Doing the Research that Informs Practice: A Retrospective View of One Group's Attempt to Study The Teaching and Learning of Organic Chemistry.

The idea that the focus of educational research should be on results that can inform the practice of teaching has been an implicit assumption for so many years that one would be hard-pressed to trace it back to an individual source. At one time, the people doing such research in STEM disciplines were faculty in schools or colleges of education who focused on K-12 classrooms and looked for ideas, concepts, and principles that would be valid across a range of STEM disciplines. Eventually, this research was done on college- or university-level students, as well, and there was a shift toward what has been called discipline-based educational research (DBER) that looks at the problems associated with the teaching and learning of a given discipline, such as chemistry. This paper will discuss the results of research on problem-solving in chemistry that has been done in our research group, with particular emphasis on the challenges of teaching and learning organic chemistry. The goal of this paper is to show what can happen when one listens carefully to students and begins to appreciate the difference between what we think we have taught and what the students learned. The examples we will use have the potential for convincing those of us who teach chemistry to rethink what we do in our classes to find better ways of helping our students understand the material we are trying to teach. Although this paper will focus on results from the second-year organic chemistry course, similar results have been observed in both inorganic and physical chemistry, as well as biochemistry courses.

The development of bulky palladium NHC complexes for the most-challenging cross-coupling reactions.

Palladium-catalyzed cross-coupling reactions enable organic chemists to form C-C bonds in targeted positions and under mild conditions. Although phosphine ligands have been intensively researched, in the search for even better cross-coupling catalysts attention has recently turned to the use of N-heterocyclic carbene (NHC) ligands, which form a strong bond to the palladium center. PEPPSI (pyridine-enhanced precatalyst preparation, stabilization, and initiation) palladium precatalysts with bulky NHC ligands have established themselves as successful alternatives to palladium phosphine complexes. This Review shows the success of these species in Suzuki-Miyaura, Negishi, and Stille-Migita cross-couplings as well as in amination and sulfination reactions.

Amination with Pd-NHC complexes: rate and computational studies involving substituted aniline substrates.

The amination of aryl chlorides with various aniline derivatives using the N-heterocyclic carbene-based Pd complexes Pd-PEPPSI-IPr and Pd-PEPPSI-IPent (PEPPSI=pyridine, enhanced precatalyst, preparation, stabilization, and initiation; IPr=diisopropylphenylimidazolium derivative; IPent= diisopentylphenylimidazolium derivative) has been studied. Rate studies have shown a reliance on the aryl chloride to be electron poor, although oxidative addition is not rate limiting. Anilines couple best when they are electron rich, which would seem to discount deprotonation of the intermediate metal ammonium complex as being rate limiting in favour of reductive elimination. In previous studies with secondary amines using PEPPSI complexes, deprotonation was proposed to be the slow step in the cycle. These experimental findings relating to mechanism were corroborated by computation. Pd-PEPPSI-IPr and the more hindered Pd-PEPPSI-IPent catalysts were used to couple deactivated aryl chlorides with electron poor anilines; while the IPr catalysis was sluggish, the IPent catalyst performed extremely well, again showing the high reactivity of this broadly useful catalyst.

Amination with Pd-NHC complexes: rate and computational studies on the effects of the oxidative addition partner.

Pd-PEPPSI-IPent, a recently-developed N-heterocyclic carbene (NHC) complex, has been evaluated in amination reactions with secondary amines and it has shown superb reactivity under the most mildly basic reaction conditions. Rate and computational studies were conducted to provide insight into the mechanism of the transformation. The IPent catalyst coordinates to the amine much more strongly than the IPr variant, thus favouring deprotonation with comparatively weak bases. Indeed the reaction is first order in base and only slightly more than zeroth order in amine.

Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd-PEPPSI-IPent.

Pd-PEPPSI-IPent has proven to be an excellent catalyst for the Negishi cross-coupling reaction of secondary alkylzinc reagents with a wide variety of aryl/heteroaryl halides. Importantly, ß-hydride elimination/migratory insertion of the organometallic leading to the production of isomeric coupling products has been significantly reduced using the highly-hindered Ipent ligand.

Pd-PEPPSI-IPent: an active, sterically demanding cross-coupling catalyst and its application in the synthesis of tetra-ortho-substituted biaryls.

Incredible Bulk: A series of N-heterocyclic carbene catalysts (see picture) were prepared and evaluated in the Suzuki-Miyaura reaction. A variety of sterically encumbered tetra-ortho-substituted biaryl products were formed from unreactive aryl chlorides using the isopentyl-substituted catalyst at temperatures ranging from 65 degrees C to room temperature. The cyclopentyl-substituted catalyst was virtually inactive, demonstrating that "flexible bulk" is essential to promote these transformations.

An improved method for the protection of carboxylic acids as 1,1-dimethylallyl esters.

1,1-Dimethylallyl (DMA) esters of various N-protected amino acids have been synthesized using prenyldimethylsulfonium tetrafluroborate, a reagent that can be readily made and stored, in conjunction with catalytic CuBr. These reactions were complete within several hours and afforded DMA esters in high yields. As has been previously shown in our group, DMA esters represent a palladium-labile proctecting group for carboxylic acids that resists nucleophilic attack as a tert-butyl ester would.

Solid-phase synthesis and configurational reassigment of callipeltin E. Implications for the structures of callipeltins A and B.

Two possible isomers of the natural product callipeltin E (1, 5) were synthesized by using an Fmoc-based solid-phase strategy in 7 steps, in 20% and 26% overall yields, respectively. The (1)H NMR spectrum of synthetic 5 correlated closely with that of the natural product, whereas that of 1 did not, providing confirmation of the configurational reassignment of the N-terminal residue of callipeltin E as D-allothreonine. This result strongly implies that the corresponding residue in the closely related cyclic depsipeptides callipeltins A and B should also be considered a D-allothreonine residue.

Synthesis of N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine: An application of lanthanide-catalyzed transamidation.

N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) was synthesized from tert-butyl N-Boc-(2S,3S,4R)-dimethylpyroglutamate (13). This synthesis involved selective deprotection of a Boc group from a lactam nitrogen in the presence of a tert-butyl ester, Fmoc protection of the lactam, and a lanthanide-catalyzed transamidation reaction of the Fmoc-protected lactam, using ammonia and dimethylaluminum chloride. The scope of Lewis acid-catalyzed transamidation of acylated lactams was explored through the variation of lanthanide, lactam, acyl group, amine, and aluminum reagent. The reactivity of various metal triflates was found to vary in the following qualitative order: Yb approximately Sc > Er approximately Eu approximately Sm > Ce approximately Ag(I) > Cu(II) approximately Zn. Intriguingly, catalysis was only observed when ammonia was the nitrogen nucleophile; addition of other amidoaluminum complexes to acyl lactams was found to be insensitive to the addition of lanthanides.