Privileged strategies for direct transformations of inert aliphatic C–H bonds

化学反应的本质是旧化学键断裂与新化学键生成，如何有效活化化学键并使其反应生成新化学键一直是合成化学的核心。传统合成科学依赖于活性官能团的相互转化。将从化石燃料中获得的简单碳氢化合物转化为具有活性官能团的起始原料往往需要苛刻的反应条件、冗长的合成步骤，并且会产生大量有害副产物。如果能够在温和的条件下高效、高选择性地实现碳氢（C–H）键的直接化学转化，则可以避免传统合成中对于原料繁琐的预官能团化步骤，大大提高反应的原子经济性和步骤经济性，实现提高生产效益和减轻环境污染的双赢目标，促进合成科学的革命性发展。 
无疑，C–H键官能团化有着明显的优势和应用潜力，但是，要实现这一目标却面临重重困难： 
 
(1) C–H键具有很高的键能，使得C–H键的断裂在热力学上是不利的； 
 
(2) 对特定C–H键的选择性官能团化相当困难; 
 
(3) C–H键官能团化后的产物往往比原料更加活泼，需要避免过度反应。由于该研究的重要性和挑战性，C–H键官能团化一直被誉为化学中的“圣杯” (The Holy Grails of Chemistry)。 
 
除了以上挑战外，对于活性很低的烷烃C(sp3)–H键，则还存在更大挑战：烷烃C–H键具有更高的键解离能以及更大的空间位阻，而且，由于没有如芳烃、烯烃（C(sp2)–H键）中存在的π-电子参与，烷烃C–H键与过渡金属的作用更加困难，对烷烃C–H键进行官能团化将面临更大阻力。尽管困难重重，在过去20年间，烷烃C–H键活化还是取得了巨大进步。各种活化策略的应用是该领域一直向前推进的主要动力。这些活化策略包括基于自由基过程的策略、基于卡宾、氮宾（乃春）的插入反应、基于过渡金属参与的活化方式。 
古老的自由基化学在化学家的操控下变得有用起来，底物控制的Hoffmann–Loffler–Freytag (HLF)反应、催化剂控制的Fenton和Gif反应、交叉脱氢偶联反应（Cross-Dehydrogenative Coupling，CDC）等基于自由基化学的反应都在近几年得到了长足的发展，而且，不少反应还应用在天然产物的合成过程中。 
卡宾、氮宾对烷烃C–H键的插入反应是迄今为止研究得最为深入的C–H活化方式之一。由于其广泛的底物类型以及成熟的不对称催化形式，该类型的反应在化学合成中已经得到了广泛应用。 
由于其丰富的种类以及多样的反应形式，过渡金属催化的C–H键活化一直是化学研究的重要分支。在过渡金属催化的C–H键活化领域，碳–金属键（C–M）的形成是反应的关键。因此，根据形成C–M的方法，过渡金属催化的C–H键活化又分为氧化加成、亲电取代、σ-复分解以及过渡金属促进的均裂四种类型。在这些反应中，除了氧化加成研究得较为成熟以外，其余三种都还处于初始阶段，尤其是σ-复分解和过渡金属促进的均裂，虽然从原理上可行，但是实际的研究成果还未见报道。 
可以说，虽然烷烃的C–H键活化具有很多传统方法无法比拟的优势，但是，其研究还处于发展阶段，我们还需要发展更多、更加有效的策略来实现烷烃的C–H键转化。

