Steven E. Beutick‡
ab,
Song Yu‡
a,
Laura Orian
b,
F. Matthias Bickelhaupt
acd and
Trevor A. Hamlin
*a
aDepartment of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands. E-mail: t.a.hamlin@vu.nl
bDipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, Padova, 35129, Italy
cInstitute of Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen, 6525 AJ, The Netherlands
dDepartment of Chemical Sciences, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa
First published on 27th August 2024
The retro-Cope elimination reaction between dimethylhydroxylamine (DMHA) and various cyclic alkynes has been quantum chemically explored using DFT at ZORA-BP86/TZ2P. The purpose of this study is to understand the role of the following three unique activation modes on the overall reactivity, that is (i) additional cycloalkyne predistortion via fused cycles, (ii) exocyclic heteroatom substitution on the cycloalkyne, and (iii) endocyclic heteroatom substitution on the cycloalkyne. Trends in reactivity are analyzed and explained by using the activation strain model (ASM) of chemical reactivity. Based on our newly formulated design principles, we constructed a priori a suite of novel bioorthogonal reagents that are highly reactive towards the retro-Cope elimination reaction with DMHA. Our findings offer valuable insights into the design principles for highly reactive bioorthogonal reagents in chemical synthesis.
Recently, Kang et al. presented the retro-Cope elimination reaction (hydroamination of cyclic cyclooctyne) between functionalized (cyclic) alkynes and N,N-dialkylhydroxylamines as a novel bioorthogonal reaction (Scheme 1a).10 The calculated Gibbs free energy activation barrier at M06-2X/6-311G(2d,p)//M06-2X/6-31G(d,p) for the parent cyclooctyne was determined to be 18.9 kcal mol−1, which is adequate for the reaction to proceed at room temperature. Experimentally, the retro-Cope elimination reaction between the non-substituted cyclooctyne (COT) and hydroxylamine in CD3CN at room temperature shows second-order rate constants of 3.25 × 10−2 M−1 s−1, an order of magnitude higher than the strain-promoted azide–alkyne cycloaddition (SPAAC) reaction with benzyl azide.10a,11 Notably, the retro-Cope elimination reaction is highly regioselective when the COT is substituted with electronegative heteroatoms at the propargylic position. Furthermore, Kang et al. showcased the retro-Cope elimination reaction in an in vitro study and demonstrated mutual orthogonality in conjunction with the inverse electron demand Diels Alder (IED-DA) reaction between tetrazine and strained alkenes.10a,12 In doing so, they nicely underscored the potential of this reaction to be applied in mutually orthogonal bioorthogonal chemistry.
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Scheme 1 (a) The retro-Cope elimination reactions between cyclic alkynes or alkenes and hydroxylamines. (b) Effects of modifying cyclic octynes on the reactivity in the retro-Cope elimination reaction with diethylhydroxylamine.10a a The second-order rate constants were determined for a 1![]() ![]() |
Decorated cyclooctynes have emerged as functional bioorthogonal reagents in 1,3-dipolar cycloadditions.5e,13 Similarly, these cyclic alkynes show high reactivity and selectivity towards the retro-Cope elimination reaction.10a Kim and co-workers10a reported only a minor reactivity enhancement after the introduction of additional strain by three-membered ring fusion in bicyclo[6.1.0]nonyne (BCN), in contrast to a drastic two-order magnitude increase in the second-order rate constants observed for the SPAAC reaction reported by Dommerholt et al.14 The authors described further enhanced reactivity upon adding electronegative substituents on the exocyclic propargylic position, achieving up to three orders of magnitude increase in the second-order rate constants (Scheme 2). Using the distortion/interaction model, Kang et al. show that the predistortion gives rise to the lowering of the activation barrier for the strained cyclooctyne relative to its linear counterpart.15,16a Interestingly, upon the addition of electronegative substituents on the propargylic position, they found that the lowering of the activation barrier was not caused by a less favorable interaction term but, rather, driven by the lowering of the strain energy for both fragments. They further attribute this to a shift of the transition state towards the reactants in accordance with the Hammond postulate.
