The reactivities and π-facial stereoselectivities of Diels-Alder reactions of 5-substituted cyclopentadienes were studied using density functional theory. Burnell and co-workers previously showed that the π-facial selectivities result from the energies required to distort the reactants into the transition state geometries. We have discovered the origins of these distortions. C₅-X σ-donors predistort the cyclopentadiene into an envelope conformation that maximizes the stabilizing hyperconjugative interaction between the C₅-X σ-bond and the diene π-system. This envelope conformation geometrically resembles the anti transition state. To minimize the destabilizing effect of negative hyperconjugation, C₅-X σ-acceptors predistort in the opposite direction toward an envelope geometry that resembles the syn transition state. We now show how hyperconjugative effects of the C₅-X substituent influence the stereoselectivities and have developed a unified model rationalizing the stereoselectivities and reactivities of 5-substituted cyclopentadiene Diels-Alder reactions.

We report a DFT computational study (M06-2X) of π-facial selectivity in the Diels-Alder reactions of thiophene 1-oxide. The preference for the syn cycloaddition arises because the ground state geometry of thiophene 1-oxide is predistorted into an envelope conformation that resembles the syn transition state geometry. The syn distortion occurs to minimize the effect of hyperconjugative antiaromaticity in the thiophene 1-oxide, arising from overlap of the σ*_SO with the π-system. The syn selectivity follows through to the product structure that is stabilized by a π-σ*_SO interaction, related to the 7-norbornenyl ion stability.

Lindner and Lemal showed that perfluorination of keto-enol systems significantly shifts the equilibrium toward the enol tautomer. Quantum mechanical calculations now reveal that the shift in equilibrium is the result of the stabilization of the enol tautomer by hyperconjugative π → σ*_CF interactions and the destabilization of the keto tautomer by the electron withdrawal induced by the neighboring fluorine atoms. The preference for the enol tautomer further increases in smaller perfluorinated cyclic keto-enol systems. This trend is in contrast to the nonfluorinated compounds, where the enol is strongly disfavored in the smaller rings. The fluoro effect overrides the effect of the ring size that controls the equilibria in nonfluorinated compounds. The increased overlap of the enol π bond with the σ*_CF orbitals of the allylic C-F bonds results in the increased preference for the enol tautomer in smaller perfluorinated keto-enol systems. We show here why the effect is much greater than in 3,3-difluorocyclooctyne.

A new class of bioorthogonal reagents based on the cyclopentadiene scaffold is described. The diene 6,7,8,9-tetrachloro-1,4-dioxospiro[4,4]nona-6,8-diene (a tetrachlorocyclopentadiene ketal, TCK) is ambiphilic and self-orthogonal with remarkable stability. The diene reacts rapidly with a trans-cyclooctene and an endo-bicyclononyne, but slowly with dibenzoazacyclooctyne (DIBAC), allowing for tandem labeling studies with mutually orthogonal azides that react rapidly with DIBAC. TCK analogues are synthesized in three steps from inexpensive, commercially available starting materials.

The endo and exo stereoselectivities of Diels-Alder reactions of cyclopropenone, iminocyclopropene, and substituted triafulvenes with butadiene were rationalized using density functional theory calculations. When cyclopropenone is the dienophile, there is a 1.8 kcal/mol preference for the exo cycloaddition with butadiene, while the reaction of 3-difluoromethylene triafulvene with butadiene favors the endo cycloaddition by 2.8 kcal/mol. The influence of charge transfer and secondary orbital interactions on the stereoselectivity of Diels-Alder reactions involving triafulvenes and heteroanalogs is discussed. The predicted stereoselectivity correlates with both the charge and highest occupied molecular orbital (HOMO) coefficient at the C₃ carbon of the triafulvene motif.

The Diels-Alder reactivity of 4,4-difluoro-3,5-diphenyl-4H-pyrazole was investigated experimentally and computationally with endo-bicyclo[6.1.0]non-4-yne. The computationally predicted rate enhancement from hyperconjugative antiaromaticity induced by fluorination of cyclopentadienes at the 5-position extends to five-membered heterocyclic dienes containing a saturated center. 4,4-Difluoro-4H-pyrazoles are new electron-deficient dienes with rapid reactivities toward strained alkynes.

We have investigated the inverse electron-demand Diels-Alder reactions of trans-cyclooctene (TCO) and endo-bicyclo[6.1.0]nonyne (BCN) with a 1,2,4,5-tetrazine, a cyclopentadienone, and an ortho-benzoquinone. Tetrazines react significantly faster with TCO compared to BCN because the highest occupied molecular orbital (HOMO) of TCO is significantly higher in energy than the HOMO of BCN and there is less distortion of the tetrazine. Despite the different HOMO energies, TCO and BCN have similar reactivities toward cyclopentadienones, while BCN is significantly more reactive than TCO in the cycloaddition with ortho-benzoquinone. We find that the higher reactivity of BCN compared to TCO with ortho-benzoquinone is due to secondary orbital interactions of the BCN HOMO-1 with the diene LUMO.

The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol^-1 lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction-activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO-LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions.

The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Now it is shown that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure-activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 L mol^-1  s^-1 were accessible by combining bulky and electron-withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles.

The structure and function of self-assembled monolayers (SAMs) at the nanoscale are determined by the steric and electronic effects of their building blocks. Carboranethiol molecules form pristine monolayers that provide tunable two-dimensional systems to probe lateral and interfacial interactions. Additional ω-functionality, such as carboxyl groups, can be introduced to change the properties of the exposed surfaces. Here, two geometrically similar isomeric m-carborane analogues of m-mercaptobenzoic acid, 1-COOH-7-SH-1,7-C2B10H10 and racem-1-COOH-9-SH-1,7-C2B10H10, are characterized and their SAMs on Au{111} are examined. The latter isomer belongs to the rare group of chiral cage molecules and becomes, to our knowledge, the first example assembled on Au{111}. Although different in symmetry, molecules of both isomers assemble into similar hexagonal surface patterns. The nearest-neighbor spacing of 8.4 ± 0.4 Å is larger than that of non-carboxylated isomers, consistent with the increased steric demands of the carboxyl groups. Computational modeling reproduced this spacing and suggests a tilt relative to the surface normal. However, tilt domains are not observed experimentally, suggesting the presence of strong lateral interactions. Analyses of the influence of the functional groups through the pseudo-aromatic m-carborane skeleton showed that the thiol group attached to either carbon or boron atoms increases the carboxyl group acidity in solution. In contrast, the acidity of the exposed carboxyl group in the SAMs decreases upon surface attachment; computational analyses suggest that the driving force of this shift is the dielectric of the environment in the monolayer as a result of confined intermolecular interactions, proximity to the Au surface, and partial desolvation.