Over the past two decades, borylation has emerged as a means of replacing the abundant inactive carbon-hydrogen bonds found in many feedstock chemicals. The hydrogen atom transfer (HAT) process can overcome the strong bond dissociation energy (BDES) of the inert C(Sp3)-H bond, thereby converting the raw alkanes into value-added fine chemicals. However, the high reactivity of the HAT reagent, combined with the small differences between the different C(Sp3)-H bond strengths, makes site-selective conversion of linear alkanes a great challenge.
Here,Professor Hu Peng of Sun Yat-sen University and othersA photocatalytic intermolecular radical sampling process in a substrate with small steric hindrance is proposed for iron-catalyzed boronylation of terminal C(Sp3)-H bonds, including non-branched alkanes. Mechanistic studies have shown that the reaction proceeds through a reversible HAT process followed by selective boroylation of carbon radicals, and the boron-sulfoxide complex may contribute to the observed high terminal regioselectivity.
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Background:
Chemists have long sought to efficiently and sustainably convert non-reactive feedstock alkanes into value-added fine chemicals through C-H bond functionalization. The emergence of transition metal catalysis has led to great progress in the functionalization of C(Sp2)-H bonds in aromatic compounds and C(Sp3)-H bonds in substrates with directional groups. Still, the direct modification of inert alkanes in a selective manner remains a major challenge, with only a few groundbreaking studies using *** catalysts reported. In addition, the reactivity of the C-H bond to the transition metal catalyst is often dependent on the corresponding bond acidity (Figure 1A), and the terminal alkyne and aromatic ring preferentially react with the alkane fragment, resulting in the restriction of the substrate to the functionalization of the C(Sp3)-H bond.
In contrast, the activity of the C-H bond pair homogeneous solution is mainly dependent on the dissociation energy (BDE) of the bond, with the C(sp3)-H bond having the lowest BDE level (Figure 1A). Thus, by activating the species, the cleavage of the C(Sp3)-H bond can be made partially compatible with aromatics, olefins, and even terminal alkynes by the HAT (Hydrogen Atom Transfer) process, while the C(Sp3)-H bond is cleaved to form an alkyl radical for further reaction. Although HAT is an essential mechanism in a variety of chemical, environmental, and biological processes, traditional HAT reactions often require the application of stoichiometric HAT precursors or harsh conditions. Intramolecularly, the HAT strategy has been used in matrices containing directed groups that can generate free radicals, facilitating cleavage of distal C-H bonds.
However, achieving intermolecular homogeneous resolution of C(sp3)-H bonds under mild conditions often requires the use of highly active HAT reagents, which often exhibit low regioselectivity and result in product mixtures. The slight difference in BDE values between the C(sp3)-H bonds is another reason for poor selectivity, although thermodynamically methylene or methyl groups represent the preferred reaction site due to their lower bond strength (Figure 1B). To address this long-standing problem, some ingenious studies have used substrates with C(sp3)-H bonds, with different steric hindrances or different electronic properties, to produce regioselective C(sp3)-H functionalized products. However, achieving selective modification of simple alkanes, especially end-functionalization of non-branched chains, is a great challenge (Figure 1B).
What to study
In this paper, two general pathways are considered to address the regioselective challenge of using n-hexane as a model molecule (Figure 1c). The first pathway involves a region-selective HAT, followed by functionalization. However, due to the difficulties noted earlier, this process has so far achieved only modest terminal selectivity. As an example, pioneering work has previously been reported on methylselective borylation at the end of a sterically hindered substrate that uses an in-situ formed chlorine radical-boron "acid" complex as a selective HAT catalyst. This approach abstracts the spatially unhindered c(sp3)-h bond and achieves unusual selectivity. However, when applied to straight-chain substrates such as pentane, this system exhibits unsatisfactory regioselectivity.
The second pathway begins with a non-selective HAT step that enables the formation of primary and secondary radicals, followed by a radical sampling procedure to enable the formation of terminal functionalized products. Non-reactive secondary radicals revert to substrate molecules by a reverse HAT reaction (Figure 1C), a strategy that appears to be more reliable when the system is able to distinguish between primary and secondary radicals based on steric hindrance. Ferric(III) chloride has been identified as a promising precursor for the generation of chlorine radicals through a photoinduced ligand-to-metal charge transfer (LMCT) process.
Figure 1Achieved in non-branched alkanes by HATc(sp3)-hKey selective challenges
Figure 2Range of simple substrates.
Figure 3Further applications.
Figure 4Mechanistic studies.
Figure 5The mechanism is further proposed
In summary, the regioselective c(sp3)-h boronylation of non-branched alkanes and substrates with different steric hindrances was achieved by ferric chloride photocatalysis. Unlike traditional metal-catalyzed methods, this method demonstrates the ability to selectively functionalize C(Sp3)-H bonds on C(Sp2)-H and C(Sp)-H bonds, showing a wide range of functional group tolerance. This strategy provides a simple and convenient method for the functionalization of regioselective C(sp3)-H bonds by HATs, especially for substrates with small steric hindrance challenges.
miao wang, yahao huang, peng hu*,terminal c(sp3)-h borylation through intermolecular radical sampling, science (2024).