST~EIMER, F. H., J. O T ~ Chem., . 30, 1859 (1965); KIRSCHBAUM, J., J. CHEM.EDUC.,45,28 (1968). Loev. B.. AND SNADER.K. M.. J. Ow. Chem.,. 30, 1915 (19'65): COOK,N. C., AND LYON,J. E., J. Am. Chem. Soc., 87,3283 (1965); 88, 3396 (1966). A., AND QURESHI,A. A,, Pakistan J. Sci. Res., 15,35 KAMAL, (1963) [Chm. Ab., 60,1689h (1964)l. TRABER,W., AND KARRER,P., Helu. Chim. Acta, 41, 2066 T.S., J . OW. (1958); KOSOWER, E. M., AND SOBENSON, Chem., 27, 3764 (1962). LYLE,R. E., AND NELSON,D. A., J. f i g . Chem., 28, 169 (1963). ~
Volume 46, Number 10, Odober 1969
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