1,3-Dipolar Cycloaddition with Diazo Groups: Noncovalent Interactions Overwhelm Strain

Like azides, diazoacetamides undergo 1,3-dipolar cycloadditions with oxanorbornadienes (OND) in a reaction that is accelerated by the relief of strain in the transition state. The cycloaddition of a diazoacetamide with unstrained ethyl 4,4,4-trifluoro-2-butynoate is, however, 35-fold faster than with the analogous OND because of favorable interactions with the fluoro groups. Its rate constant (<i>k</i> = 0.53 M^–1 s^–1 in methanol) is comparable to those of strain-promoted azide–cyclooctyne cycloadditions

Moderating Strain without Sacrificing Reactivity: Design of Fast and Tunable Noncatalyzed Alkyne–Azide Cycloadditions via Stereoelectronically Controlled Transition State Stabilization

Recently, we have identified two strategies for selective transition state (TS) stabilization in catalyst-free azide/alkyne cycloadditions. In particular, the transition states for the formation of both 1,4- and 1,5-isomers can be stabilized via hyperconjugative assistance for the C···N bond formation, whereas the 1,5-TS can be stabilized via C–H···X H-bonding interactions. When the hyperconjugative assistance is maximized by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, the combination of these TS-stabilizing effects was predicted to lead to ∼1 million fold acceleration of the cycloaddition with methyl azide. The present work investigated whether hyperconjugative assistance and H-bonding can be combined with strain activation for the design of even more reactive alkynes and whether reactivity can be turned “on demand.” When stereoelectronic amplification is achieved by optimal positioning of σ-acceptors at the endocyclic bonds antiperiplanar to the breaking alkyne π-bonds, the stabilization of the bent alkyne geometry leads to a significant <i>decrease</i> in strain in cyclic alkynes <i>without</i> compromising their reactivity in alkyne–azide cycloadditions. The approach can be used in a modular fashion where the TS stabilizing effects are introduced sequentially until the desired level of reactivity is achieved. A significant increase in reactivity upon the protonation of an endocyclic NH-group suggests a new strategy for the design of click reactions triggered by a pH-change or introduction of an external Lewis acid

1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

The diazo group has untapped utility in chemical biology. The tolerance of stabilized diazo groups to cellular metabolism is comparable to that of azido groups. However, chemoselectivity has been elusive, as both groups undergo 1,3-dipolar cycloadditions with strained alkynes. Removing strain and tuning dipolarophile electronics yields diazo group selective 1,3-dipolar cycloadditions that can be performed in the presence of an azido group. For example, diazoacetamide but not its azido congener react with dehydroalanine residues, as in the natural product nisin

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3‑Dipolar Cycloadditions

The diazo group has attributes that complement those of the azido group for applications in chemical biology. Here, we use computational analyses to provide insights into the chemoselectivity of the diazo group in 1,3-dipolar cycloadditions. Dipole distortion energies are responsible for ∼80% of the overall energetic barrier for these reactions. Here, we show that diazo compounds, unlike azides, provide an opportunity to decrease that barrier substantially without introducing strain into the dipolarophile. The ensuing rate enhancement is due to the greater nucleophilic character of a diazo group compared to that of an azido group, which can accommodate decreased distortion energies without predistortion. The tuning of distortion energies with substituents in a diazo compound or dipolarophile can enhance reactivity and selectivity in a predictable manner. Notably, these advantages of diazo groups are amplified in water. Our findings provide a theoretical framework that can guide the design and application of both diazo compounds and azides in “orthogonal” contexts, especially for biological investigations

Alkynyl Crown Ethers as a Scaffold for Hyperconjugative Assistance in Noncatalyzed Azide–Alkyne Click Reactions: Ion Sensing through Enhanced Transition-State Stabilization