We have computationally investigated the concerted retro-Cope elimination reaction between dimethylhydroxylamine (DMHA) and cyclic alkynes at ZORA-BP86/TZ2P (Scheme 2). Three sets of cyclooctynes were studied. The first set includes cyclic alkynes with increased predistortion due to the introduction of cyclic functionality (DIBO and BCN). The second and third sets consist of cycloalkynes modified at the exocyclic (HO-COT and DIFO) and endocyclic (N-COT, O-COT, and S-COT) propargylic position, respectively. The anti-pathways (dimethyl groups and propargylic substituent on opposite sides) and the syn-pathways (dimethyl groups and propargylic substituent on the same side) were investigated. To gain insight into the physical factors that control the reactivity, the activation strain model (ASM)16 of reactivity in conjunction with the matching energy decomposition analysis (EDA) and quantitative Kohn–Sham molecular orbital (KS-MO)17 theory analysis. Based on our found rational design principles, we constructed a priori a suite of novel bioorthogonal reagents that are highly reactive towards the retro-Cope elimination reaction with DMHA.
ΔE(ζ) = ΔEstrain(ζ) + ΔEint(ζ) | (1) |
The ΔEstrain(ζ) is associated with the rigidity and the structural deformation of the reactants from their equilibrium structure to the geometry they adopt at the coordinate of ζ during the reaction. The ΔEint(ζ) is related to the electronic structure of the reactants and their spatial orientation and represents the mutual interactions between the deformed reactants.
To obtain a deeper insight into the physical mechanism behind ΔEint(ζ), we employed our canonical energy decomposition analysis (EDA),17 which decomposes the ΔEint between the deformed reactants, within the framework of Kohn–Sham MO theory, into three physically meaningful terms [eqn (2)].
ΔEint(ζ) = ΔVelstat(ζ) + ΔEPauli(ζ) + ΔEoi(ζ) | (2) |
The electrostatic interaction, ΔVelstat(ζ), corresponds to the classical electrostatic interaction between the unperturbed charge distributions of the deformed reactants. The Pauli repulsion, ΔEPauli(ζ), comprises the Pauli-repulsive orbital interactions between closed-shell orbitals. The term ΔEoi(ζ) represents the stabilizing orbital interactions, such as charge transfer, namely, the interactions between the occupied orbitals of one reactant and the unoccupied orbitals of the other reactant, and polarization, that is, the occupied–unoccupied orbital mixing within one reactant due to the presence of the other reactant.
![]() | (3) |
Here, ρ(r) is the electron density of the molecule, and is the superposition of atomic densities ρB of a fictitious promolecule without chemical interactions that is associated with the situation in which all atoms are neutral. The interpretation of the VDD charge QVDDA is rather straightforward and transparent: instead of measuring the amount of charge associated with a particular atom A, QVDDA directly monitors how much charge flows, due to chemical interactions, out of (QVDDA > 0) or into (QVDDA < 0) the Voronoi cell of atom A.
2-Butyne | COT | |
---|---|---|
a Computed at ZORA-BP86/TZ2P.b Δr is the difference in length between the forming C⋯N and C⋯H bonds at the transition state.c The relative second-order rate constants (krel) were calculated relative to the COT (k/kCOT). | ||
Δrb | 0.74 | 0.70 |
ΔERC | −3.0 | −3.0 |
ΔE‡ | 15.8 | 4.6 |
ΔErxn | −6.9 | −14.4 |
ΔG‡ | 26.7 | 15.8 |
krelc | 1.2 × 10−8 | 1.0 |
To identify the physical factors leading to the enhanced retro-Cope elimination reactivity of the strained alkynes relative to the linear 2-butyne, the activation strain model (ASM) of reactivity is applied (Fig. 1a). We find that predistortion of the alkyne in COT serves to enhance retro-Cope elimination reactivity via (1) reducing the activation strain and (2) enhancing the overall interaction energy via more stabilizing orbital interactions. Kim et al. also observed a notable reduction in the activation strain of the retro-Cope elimination reaction with COT.10 Relative to its linear counterpart, the strain in COT is reduced by approximately 10 kcal mol−1 at a consistent geometry, where the lengths of the C⋯H bond are 1.45 Å, and the slope of the strain in the alkyne fragment is smaller along the reaction coordinate. By partitioning the strain energy in terms of the two fragments (Fig. 1b), we confirm that the strain is lowered for the COT fragment, due to the alkyne predistortion in the COT reagent. To understand the origin of this effect, further analysis of both equilibrium geometry and consistent geometry (Fig. 1c and d) reveals that the reaction of predistorted alkyne, COT, simply requires less bending of the alkyne to react with DMHA.
In addition, we show how predistortion of COT also acts to enhance the stabilizing interaction energy with DMHA (Fig. 1a). Using our EDA, we could pinpoint the enhanced interaction energy originates from significantly more stabilizing orbital interactions (Fig. S3b†). The predistortion of the alkyne results in a stabilization of the LUMO and a slight destabilization of the HOMO.30 The lowering of the LUMO, is caused by the in-phase mixing of the σ* and π* orbitals, resulting in a smaller π*-LUMOCOT and HOMODMHA energy gap.
COT | DIBO | BCN | |
---|---|---|---|
a Computed at ZORA-BP86/TZ2P.b Δr is the difference in length between the forming C⋯N and C⋯H bonds at the transition state.c The relative second-order rate constants (krel) were calculated relative to COT (k/kCOT). | |||
Δrb | 0.70 | 0.85 | 0.67 |
ΔERC | −3.0 | −2.7 | −3.1 |
ΔE‡ | 4.6 | 4.1 | 2.1 |
ΔErxn | −14.4 | −9.4 | −12.7 |
ΔG‡ | 15.8 | 15.6 | 13.9 |
krelc | 1.0 | 1.5 | 27.0 |
The physical factors leading to the enhanced retro-Cope elimination reactivity of DIBO and BCN compared to COT are next analyzed using the ASM. In Fig. 2b, the ASM diagram shows that the retro-Cope elimination reaction of DIBO benefits from significantly less destabilizing strain energy (ΔEstrain), as compared to COT. The retro-Cope elimination reaction of BCN with DMHA also benefits from less destabilizing strain but is paralleled by a more stabilizing interaction energy (ΔEint), as compared to COT (Fig. 2b). Decomposition of the strain energies reveals that DIBO benefits a reduced strain in both the DIBO and DMHA fragments, whereas the reduced strain for BCN at consistent geometry originates solely from the BCN fragment (Fig. 2d). Our structural analyses at the equilibrium geometry show that DIBO and BCN both have a more predistorted backbone than the parent COT (157.6°) in the equilibrium geometry, with internal C–CC alkyne bond angles of 154.7° and 154.6°, respectively. This predistortion results in a structurally less distorted alkyne fragment at consistent geometry (Fig. 2d), and, consequently, reduced activation strain. For DIBO, the lowering of the activation strain is more pronounced because also the O⋯H bond breaking distance and compression of the H–O–N angle are less progressed, which causes the strain of the DMHA fragment to be shifted to the right (Fig. 2a). As will be explained in more detail later on, this can be traced back to a more slanted reaction path, that is, the C⋯N bond is formed later than the C⋯H bond for DIBO (Δr = 0.76 Å, where Δr is the difference in length between the C⋯N and C⋯H bonds at the consistent geometry) than for COT (Δr = 0.67 Å).
Hamlin and coworkers have shown that, in addition to the reduction of the destabilizing strain, a more stabilizing interaction energy is at the root of the enhanced reactivity in 1,3-dipolar cycloaddition between azides and strained alkynes (SPAAC).30 Energy decomposition analyses in conjunction with KS-MO analyses illustrated that the bending of alkynes has a profound effect on the frontier molecular orbitals (FMOs), i.e., the LUMO is stabilized and the HOMO (πin-plane) is slightly destabilized because of mixing with the adjacent σ*- and σ-orbitals, respectively. Thus, a more bent alkyne has a lower LUMOalkyne, giving rise to a smaller HOMODMHA–LUMOCOT gap. Therefore, the reaction of BCN, which has a 3.0° smaller internal C–C
C angle at equilibrium geometry, goes with a smaller initial HOMODMHA–LUMOBCN gap than the reaction of COT (Fig. 3). It must be noted that, with the exception of DIBO, the
along the reaction coordinate (the slope), relative to the energy at equilibrium geometry, is approximately equal (Fig. S4d†). As for BCN the Δr remains equal, this leads to a larger S2/Δε term, i.e., the more favorable HOMODMHA–LUMOBCN interaction and, consequently, more stabilizing orbital interactions associated with the retro-Cope elimination reaction between BCN and DMHA.
Despite DIBO having a lower energy than COT, the overall orbital interactions for the DIBO reaction are less stabilizing (Fig. 3). This can be rationalized by the reduced HOMODMHA–LUMODIBO orbital overlap brought about by the C⋯N bond formation distance in the reaction of DIBO (Δr = 0.76 Å) lagging substantially behind that of COT (Δr = 0.67 Å). This geometric effect also brings about considerably less destabilizing Pauli repulsion. At a double consistent geometry (Table S4†), where Δr is equal to that of COT at consistent geometry (Δr = 0.67 Å), the Pauli repulsion exceeds the more stabilizing orbital and electrostatic interaction. This is due to the overlap of various filled in-plane orbitals of the DMHA fragment overlapping with the HOMO−4, HOMO−2 and, HOMO−1 of DIBO (Fig. S7†). It is the buildup of this Pauli repulsion that is effectively absorbed into the reaction path causing the more slanted reaction path (higher Δr). As a result, the Pauli repulsion is lowered, and, concomitantly, the orbital overlaps between the two fragments are reduced, also decreasing the HOMODMHA–LUMODIBO overlap. Similar to the retro-Cope elimination reaction with linear alkynes with added steric bulk,28 the Pauli lowering effect originates in more (not less) steric repulsion introduced by the fused aryls in DIBO.
We observe that the additional repulsive interaction occurs between the various in-plane orbitals of DMHA and the HOMO−1, HOMO−2, and HOMO−4 orbitals in DIBO. In contrast, the literature attributes this repulsive effect to “flagpole” hydrogens.6d,32 At double consistent geometry, the occupied–occupied orbital overlaps that actually increase are not in the vicinity of the “flagpole” hydrogen atoms. Instead, the three orbitals are combinations of the πin-plane-HOMO of COT and the π-HOMOs of the benzene substituents. The πin-plane-HOMO of COT is allowed to mix with the π-system benzene substituents due to the twisted nature of DIBO (Fig. S7†).
Thus, although the introduction of fused benzenes causes a substantially smaller HOMODMHA–LUMODIBO gap (Fig. 3), the more stabilizing orbital interaction are hampered by lowered HOMODMHA–LUMODIBO overlaps, due to the C⋯N bond forming distance in DIBO lagging behind that of COT. The greater C⋯N bond forming distance can be traced back to the increased two-center four-electron Pauli repulsion, which is absorbed into the geometry of the reaction system by forcing it into a slanted reaction path. As a result, the overlap between the filled FMOs decreases, ultimately reducing Pauli repulsion, which outweighs the concurrent decrease in stabilizing orbital and electrostatic interactions. The smaller HOMODMHA–LUMODIBO gap in DIBO, together with the introduction of additional HOMO–LUMO interactions, limit the destabilization by the additional in-plane steric bulk between the two fragments.
