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Research Interests
Organic synthetic methods; specifically, the development of new or considerably improved synthetic reactions, with emphasis on (1) chemo- and regioselective reactions of epoxides, and (2) epoxide synthesis. We have also developed a number of novel undergraduate organic laboratory experiments that combine synthesis and mechanistic discovery.
1) Chemo- and Regioselective Reactions of Epoxides
Synthesis of beta-hydroxy nitriles and 1,3-amino alcohols from epoxides using acetone cyanohydrin as a LiCN precursor
Treatment of acetone cyanohydrin in anhyd hexanes at -5 to -10 oC with 0.5-1.0 equiv of MeLi immediately affords an approx. 1:1 LiCN·acetone complex as a white precipitate; solvent evaporation provids good yields of the complex on either a milligram or multigram scale. Reaction of the cyanide complex with epoxides, either in one pot or using isolated samples of the complex, gave the corresponding beta-hydroxy nitriles in good yields, cleanly, and in reaction times notably shorter than those we reported for reactions using commercial samples of LiCN. In situ nitrile reduction with either LAH or BH3:THF afforded amino alcohols in satisfactory yields (Ciaccio et al., Tetrahedron Lett. 2004, 45, 7201).
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The LiCN:acetone ratio of the cyanide complex varied slightly (approx. 1:1, estimated by 13C NMR peak intensity and integration of CN and C=O in comparison with an authentic 1:1 sample); acetone could not be removed in vacuo (overnight, room temp) or by sample filtration and sequential washing with solvents; however, it evaporated readily from samples that were placed in a drying pistol (< 0.1 mm Hg; refluxing toluene).
2) Epoxide Synthesis
"Instant methylide” modification of the Corey-Chaykovsky epoxide synthesis
The Corey-Chaykovsky epoxide synthesis is a common method for the preparation of monosubstituted and geminally disubstituted epoxides from aldehydes and ketones, respectively, using methylsulfonium and methyloxosulfonium methylides as methylene-transfer agents. In the traditional protocol the methylides are pre-formed by treating (CH3)3S(O)+I-(1) or (CH3)3S+I-(2) with NaH in dry DMSO or DMSO/THF mixtures. Condensation with carbonyl compounds is performed at 0-25 oC using methylsulfonium methylide (Me2S=CH2), and at 50 oC using methyloxosulfonium methylide (Me2SO=CH2).
We have found that 1 and 2 form stable, dry mixtures with KOt-Bu and NaH, respectively, which remain stable upon prolonged storage (>1 yr). The corresponding methylides (Me2SO=CH2 and Me2S=CH2) are generated upon addition of DMSO or DMSO/THF solutions of carbonyl compounds, cleanly affording epoxides via the Corey-Chaykovsky reaction in good yields using short reaction times (as short as 20 min when 1-2 mmol of various ketones and aldehydes were treated with a mixture of 1 and KOt-Bu at 50-60 oC) (Ciaccio et al., Synth. Commun. 2003, 33, 2135).
More recently, in a modification of the Corey-Chaykovsky cyclopropanation reaction, we have found that treatment of various electron-deficient alkenes in DMSO with stable, dry, equimolar mixtures of either Me3S(O)I/ KOt-Bu or Me3S(O)I/NaH cleanly afforded the corresponding substituted cyclopropanes in good yields and short reaction times (<20 min for reactions at 50-60 oC using 0.4-4.0 mmol alkene) (Ciaccio & Aman, Synth. Commun. 2006, 36, 1333).
3) Undergraduate Organic Lab Experiments Combining Synthesis and Mechanistic Discovery
(a) The ring's the thing; epoxide chemistry in the undergraduate organic lab
Despite the prevalence of epoxide chemistry in the chemical literature and in all modern undergraduate organic textbooks, neither their reactions nor their preparation are common subjects of undergraduate organic lab experiments. We have devised two operationally straightforward, experiments that can be presented to students in the form of mechanistic "puzzles" which probe the stereoselectivity of epoxide reaction and formation: (1) a diastereospecific synthesis of trans-stilbene oxide from trans-stilbene via its corresponding erythro bromohydrin (Journal of Chemical Education 1995, 72, 1037); and (2) the regioselective alkylation of styrene oxide with PhMgBr, an alternative to traditional Grignard preparations (Journal of Chemical Education 1996, 73, 1196). Both experiments complement the increasing number of puzzle-oriented undergraduate experiments combining synthesis and mechanistic discovery that continue to appear in the chemical literature.
(b) Diastereoselective Grignard reactions suitable for a large organic lab course
We have developed a project-based, undergraduate experiment that probes the diastereoselectivity of the reaction between a Grignard reagent and a common, inexpensive a-chiral ketones (Journal of Chemical Education 2001, 78, 531). Students isolate a single diastereomer of (+/-)-1,2-diphenyl-1,2-propanediol by treatment of (+/-)-benzoin with CH3MgI. Since the mp ranges of the two possible diol diastereomers differ by 10 oC, the reaction’s diastereoselectivity can be established by mp determination alone, and it can be rationalized by the preferential addition of CH3MgI to the least sterically hindered face of the carbonyl group in a rigid, five-membered cyclic intermediate (the "Cram chelate model"). This experiment is an interesting alternative to traditional Grignard experiments,is operationally straightforward and easily performed in large lab courses, and introduces students to pi-facial discrimination by having them establish the stereochemical course of kinetically controlled nucleophilic addition to a carbonyl.
(c) Straightforward Synthesis and NMR Spectral Analysis of Amine Heterocycles: Discovering the Effect of Asymmetry on the 1H and 13C NMR Spectra of N,O-Acetals
In collaborative work initiated by Prof. Shahrokh Saba of our Department, we have developed an undergraduate organic laboratory experiment for which students use reactions found in standard textbooks to prepare two structurally similar heterocyclic amines, one achiral (3-isopropyl-1,3-oxazolidine (2)), the other chiral (3-isopropyl-2-(4-nitrophenyl)oxazolidine (3)) (Journal of Chemical Education 2007, 84, 1011). These N,O-acetals differ only by the presence of a single ring substituent that introduces asymmetry; thus, each have distinct 1H and 13C NMR spectral patterns. Each student prepares 2-(isopropylamino)ethanol (1) by reductive isopropylation of ethanolamine using acetone and NaBH4, and then the class is divided into two groups: one treats 1 with N,N,N',N'-tetramethyldiaminomethane (an alternative to the Mannich intermediate [CH2=NMe2]+X-) to prepare 2 and the other condenses 1 with 4-nitrobenzaldehyde to prepare 3. NMR spectroscopy clearly indicates that the nuclei of the methyl groups of 2 and 3 are enantiotopic and diastereotopic, respectively. Students must explain why the NMR spectra of 3 have more peaks in the aliphatic region, and increased coupling in the 1H spectrum, leading to a discussion of prochirality and the topicity of ligands within a single molecule. This operationally straightforward experiment is a meaningful exercise in chemical synthesis and spectral problem solving, and students sample the benefits of collaborative work by dividing up the synthetic and analytical tasks and then sharing their data.
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