George W. Gokel and lvar K. Ugi
University of Southern Coliiornio Los Anaeles. - . 90007
I I
I
Preparation and Resolution of
N,N-Dimethyl-a-Ferr~~enyIethyIamine An advanced organic experiment
The discovery of ferrocene (I) two decades ago (1) as the first of the so-called "sandwich complexes" led to a period of great endeavor in this field. The observation (2) that ferrocene behaves as an aromatic system led to the preparation and investigation of many derivatives in analogy to the chemistry of benzene derivatives (3). In many ways, of course, the chemistry of ferrocene derivatives is quite similar to that of benzene derivatives. Important diierences between the chemistry of metallocines and benzenoid aromatic compounds arise, however, when the stereochemistry of these systems is considered. The stereochemistry of metalloccne derivatives is an area in which there has been a great deal of interest in thc recent past (4-8). This interest is due in part to the fact that it was recognized that ferrocene derivat i v c ~are chiral if one ring carries two different substituents (11, X # Y) (4). It should be noted that these compounds are optically active even though there may be no center of asymmetry but only a planar element of chirality (4,9).
The compound which is the final product of the synthetic sequence presented herein is relatively easy to prepare and provides a unique access (10a) to a very wide variety of chiral ferrocene derivatives with either centers of chirality and/or planes of chirality. The reaction sequence starts with the conversion of ferrocene' into acetylferrocene (111) by a FriedelCrafts reaction (lob). The increased reactivity of ferrocene in electrophilic aromatic substitution and the potential for heteroannular diacylation requires reaction conditions substantially milder than those applied to henzene. Ferrocene methyl ketone is readily reduced to a-ferrocenylethanol by lithium aluminum hydride or sodium dihydrobismethoxyethoxyaluminate (11); it is not rcduccd well by the less reactive hydrides like NaBH4 or IiBHa. We have chosen the above mentioned reagent because its reactivity parallels L'iAIHe, and it is commercially available in rather concentrated benzenc solution. It is among the hydride reducing agents particularly easily handled b$8/ioo ~ g. t
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by a student; although it reacts vigorously with water, it does not catch fire. a-Ferrocenylethyl acetate (12) is formed in one of the less commonly performed esterifications. Approximately one equivalent each of the acid and alcohol are refluxed in henzene (no mineral acid catalyst) and separated by means of a water separator (Dean and Stark trap). This is informative because the student can follow the progress of the reaction by the production of water. This product is not isolated because of the difficulty of removing residual acetic acid without a high vacuum evaporator, hut if the laboratory is so provided, this can easily be done. N,N-dimethyl-a-ferrocenylethylamine(13) is formed by nucleophilic displacement of the acetate group by dimethyl amine in aqueous methanol. Generally, in the reactions of carboxylate esters with amines, reaction takes place at the ester carhonyl, giving the corresponding amide and alcohol as products (14). In this case, however, the aminolysis proceeds with alkylation of the amine and cleavage of the carboxylic acid. This is because the a-ferrocenyl ethyl carbonium ion is so stable that a carboxylate anion is a sufficiently good leaving group to provide for its formation. In addition, the carbonium ion is stable enough under the given conditions to he selective and react with the strongest nucleophile available in the solution. It is very unusual that both enantiomers can he isolated so'readily and with the same resolving agent. This is a fortunate circumstance because N,N-dimethyl-a-ferrocenylethylamine is a key intermediate in the stereochemistry of ferrocenes (7, 10). We have successfully performed the resolution with tartaric acid (7) in Erlenmeyer flasks. This final step is educational because both antipodes are isolated in high yield in a total of 4-6 crystallizations. This particular sequence was chosen in part because we felt that it successfully simulated an actual research level synthetic sequence. At each stage in the sequence, we require the students to ascertain purity by thin layer chromatography on microscope slides (15),and particularly in the last synthetic step (the amination) we have the students follow the progress of the reaction by this technique. We also have found that the infrared, ultraviolet and nmr spectra are informative and distinctive. The functionalities are clear in the ir, and the nmr spectra are all first-order. The effect of the metal on the aromatic ring protons in particularly notable in the nmr (3). In order to handle these experiments, the student should be provided with a magnetic stirrer, any simple
water separator and a 4-qt plastic bucket.% The most expensive reagent is the ferroeene.' The first reaction is carried out on a half molar scale. On this scale, we have found that the average inexperienced student will produce 26 g of amine (0.1 mole) and will obtain 7-10 g of each tartrate salt after resolution. Half of this scale wouldstillhewithin reason, and couldbe even more economical. On the half molar scale, however, the amination is a problem because of the volume of solvent required. We have solved this problem by performing this step in a solvent bottle. Finally, there should be a rotatory evaporator, available to the student, as stripping off the-solvent in each of the steps is laborious otherwise.