Considering that orbital interactions play a key role in the enhanced reactivity of DIBO and BCN compared to COT, we performed an additional analysis on the key π*-LUMOin-plane that engages with the π-HOMODHMA. We sought to determine the factors that lead to the observed lowering of the π*-LUMOin-plane orbital energies of DIBO and BCN relative to COT. To do so, we constrained COT in the equilibrium geometries of the respective substituted cyclic alkynes and reported the π-HOMOin-plane and π*-LUMOin-plane orbital energies in Fig. S4c.† The root of the π*-LUMOin-plane-lowering in the equilibrium geometry was further analyzed by decomposing the change in orbital energy, ΔεMO, into substituent, Δεsub, and bending, Δεdeform, contributions, which were defined as (Fig. S4a and b†):
ΔεMO = ΔεMO,predist + ΔεMO,sub | (4) |
ΔεMO,predist = εMO(COTconstrained) − εMO (COTeq) | (5) |
ΔεMO,sub = εMO (sub) − εMO (COTconstrained) | (6) |
At the equilibrium geometry, the π*-LUMOin-plane-lowering of BCN is primarily caused by the additional bending of the alkyne enforced by the fused cyclopropane (0.14 eV (79%)) and only lowered by 0.04 eV (21%) because of the addition of the fused cyclopropane to the deformed cyclooctyne. In contrast, the π*-LUMOin-plane-lowering in DIBO primarily finds its origin in substituent effects instead of the additional bending of the alkyne. In equilibrium geometry, DIBO is stabilized by the bending of the alkyne enforced by the more rigid cyclic backbone by only 0.24 eV (23%), whereas the substitution by the dibenzo-substituents accounts for a stabilization of 0.78 eV (77%).
Additionally, the π*-LUMOin-plane orbital energies along the reaction coordinate associated with the retro-Cope elimination reaction are shown in Fig. S4d.† The orbital energy profiles of the π*-LUMOin-plane orbitals look alike with similar steepness along the reaction coordinate and differ primarily in the π*-LUMOin-plane orbital energy in the equilibrium geometry. DIBO stands out in that the steepness is lower, i.e., the rigid DIBO is less affected by deformation of the alkyne along the reaction coordinate. This is likely due to the smaller angle deformation needed for consistent geometry (Fig. 2a), resulting from the more slanted reaction path (larger Δr).
COT | HO-COT | DIFO | |
---|---|---|---|
a Computed at ZORA-BP86/TZ2P.b Δr is the difference in length between the forming C⋯N and C⋯H bonds at the transition state.c The relative second-order rate constants (krel) were calculated relative to the parent propyne (k/kCOT). Only the anti-pathway was considered. | |||
Δrb | 0.70 | 0.56 | 0.54 |
ΔERC | −3.0 | −4.9 | −2.1 |
ΔE‡ | 4.6 | 2.3 | 0.2 |
ΔErxn | −14.4 | −15.3 | −15.9 |
ΔG‡ | 15.8 | 14.6 | 13.0 |
krelc | 1.0 | 8.7 | 1.3 × 102 |
Kang et al. suggested that the reaction does not benefit from a more stabilizing interaction energy upon the addition of electronegative substituents but, rather, from a decrease in strain energy.10a Our analysis at the transition states also furnishes the same insight. However, performing our activation strain and energy decomposition analyses along the full reaction coordinate provides us with a more comprehensive picture of the factors dictating the reactivity.22a In Fig. 4a, the ASM diagram reveals that, at consistent geometry, the activation strain follows a trend opposite to the activation barriers. This would indicate, at odds with Kang et al.10a that the strain is not responsible for observed rate enhancements, but instead it is the progressively more stabilizing interaction energy going from COT to HO-COT to DIFO that is key for the enhanced reactivity. Because the HO-COT and DIFO benefit from more stabilizing interaction energy, the transition states shift to an early point on the reaction coordinate towards the reactants. This, in turn, causes the reactants to be less structurally deformed in their respective TSs.