Our recent work has provided an alternative strategy for acceleration of azide/alkyne cycloadditions via selective transition state (TS) stabilization. Optimization of hyperconjugative assistance, provided by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, is predicted to relieve strain in cyclooctynes while providing large acceleration to the cycloaddition. The present work investigates this strategy in alkynyl crown ethers, where propargylic C–O bonds contained within the macrocycle are constrained close to proper alignment for hyperconjugative assistance. Preorganization of σ-acceptors into the optimal arrangement for hyperconjugative interactions may alleviate a portion of the entropic penalty for reaching the TS. Optimal alignment can be reinforced, and transition-state stabilization can be further amplified by binding positively charged ions to the crown ether core, highlighting the potential for applications in ion sensing

Electronic and Steric Optimization of Fluorogenic Probes for Biomolecular Imaging

Fluorogenic probes are invaluable tools for spatiotemporal investigations within live cells. In common fluorogenic probes, the intrinsic fluorescence of a small-molecule fluorophore is masked by esterification until entry into a cell, where endogenous esterases catalyze the hydrolysis of the masking groups, generating fluorescence. The susceptibility of masking groups to spontaneous hydrolysis is a major limitation of these probes. Previous attempts to address this problem have incorporated auto-immolative linkers at the cost of atom economy and synthetic adversity. Here, we report on a linker-free strategy that employs adventitious electronic and steric interactions in easy-to-synthesize probes. We find that X···CO <i>n</i>→π* interactions and acyl group size are optimized in 2′,7′-dichloro­fluorescein diisobutyrate. This probe is relatively stable to spontaneous hydrolysis but is a highly reactive substrate for esterases both <i>in vitro</i> and <i>in cellulo</i>, yielding a bright, photostable fluorophore with utility in biomolecular imaging

Divergent Cyclizations of 1‑R-Ethynyl-9,10-anthraquinones: Use of Thiourea as a “S^2–” Equivalent in an “Anchor-Relay” Addition Mediated by Formal C–H Activation

The EtONa-mediated reaction of <i>peri</i>-R-ethynyl-9,10-anthraquinones with thiourea yields 2-R-7<i>H</i>-dibenzo­[<i>de</i>,<i>h</i>]­quinolin-7-ones and 2-R-anthra­[2,1-<i>b</i>]­thiophene-6,11-diones. Although 2-R-7<i>H</i>-dibenzo­[<i>de</i>,<i>h</i>]­quinolin-7-ones were observed previously in reactions with other N-centered nucleophiles (hydrazine, guanidine, and urea), the formation of 2-R-anthra­[2,1-<i>b</i>]­thiophene-6,11-diones is a new reactivity path. DFT computations analyzed factors responsible for the switch in reactivity and the relative importance of two possible pathways: (1) the “anchor-relay” mechanism mediated by nucleophilic attack at the carbonyl and (2) direct attack at the alkyne. The two pathways converge on a vinyl sulfur anion, set up for a 5-endo-trig cyclization at the <i>ortho</i>-position. Subsequent rearomatization/oxidation provides the fused thiophene product via formal C–H activation. The calculations suggest that the latter pathway, the direct attack at the alkyne, is more likely, due to the relatively high barrier for the 8-endo-dig cyclization (pathway 1). Computational insights led to a more selective synthesis of fused thiophenes, based on the reaction of acetylenic anthraquinones with sodium sulfide. This reaction does not require prefunctionalization at the <i>ortho</i>-position since direct C–H activation is efficient. The absence of fused five-membered heterocycles in earlier work was investigated computationally. The other N-centered nucleophiles form stronger anion−π complexes with the electron-deficient quinone core, promoting carbonyl attack over direct alkyne attack

Rerouting Radical Cascades: Intercepting the Homoallyl Ring Expansion in Enyne Cyclizations via C–S Scission

The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C–C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C–S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu₃Sn-functionalized naphthalenes

Selective Transition State Stabilization via Hyperconjugative and Conjugative Assistance: Stereoelectronic Concept for Copper-Free Click Chemistry

Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide–alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C···N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C–H···F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ∼1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions (i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable “click chemistry”. Further computational and experimental studies confirmed the generality of the above accelerating effects and compared them with the conjugative TS stabilization by π-acceptors

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative <b>8</b> outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling