Transformation of aliphatic carbon (C)-hydrogen (H) bonds has become an increasingly powerful tool for efficient upgrading of chemical feedstocks and polymers as well as late-stage modification of bioactive compounds.
However, the selective functionalization of CH still has the following problems:
1. Selective functionalization of strong C(sp 3 )-H bonds ubiquitous in organic molecules remains challenging
Selective functionalization of strong C(sp 3 )-H bonds ubiquitous in organic molecules remains challenging. Although many elegant strategies exist to achieve efficient functionalization of aliphatic C-H bonds, systematic tuning of site selectivity is only possible in selected cases.
2. The selective, non-directional activation of primary CH bonds is still in its primitive stage
The reiodination reaction of C ( sp 3 ) – H functionalization can be achieved by using reagents or directing groups , but how to achieve adjustable site selectivity and overcome inherent substrate preference still needs to be studied, and the primary C – Research on selective, non-directional activation of H-bonds is still in its infancy.
3. The development of novel FRPs for organic synthesis is still an uncharted territory
Frustrated Lewis acid-base pairs (FLPs) can undergo one-electron transfer to generate free radical pairs (frustrated radical pairs, FRPs). FRPs may be useful reagents in chemical synthesis, but studies on FRPs so far have mainly focused on elucidating their Structurally and in terms of formation mechanism, their applications are still limited.
In view of this, the research group of Professor Lin Song from Cornell University and others demonstrated that the functionalization of C(sp 3 ) -H bonds can be achieved by a class of FRPs generated from diazide donors and N-oxoammonium acceptors. done . Together, these species undergo single-electron transfer, generating transient and persistent radical pairs capable of cleaving unactivated CH bonds to provide aminated products. By tuning the structure of the donor, regioselectivity and reactivity to tertiary, secondary, or primary bonds can be controlled. Mechanistic studies strongly support the formation and participation of free radical pairs in targeted reactions.
1. Introduce the development of FRPs and the FRPs in this paper
Frustrated free radical pairs (FRPs) are one-electron reactive, and here FRP, which consists of a transient hydrogen atom acceptor (HAA) and a persistent free radical trap generated by an oxidation-reductant pair, can provide multiple functional intermediate.
2. Explored the applicability of the method
The authors confirmed the applicability of FRPs on cycloalkanes, saturated heterocycles, silanes, phenyls, and a variety of complex substrates, demonstrating the broad substrate scope of this method.
3. Site-selective control by regulating HAA in FRPs
The authors confirmed that the selectivity comes from the steric hindrance of HMDS by changing the steric hindrance profile of HAA, the structure-selectivity relationship of different substrates is consistent, and this strategy has broader utility in distinguishing CH bonds.
4. Analyzing the reaction mechanism of FRPs
The authors performed a series of experiments to confirm the formation of FRPs and their role in the observed CH activation, showing the formation of carbon-centered radicals by HAT, and further understanding the nature of FRPs by DFT.
1. A new type of FRP is reported, which can realize the functionalization of C(sp 3 ) -H bond
The authors report a FRP consisting of a transient hydrogen atom acceptor (HAA) and a persistent radical trap generated by an oxidation-reductant pair for the functionalization of C(sp 3 )-H bonds .
2. Selective control can be achieved through structural regulation
By tuning the structure of the donor, the regioselectivity and reactivity to tertiary, secondary, or primary bonds can be controlled, providing strong support for the formation and participation of free radical pairs in targeted reactions.
Introduction to FRPs
Frustrated Lewis pairs (FLPs) are a well-established class of complexes comprising a strong electron acceptor (eg, borane) and a strong electron donor. Recent studies have shown that some typical FLPs can also form frustrated free radical pairs (FRPs) with one-electron reactivity through single-electron transfer (SET) reactions. Here we describe a FRP consisting of a transient hydrogen atom acceptor (HAA) and a persistent free radical trap generated by an oxidation-reductant pair. HAA is able to cleave strong aliphatic CH bonds, and persistent free radicals can quickly capture alkyl radicals subsequently formed on HAT. This reaction provides a versatile intermediate that can be further derivatized into synthetically useful products.
Explored the range of FRPs substrates
Next, the substrate scope of this method was explored for a variety of simple and complex compounds containing inert and activated CH bonds, showing that the aminoacylation of cycloalkanes proceeds well. The successful functionalization of α- or β-CH bonds in silanes provides a potential approach for the chemical modification of silicone polymers. A variety of electron-dissimilar arenes with phenyl CH bonds are also good substrates. In particular, the reaction tolerates useful functional groups such as halides, nitriles, trifluoromethyl, methyl esters, nitro, and aryl boroesters, as well as compounds including 2-methylfuran, rutin, and 1,3-dimethyl Heteroaromatics including pyrazoles. Allyl and propyl substrates yield higher yields. Furthermore, in saturated heterocyclic rings, the CH bonds of α to heteroatoms are selectively oxidized. This method also successfully functionalized cyclododecane on a gram scale with a 77% increase in yield. Finally, the reaction was demonstrated on structurally more complex substrates, such as (−)-ambromide derivatives, (+)-longifolene and the protected neomenthol, (−)-ambromide, Methyl dehydroabietate and biflavonoid analogues, etc.
The authors found that for certain substrates with multiple types of CH bonds, primary sites are preferentially functionalized over thermodynamically favored secondary and tertiary sites. The authors confirmed that the selectivity comes from the steric hindrance of HMDS by changing the steric hindrance spectrum of HAA. The structure-selectivity relationships of the different substrates are consistent, with HPDS· showing high selectivity for the most accessible CH bonds and tBuO· for the weakest CH bonds. For complex bioactive substrates, a clear shift in site selectivity was observed depending on base choice, suggesting broader utility of this strategy for discriminating CH bonds.
The authors performed a series of experiments to confirm the formation of FRPs and their role in the observed CH activation. After mixing the FRP precursors, the in situ formed TEMPO was detected by electron paramagnetic resonance (EPR) spectroscopy, clearly showing the electron transfer between all three base donors and TEMPO + . The role of radicals in the CH functionalization was further explored, showing the formation of carbon-centered radicals via HAT. Finally, using DFT calculations to help understand the properties of FRPs, two possible covalent complexes composed of TEMPO/HMDS pairs were identified. Insights from these mechanisms will serve as the basis for the strategic design and application of FRPs to address various other synthetic challenges.
In summary, the authors demonstrate that C(sp 3 )-H bonds can be functionalized by FRPs generated from diazide donors and N-oxoammonium acceptors . Through structural design, it is shown that adjusting the structure of the donor can control the regioselectivity and reactivity to tertiary, secondary or primary bonds, which provides an important support for the formation and participation of free radical pairs in the target reaction.