Our energy decomposition analyses (EDA) (Fig. 4b) show that the more stabilizing ΔEint term associated with the retro-Cope elimination reactions of HO-COT and DIFO arises from a more stabilizing ΔEoi, reinforced by a smaller contribution from the ΔVelstat. The reverse trend in ΔEPauli to that of ΔEint shows that ΔEPauli is not responsible for the more stabilizing interaction energy.
To determine the origin of the enhanced orbital interactions, we quantified all donor–acceptor orbital interactions associated with the retro-Cope elimination reaction of COT, HO-COT, and DIFO at consistent geometry where C⋯H bond forming distance is 1.60 Å and confirmed the HOMODMHA–LUMOX-COT interaction as the most important contributor (Fig. S8†). Further KS-MO analyses reveal that the enhanced orbital interactions of HO-COT and DIFO compared to COT originate in their lowered LUMOs and a slightly more efficient orbital overlap. Especially the former brings about a larger orbital interaction term (∝S2/Δε term) as the energy gap reduces from 3.5 to 2.8 to 2.4 eV going from COT to HO-COT to DIFO (Fig. 5). The origin of the π*-LUMOin-plane-lowering in the equilibrium geometry was further analyzed by decomposing the change in orbital energy into, Δεπ*-LUMO, into substituent, Δεsub, and bending, Δεbend, contributions. We confirmed that the LUMO-lowering effect principally stems from the substituent effect and not the deformation of the alkyne (Fig. S4c†).
COT | N-COT | O-COT | S-COT | |
---|---|---|---|---|
a Computed at ZORA-BP86/TZ2P.b Δr is the difference in length between the forming C⋯N and C⋯H bonds at the transition state.c The relative second-order rate constants (krel) were calculated relative to COT (k/kCOT). Only the anti-pathway was considered. | ||||
Δrb | 0.70 | 0.67 | 0.59 | 0.66 |
ΔERC | −3.0 | −2.9 | −2.7 | −2.7 |
ΔE‡ | 4.6 | 2.9 | 1.0 | 5.8 |
ΔErxn | −14.4 | −15.8 | −19.5 | −13.4 |
ΔG‡ | 15.8 | 14.3 | 13.1 | 17.0 |
krelc | 1.0 | 13.7 | 95.3 | 0.1 |
To gain a quantitative understanding of the physical factors that are at the root of the trends in reactivity, we again turned to ASM. In Fig. 6a, the activation strain diagram highlights that the reduction in activation barrier height from COT to N-COT to O-COT cyclooctyne is driven by an increasingly stabilizing ΔEint term. Despite observing a more favorable interaction energy for the S-COT cyclooctyne at consistent geometry, this is offset by the considerable increase in activation strain (Fig. S9†). The larger atomic radius of the sulfur relative to oxygen allows the alkyne to be less bent i.e., less predistorted, and consequently, a greater structural deformation of the Δ∠(C–CC) is necessary at consistent geometry (Table S6†). Consequently, the reduced reactivity of S-COT towards the retro-Cope elimination reaction is attributed to the higher activation strain.
Our canonical EDA analyses (Fig. 6b) reveal that the more stabilizing ΔEoi is responsible for the progressively more stabilizing ΔEint term associated with the retro-Cope elimination reaction going from COT to N-COT to O-COT. The differences in the ΔVelstat curves are minimal, whereas the ΔEPauli shows a reverse trend to that of ΔEint and is, thus, not responsible for the more stabilizing interaction energy.
