Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200400655

Controlled microwave heating in modern organic synthesis.

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Asymmetric 1,3-Dipolar Cycloaddition Reactions

The Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.

https://www.ch.ic.ac.uk/local/organic/pericyclic/DA.pdf

The Diels--Alder reaction in total synthesis.

Introduction Cationic domino reactions Anionic domino reactions Radical domino reactions Pericyclic domino reactions Photochemically induced domino processes Transition metal catalysis Domino reactions initiated by oxidation or reduction Enzymes in domino reactions Multicomponent reactions Special techniques in domino reactions

Domino Reactions in Organic Synthesis

Thermochemistry of carbene and nitrene rearrangements

The s-Z and s-E conformers of acetylketene (5) were generated by flash vacuum pyrolysis (FVP) and matrix photolysis of precursors 1-4. Both conformers were characterized by low-temperature IR spectroscopy in argon, xenon, and nitrogen matrices. The observed frequencies and intensities are in excellent agrement with ab initio calculations at the MP2/6-31G* level. UV irradiation of s-Z/s-E-5 in nitrogen or xenon matrices allows the clean interconversion of conformers. Prolonged UV irradiation resulted in decarbonylation and formation of methylketene (7). However, the photolysis of argon matrix isolated 5 produced a new set of bands in the IR spectrum very close to the s-Z/s-E absorptions. Annealing of the matrix to 35 K removed these bands. This unusual phenomenon was shown to be due to a photochemically induced matrix site effect. Consistent with experimental observations, high-level calculations (QCISD(T)/6-311+G(2d,p)+ZPVE) predict that the s-Z and s-E conformers have virtually identical energies.

Acetylketene : conformational isomerism and photochemistry matrix isolation infrared and ab initio studies

Dipivaloylketene (8) is generated by preparative flash vacuum pyrolysis of furandione 6. While dimerization of 8 in apolar and several polar solvents leads to the previously reported [2 + 4] dimer 7, dimerization in the presence of DMSO, tributylphosphine oxide, or pyridine instead surprisingly occurs across the C=O bond of the ketene function, affording dioxinone 9. This is a novel type of alpha-oxo ketene dimerization. The reversibility of both dimerizations and mechanistic pathways for the formation of 9 are discussed. Cycloaddition reactions of 8 with heterocumulenes 10a,b and 12a-c yield [2 + 4] cycloadducts 11a,b and 13a-c, respectively. Oxazinones 13a-c can add a second molecule of 8 to generate novel spiro heterocycles 14a-c. In contrast, oxo ketene 7 reacts with carbodiimides 12a,b, to furnish [2 + 2] adducts 15a,b. This is the first unequivocal example of a direct [2 + 2] cycloaddition reaction of an alpha-oxo ketene. The unexpected formation of these compounds was confirmed by X-ray crystallography (15a). General aspects of [2 + 2] versus [2 + 4] cycloaddition in alpha-oxo ketenes are discussed.

Dipivaloylketene and its dimers. [2+4] versus [2+2] cycloaddition reactions of α-oxo ketenes

Tetrazolo[1,5-a] quinazoline (9) is converted to 2-azidoquinazoline (10) on sublimation at 200 degrees C and above, and the azide-tetrazole equilibrium is governed by entropy. 2-Quinazolylnitrenes 11 and 27 and/ or their ring expansion products 14 and 29 can undergo type I (ylidic) and type II (diradicaloid) ring opening. Argon matrix photolysis of 9/10 affords 2-quinazolylnitrene (11), which has been characterized by ESR, UV, and IR spectroscopy. A minor amount of a second nitrene, formed by rearrangement or ring opening, is also observed. A diradical (19) is formed rapidly by type II ring opening and characterized by ESR spectroscopy; it decays thermally at 15 K with a half-life of ca. 47 min, in agreement with its calculated facile intersystem crossing (19T -> 19OSS) followed by facile cyclization/rearrangement to 1-cyanoindazole (21) (calculated activation barrier 1- 2 kcal/mol) and N-cyanoanthranilonitrile (22). 21 and 22 are the isolated end products of photolysis. 21 is also the end product of flash vacuum thermolysis. An excellent linear correlation between the zero-field splitting parameter D (cm(-1)) and the spin density F on the nitrene N calculated at the B3LYP/EPRIII level is reported (R-2 = 0.993 for over 100 nitrenes). Matrix photolysis of 3-phenyltetrazolo[1,5-a] quinazoline (25) affords the benzotriazacycloheptatetraene 29, which can be photochemically interconverted with the type I ring opening product 2-isocyano-alpha-diazo-alpha- phenyltoluene (33) as determined by IR and UV spectroscopy. The corresponding carbene 37, obtained by photolysis of 33, was detected by matrix ESR spectroscopy.

Nitrenes, diradicals, and ylides. Ring expansion and ring opening in 2-quinazolylnitrenes.

Iminoacetonitrile (1) has been prepared by two methods: (i) thermal decomposition of the tosylhydrazone salts 13 at 200-degrees-C and (ii) Ar matrix photolysis of azidoacetonitrile (15). Ab initio calculations indicate that 1Z is of slightly lower energy than 1E, and this is confirmed by the IR spectra with use of the thermal methods. 1E/1Z undergo photochemical interconversion, giving a ca. 3:1 photostationary E:Z ratio. 1E and 1Z are fully characterized by their gas-phase, matrix, and thin-film IR spectra, which are in excellent agreement with ab initio calculations, by H-1 and C-13 NMR spectroscopy in solution, and by mass spectrometry. 1 polymerizes in solution above -40-degrees-C; pyrolysis produces HCN, and matrix photolysis produces HNC and van der Waals complexes containing HNC. N-tert-Butyliminoacetonitrile thermally fragments to tert-butyl isocyanide and HCN. N-Cyanomethanimine (3) has also been prepared by two methods: (i) pyrolysis of trimethylenetetrazole (20) at 500-800-degrees-C and (ii) pyrolysis of ditetrazolopyrazine 22 at 600-850-degrees-C. Both methods are extremely clean. 3 is fully characterized by its IR spectrum in agreement with ab initio calculations and, in conjunction with other work, by its mass and millimeter-wave spectra. 3 is thermodynamically stable in the gas phase up to ca. 800-degrees-C at low pressure and short contact times but polymerizes in the solid state above -100-degrees-C.

Curt Wentrup

Papers

Thermochemistry of carbene and nitrene rearrangements

Acetylketene : conformational isomerism and photochemistry matrix isolation infrared and ab initio studies

Dipivaloylketene and its dimers. [2+4] versus [2+2] cycloaddition reactions of α-oxo ketenes

Nitrenes, diradicals, and ylides. Ring expansion and ring opening in 2-quinazolylnitrenes.

Hcn dimers - iminoacetonitrile and n-cyanomethanimine