used the same day) is added dropwise with stirring (from a separatory funnel or with an eye dropper or pipet) until the upper layer turns from brown t o cream-yellow. The gas trap is replaced and the solution allowed to stir for 10-20 min until the sharp odor of sulfur dioxide is no longer detectable. The reaction mixture is then placed in a separatory funnel, the lower (organic phase) is separated; the remaining aqueous layer is extracted two or three times with 100-ml portions of dichloromethane or chloroform (CCL is not acceptable as decomposition of the product occurs in this solvent). The organic extracts zre combined and washed with 100 ml 5% NaOH solution and 100 ml of saturated aqueous NaCl solution. The solution is then dried over anhydrous KCO1 (N%SO, or MgSO, are also acceptable), filtered from the drying agent, and the solvent evaporated t o give 100-110 g (85595%) of an orange solid, mp 8586°C. Preparation of w-Ferrocenylethonol I V
Acetylferrocene (91 g, 0.4 mole) is dissolved in 400 ml dry (distilled) benzene in a 1-1 Edenmeyer flask equipped with s. magnetic stirring bar and a. pressure equalizing dropping funnel with drying tube. The dropping funnel is charged with Red-Al (11) solution (60 g, 59 ml, 0.21 mole) and 50-60 ml dry benzene. The hydride solution is then added dropwise with stirring a t such a rate that the temperature of the reaction mixture stays a t about 5O0C. After the addition is complete, the reaction mixture is allowed t o stir a t room temperature for an additional hour. ml) i in The drvine tube is then removed and ethvl acetate (.
ing is generally not required. The mixture is poured into a separatory funnel, the layers separated, and the lower aqueous phase extracted twice with 100-ml portions of either benzene or ether.a The combined organic extracts are then washed with water and dried as before. Evaporstion of the solvent leaves about 75 g (80%) of an orange solid which is recrystallized from n-heptane (10 ml/g) t o give yelloworange needles, mp 7&79"C. Preporofion of wFerrocenylethy1 Acetote (V)
Experimental Preporofion of Acetylferrocene (111)
Acetyl chloride (43 g, 0.55 mole) is added t o ferrocene (93 g, 0.5 mole) and 400 ml of dry dichloromethane in a 1-1 Erlenmeyer flask equipped with a large (-2-in.) magnetic stirring bar and is fitted with a drying tuhe (CaSO. or CaCl?); the reaction is carried out in the hood. If no hood is available, a gas trap has been described (16) which can also be used quite successfully. The flask is then immersed in an ice witter batha of 0-5°C. Anhydrous aluminum chloride (AlCl., 67 g, 0.5 mole) is weighed in a 250-ml beaker and covered with 8. watch glass. The aluminum chloride is then added in -10 portions, replacing the gas trap after each addition. A short period of time (generdly 2 4 min) should elapse between each addition t o allow for heat exchange. Reaction begins almost immediately after the first duminum chloride has been added as evidenoed by a color change from redbrown t o deep wine-red. After the addition is complete, the beaker is rinsed with 10-15 ml of dichloromethane to transfer all of the AICIa into the reaction mixture. The mixture is then stirred for 2 hr as the ice water bath gradually comes t o room temperature. Then the solution is once agein cooled by addition of ice t o the bath. The reaction mixture is hydrolyzed by gradual addition of 5-ml portions of cold water (with each addition removing and replacing the gas trap, without the drying tuhe, if outside the hood), until a total of 100 ml of water is added. An additional 100-150 ml of water may then be added more rapidly. Next, the ice bath is removed and 10% aqueous Na9S104solution (prepared and Plastic pails used by painters are available a t most hardware stores and cost between $0.39 and $0.49. Ether isless prone to emulsify.
a-Ferrocenylethanol (69 g, 0.3 mole) and acetic acid (20 ml, 0.33 mole) are dissolved in 500 ml of dry benzene and placed in a 1-1 round bottom flask fitted with a water separator (Dean and Stark trap), a. reflux condenser and a drying tube on top. Some boiling chips are added and the solution refluxed by heating either with a mantle or a mineral oil bath on a hot plate. (Open flames are not recommended due to the flammability of benzene). Refluxing is continued until no further water separates (about 3 hr). The reaction is then allowed t o cool until it can be handled, decanted from the boiling stones, and the benzene evaporated under reduced pressme. The product remains as a dark oil (about 80 g) which ordinarily will not solidify without high vacuum evaporation and is used directly. A small sample may be set aside far further purification. The acetate sublimes a t 50PC (2-3 mm Hg) to give 8. yellow-orange solid, mp 70-71°C. Preporofion of N,N-Dimethyl-a-Ferrocenylethylomine
a-Ferrocenylethyl acetate (68 g, 0.25 mole) is dissolved in about 1400 ml of methanol in s 2-1 conical flask (or either a 5-pt acid bottle or 8-pt solvent bottle) t o which is added 240 ml of 25% aqueous dimethyl amine solution. A magnetic stirring bar is added and the mixture stirred overnight a t room temperature. The next day (or laboratory period) the solvent is evaporated and a dark oily residue which still contains some w'ater remains. This is swirled simultaneously with 300 ml of 8.5% aqueous phosphoric acid (30 ml 85% HsP04 270 ml H 2 0 ) and 100 ml of benaene or ether* until most or all of the residue is dissolved. The layers are separated and the acid solution is then washed wit,h 100 ml of the same solvent to remove neutral by-products. (The amine is extracted from the acid solution by dichloromethane and chloroform and these solvents should be avoided.) The acidic solution of the amine is neutralized by cautious addition of solid Na.C03, allowing the effervescence to subside before each subsequent addition. This process is continued until the pH of the solution is about 10, by which time the dark solu-
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tion turns yellow. The amine is extracted with three 100-ml portions of dichloromethahe or chloroform. The amine solution is washed with 100 ml of water, dried over KnCO., and evaporated to give about 50 g of a dark red brown oil which is vacuum distilled, hp 120°C/2 mm Hg. The distillation should be done rapidly as prolonged heating decomposes the amine. The yield of amine after distillation will be in the range 35-70yo (based on a-ferroeenylethanol). Resolution of N,N-Dimefhyl-a-Ferrocenylefhylomine V I
Racemic amine (25.7 g, 0.1 mole) and 15.0 g of R(+)-tartaric acid are each dissolved in 50 ml of methanol. The amine salution is poured into a. 125-ml conical flask equipped with magnetic stirring bar, and the flask immersed in a hot (55'C) water batha with a thermometer. The tartaric acid solution is warmed in a beaker of hot water to about the same temperature (56'C) and poured into the amine solution while stirring. A few (-) seeding crystals are added. (If no seeding crystals are available, scratching the flask with a glaes rod has to do.) Let the temperature in the bath fall a t a rate of about %6'C/hr; if the temperature of the bath falls too rapidly a t first, the bath should be warmed by the addition of hot water or by bubbling steam through it. Stirring is continued overnight and about 15 g of the S (-) amine tartrate is collected by suction filtration. The mother liquor is set aside for use later. The tartrate salt is added to about 50 ml bf 20% aqueous NaOH solution in a, separatory funnel and the amine extracted with three 25-ml portions of dichloromethane. The amine solution is dried over K C 0 3 and evaporated to give optically active amine (9.5 g) as a dark oil [ a ] =~ -11' ~ (c = 1.5, ethanol). The amine thus obtained and 5.55 g of t,artaric acid, each in 25 ml of methanol are mixed and seeded as above. After slow caoling, 13-14 g of the (-) amine tartrate is obtained which is converted into 8-9 g of optically pure (-) amine, lalo" = -14.1". If the optical rotation of the amine is lower, one additional cryfitallization is required. The mother liquor from the first crystallization is concentrrtted to about one-fourth of itsoriginalvolume. Diethyl ether is added slowly to the solution (25°C) until turbidity appears. After standing at O T (refrigerator) overnight, 24.3 g of (+) amine
296 / Journal of Chemical Education
tartrate are collected. A sample of the free amine may be ohtained as described above, [ u ] ~ "= +8.0. The (+) smine tartrate crystals are recrystallized from 10:l acetone:water, allowing about 16-17 ml of solvent for each gram of salt. The amine obtained from the first recrystallization has [ a ] P = +lZ9. One further recrystallization affordsoptically pure R(+)amine, [ a l =~ +14.1°. ~ ~ Literature Cited (1) (a) KEALT,T. J.. AND PAUSON. P. L., N ~ ~ u I168. c , 1039 (1951): (b) J. A., AND T R ~ A I NJ. E F., . J. Chsm. Sor., MILLER.S. A., TEBBOTX, 632 (1952). ~ , R o s ~ x e l n s tM., , W x r ~ m a M. , C.. A N D W o o n w ~ m . (2) (a) W l ~ s l a s oG.. R. B.. J. A m r . Chrm. Soc., 74,2125 (1952). (b) W o o o w ~ n o R , . B., R o s s n e ~ n M.. ~ . AND WHITING,M. C.. J . Amer. Chem. Soc., 74, ?.&=.* < ,.,\.""",. *, (3) ROSENBLOM, M.. ''Chemistry of the Iron Group Metdlocenes: Perm. oene, Ruthenoeene, and Osmocene," Part 1, John Wiiev & Sons, Ino.. New York, 1965. (4) S c a ~ o cK.. ~ . Top. Stercochem.. 1 . 3 9 (1967). (5) ABATANL T.. GONO*.T.,AND NOSAKI,H., Tclrohedron Latt.. 2265 (1969); and Tetrahedron, 26, 5453 (1970). (6) M ~ n o u ~ n o m D.. o , HOFFMINN,P., HEITEER. H.. A N D UOI.I., J . A m ? . Chom.Soe.. 92, 1969 (1970). P.. AND (7) M * n o u ~ n o w o ,D., KLOSACEK.H., GOKEG.G,, HOFSMANN. Uor, I.. Anscw. Chcm. Int. Ed., 9 , 3 7 1 (1970) and J. Amcr. Chcm. Soc.,
".""
0 2 . 5PR9 (IY,",.
5. I., Awn BAILEY,W . D.,3. Amer, Chcm, Soc., 93, 1046 (1971). (9)
For ageneral diaouasion of ohirality, seeany of the following: M m ~ o w K., "Introduction to Stereoehemistru." W. A. Benjamin. Ino.. New Ymk, 1966; ELIEL, E. L., "Steremhemietry of Carbon Compounds," McGraw-Hill, New York, 1962; Ucr, I., M~nou*nnrso,D., KLU=ACE=, H.. GOKEG, G., AND G I ~ E S P P.. I ~ ,Angcw. Cham..Int. Ed.,
9 , 703 (1970). P.. KLOSACEL-, H.,M*RPUARDINR. D.. (10) (a) Gous,.. G.. HOFFMANN, Racx, E.,AND Uar. I.. Anoew. Chcm. Inl. Ed.. 9, 64 (1970); (b) Gonm. G.. moUor, I.. Angcw. Chcm.In1. Ed., 10. (1971). (11) (a) A L o m c ~CXEYICAG C O M P A NRed-A1 ~, product bulletinno. 15-109-2,
Aldrioh Chemiohl Commny, Milwaukee, Wise.: (b) CAPKA.M.. K.. AND KRAUB,M., Collect. Czech. C n v ~ ~ o v ~ V.. n r ,KOCXLOEPL. Chrm. Commun.. 34, 118 (1969). (12) AmMoro, F. 6.. AND HAVEN. A. C.. J. Amer. Chsm. Soc.. 77, 6295