As the more stabilizing orbital interactions were identified as a key factor that dictated the enhanced reactivity of Y-COT, we screened all orbital donor–acceptor interactions associated with the retro-Cope elimination reactions of COT, N-COT, and O-COT at consistent geometry where the length of the forming C⋯H bond is 1.56 Å (Fig. S10†). The HOMODMHA–LUMOY-COT interaction was confirmed as the most important contributor. The KS-MO analyses at the consistent geometries reveal that it is the consistent lowering of the π*-LUMOalkyne of the Y-COT cyclooctyne that causes the more favorable orbital interactions between HOMODMHA and LUMOY-COT (Fig. 7). Because of the lowering of the the HOMODMHA–LUMOY-COT energy gap is reduced from Δε = 2.6 to 2.4 to 2.1 eV. The orbital overlap is minimally affected by substitution on the endocyclic propargylic position. As the changes in orbital overlaps remain limited, we can conclude that the enhanced orbital interactions of N-COT and O-COT in retro-Cope elimination reactions can directly be ascribed to the LUMOY-COT-lowering effect of the endocyclic propargylic substitution, which causes the smaller HOMODMHA–LUMOY-COT energy gaps.
Additionally, we propose modulations of the DIBO to employ the strong LUMO-lowering effect that is observed in DIBO. By replacing the two aryl rings by borabenzenes (DIBBO) and thiophenes (DITO) the reactivity was enhanced (relative to COT) by ΔΔE‡ = −3.7 and −6.5 kcal mol−1 with krel values of 1.7 × 102 and 3.5 × 103, respectively. Lastly, we added strongly electron withdrawing groups i.e., fluoro (F-COD) and trifluoromethyl (CF3-COD) substituents on a cycloocta-1,5-dien-3-yne (COD), significantly lowering the πin-plane-LUMO, without adding additional bulk in the vicinity of the triple bond. This resulted krel values of 2.2 × 103 and 4.0 × 103, respectively (Scheme 3).
Our activation strain and Kohn–Sham molecular orbital analyses identified the enhanced retro-Cope elimination reactivity upon predistortion of the alkyne (linear to cyclic) arises from a reduction in activation strain and a strengthening of stabilizing orbital interactions. Predistortion of the alkyne via cyclization induces a stabilization of the propyne π*-LUMOalkyne, which results in a smaller, more favorable HOMODMHA–LUMOalkyne gap and thus more stabilizing inverse electron demand (IED) orbital interactions. Appending the COT with fused cycles imparts additional predistortion of the alkyne, leading to even less activation strain and even more stabilizing IED orbital interactions. Decorating COT with exo- and endocyclic heteroatom substituents also stabilizes the π*-LUMOalkyne, and consequently further enhances the stabilizing IED orbital interactions.
A secondary effect is observed in the case of DIBO, a dibenzo-annulated cyclooctyne, which exhibits a more pronounced decrease in the activation strain that occurs at the consistent geometry, that is, a consistent point along the reaction coordinate (r(C⋯H)), relative to BCN (bicyclononyne). This can be related to the more slanted reaction path, where the formation of the C⋯N bond lags behind that of the C⋯H bond because of the following: Due to the twisted nature of DIBO, the πin-plane-HOMO of COT mixes in with the π-system of the benzene substituents, heightening the steric Pauli repulsion. The strong repulsive interaction is absorbed by adapting the reaction system to a more slanted reaction path. As a consequence, the overlaps are reduced, thereby lowering both the repulsive Pauli repulsion and the favorable orbital interactions. Notably, because of this more slanted reaction path, both reactants are less distorted at consistent geometry, causing a more pronounced decrease in the activation strain.
Our rational design principles allowed us to construct a priori a suite of novel bioorthogonal reagents that are highly reactive towards the retro-Cope elimination reaction with DMHA. Based on the judicious substitution of the parent COT, our novel reagents exhibit reactivities that are two to four orders of magnitude greater than COT.
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4sc04211e |
‡ These authors contributed equally to this work. |
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