PERSPECTIVES progress in understanding the mechanisms of novel catalysts [9].
In environmental science and biomedicine, many experiments with particular features have been conducted by the SSRF users, and many interesting results have been obtained. These include studies on the distribution and transport mechanisms of toxic elements and chemical compounds in rice and vegetables [10], and the mechanism of arsenic adsorption in industrial waste water [11]. In addition, studies on high-resolution imaging of mouse lungs [12], cardiocerebral vasculature and tumor tissue are paving the way for clinical applications of medical imaging. Industrial applications have also shown an encouraging upward trend. Gaining benefits from their research at SSRF into new drug development, chemical engineering and chemical identification techniques, more than 30 enterprises have used SSRF for their research and development activities to this point.
Even with only seven beamlines in operation, the SSRF is playing an important role in supporting thousands of users in various fields. The Phase-I beamlines are using only a small portion of the capacity of the SSRF, which can be optimized to accommodate up to 60 beamlines. This huge potential is being explored and developed to promote the innovation capability in many fields of science and technology in China. Programs developing more beamlines have already been underway for a few years, and the construction of five new beamlines dedicated to protein science and one high-performance beamline dedicated to quantum functional materials are approaching completion, while the construction of another two beamlines dedicated to the research of new energy materials has already begun. A large cluster of new beamlines, the so-called SSRF Phase-II beamline project, have been proposed. Phase-II project aims at promoting the overall performance and experimental capability of the SSRF to the world leading level, and to better meet national strategic needs and important scientific challenges. When the SSRF Phase-II beamline project will be completed, which is projected to be by 2020, the SSRF will be a highly advanced platform supporting cutting-edge user research and forming one of the world's most important photon science centers. Functional group transformations are central to organic synthesis. Traditionally, the functionalities used in such transformations are highly active organic groups such as halogens, ester groups and hydroxyl groups. Carbon-hydrogen bonds are ubiquitous structural motifs in organic compounds, but they are not considered to be functional groups because (1) in general, the bond dissociation energy of a C-H bond is high, and therefore, such bonds are thermodynamically hard to break; and (2) the selective activation of one C-H bond among many similar and different C-H bonds in one organic molecule is difficult. However, direct C-H transformations, which could be used to perform synthetic chemistry in a greener and more atom-economical way, is highly appealing. The importance and challenges of this field make it one of the 'Holy Grails' of chemistry [1,2].
In the last few decades, direct C(sp 2 )-H activation of (hetero)arenes and some alkenes has been extensively investigated. Many examples and applications of such activations in organic synthesis have been reported. Some progress has also been made in achieving the direct transformation of relatively active benzylic and allylic C-H bonds. In contrast, less effort has been devoted to the activation of 'inert' aliphatic C-H bonds of alkyl groups, because the challenge is greater. The acidity of an alkyl C(sp 3 )-H bond is lower than those of other C-H bonds, making the cleavage of such bonds much more difficult. Also, the lack of a π-system adjacent to a C(sp 3 )-H bond makes their interactions with reagents weak. As a result of the efforts of several generations of chemists, significant progress has been made in the direct transformation of inert aliphatic C-H bonds. This perspective summarizes effective strategies for achieving this goal, with some representative examples.

RADICAL PROCESSES
As a result of the development of petroleum chemistry and traditional organic transformations, the photo-and thermo-induced direct halogenation of aliphatic C-H bonds via radical pathways is well known. Unfortunately, this is not an ideal organic reaction and has not been widely used in organic synthesis because of its poor selectivity. Significant efforts have been made to overcome this problem. An improved radical process, the Hoffmann-Loffler-Freytag (HLF) reaction, is probably the best-known radical reaction for constructing C-N bonds in organic synthesis. It is usually used for the synthesis of nitrogen-containing cycles and has even been successfully used in natural product chemistry, as shown in Scheme 1 [3].
Fenton and Gif chemistry is a powerful and much-used process in both synthetic chemistry and wastewater treatment. White and co-workers made significant contributions to organic synthesis in the oxidation of aliphatic C-H bonds with Fe II catalysts on nitrogen-containing ligand supports. High regioselectivity was obtained in complex molecular syntheses (Scheme 2) [4]. Yang [5] and Baran [6] showed the oxidation of independent aliphatic C-H bonds, using various peroxides as the oxidant.
Cross-dehydrogenative coupling is another good example in green chemistry of the construction of C-C bonds from two C-H bonds. Usually, a transitionmetal catalyst and a peroxide are used to perform such transformations, mainly through radical processes [7]. Recent advances in the promotion of such transformations under metal-free conditions PERSPECTIVES have made them more environmentally benign [8].
Radical processes are still the most powerful strategy for functionalizing aliphatic C-H bonds. The development of new techniques and new systems will make such strategies more controllable and useful in the near future.

CARBENE AND NITRENE INSERTIONS
Carbene/nitrene insertion in aliphatic C-H bonds is another well-studied and reliable method for direct conversion of C-H to C-C and C-N bonds [9,10]. Since the first report of this type of reaction by Meerwein in 1942, carbene and metallocarbenoid chemistry has developed rapidly. In 1982, Wenkert's and Taber's groups both reported that Rh 2 (OAc) 4 is an effective catalyst for C-H insertion reactions. Since then, Doyle, Davies and others have made significant contributions, especially in enantioselective control, using well-designed chiral ligands.
The properties of nitrenes and metallonitrenoids are similar to those of carbenes and metallocarbenoids, and C-N bonds can be constructed through C-H insertion. In 1968, Breslow and Solan first reported the insertion of a nitrene into cyclohexane by heating a mixture of dichloroamine-T and Zn in cyclohexane. Later, many groups became involved in nitrene chemistry, and it was found that carbamate/sulfamate esters combined with I III are the best nitrogen sources. Both inter-and intra-Scheme 4. Borylation and silylation via C-H activation. molecular C-N bond formation can be achieved, even enantioselectively. Such insertions have also been used in the total synthesis of natural products such as tetrodotoxin (Scheme 3) [11], showing the potential of this method for future applications.

TRANSITION-METAL-MEDIATED C-H CLEAVAGE
Transition-metal-mediated C-H cleavage and further stoichiometric and catalytic transformations represent another powerful method for direct C-H bond transformations. Because the formation of C-M intermediates is key to the reaction, the process is referred to as C-H activation rather than C-H transformation. In this strategy, oxidative addition, electrophilic substitution, σ -bond metathesis and transition-metal-promoted homolysis are the four major pathways.

Oxidative addition
Since the first two studies independently reported by Bergman and Graham in 1982, the oxidative addition of aliphatic C-H bonds to low-valent-transitionmetal complexes has become one of the major pathways for aliphatic C-H bond cleavage. Crabtree and Felkin showed that this important process could be used in hydrogen transfer from alkanes to alkenes. Hartwig and co-workers performed such transformations catalytically to build up C-B and C-Si bonds, leading to further advances in this area of chemistry (Scheme 4) [12,13]. However, σ -bond metathesis is also a possible pathway in catalytic transformations. This chemistry potentially provides a green method for the direct functionalization of hydrocarbons to valuable chemicals. The regulation of the distribution of mixed alkanes to produce valuable petroleum products is another useful application of this method.

Electrophilic metalation
Shilov and co-workers developed a method for the conversion of methane to methanol, using a high-valent metal catalyst, thus is known as the Shilov system. The key intermediate, Me-Pt, is formed by electrophilic substitution of a C-H bond with a Pt IV catalyst, and is then oxidized to C-O bonds in the presence of appropriate oxidants. It was later found that many other metals can also be used in this transformation, for example, Pd, Hg, Cu and Au [14].
In the late 1990s, this chemistry was extended to the independent aliphatic C-H bonds of functionalized molecules. Pt plays a valuable role in the oxidative lactonization of amino acids (Scheme 5) [15]. Recently, Pd was shown to be useful in this field. Remote aliphatic C-H bonds can be catalytically transformed to C-C, C-O and C-N bonds, using directing groups or intramolecular initiators. Most importantly, various chiral ligands can be used to achieve asymmetric transformations, leading to a new area of Pd chemistry, other than cross coupling. The characteristics of this transformation suggest that it takes place via a concerted proton abstraction pathway, known as CMD (concerted metalation-deprotonation).

σ -Bond metathesis
Compared with the two abovementioned pathways, σ -bond metathesis has been well studied theoretically, but it has not been widely used in organic synthesis. Only one successful example has been reported, by Tilley and co-workers, showing the direct hydromethanation of isobutene. However, this reaction is still little studied because the turnover number of the transformation is too low for the reaction to be useful. We believe that it could provide a potential strategy for transforming unfunctionalized molecules into valuable chemicals, and therefore should be paid increased attention.

Transition-metal-promoted homolysis
The transition-metal-promoted homolysis of aliphatic C-H bonds is, in principle, possible, and this has been proved experimentally. However, no examples supporting its use in organic synthesis have been reported. This process is complicated, because two metal centers are needed to cleave one C-H bond, and C-M and H-M intermediates are both formed; it therefore needs to be further developed.

CONCLUSION AND OUTLOOK
Direct C(sp 3 )-H functionalization is undoubtedly one of the most challenging and promising areas of organic synthesis. Much research continues to be devoted to achieving this goal, and many significant contributions have been made in this field. It is important to note that several successful and elegant strategies have been developed and used in organic synthesis. However, compared with traditional organic transformations, this area is still less well studied, and much research is still needed. For example, more reliable, cheaper and more efficient processes for potential applications are desirable [16]. The development of efficient asymmetric catalytic systems is also challenging [17].
Developing new strategies for functionalizing independent aliphatic C-H bonds is highly desirable, and there are many challenges and opportunities in this area for chemists. We believe that the efforts of several generations of chemists will lead to exciting developments, making organic synthesis greener and more environmentally benign.