Science: overturning textbook calcium can make benzene ring alkylate directly

The substitution of C-H bond of benzene is an important reaction in organic chemistry However, because benzene is an electron rich group, it has a high enough resistance to organic nucleophiles and is difficult to react with them In order to prepare alkylated benzene, Friedel crafts alkylation is the only choice The aromatic ring is easy to react with the electrophilic reagent However, the reaction 140 years ago has two main disadvantages: it can not connect the straight chain alkanes to the aromatic rings, and because the products of alkylation reaction will further react, some by-products that affect the yield will be produced In the past experience, benzene, as an electron rich molecule, was born to repel nucleophiles, which made it impossible to connect alkyl groups directly on the benzene ring by using nucleophiles The unique mechanism of benzocycloalkylation (source: Science) calcium plays an important role in biology and mineralogy But in organic chemistry, the role of calcium has been largely ignored and covered up due to the light of its cousin lithium and magnesium compounds Now, the direct alkylation of benzene ring, which was once considered as insurmountable, can be conquered by powerful organoalcium nucleophiles Michael Hill from the University of bath in the UK, together with Andrew Wilson, a doctoral student at the University of Sabatier in Toulouse, France, and Laurent Maron, a computational chemist, have found a new reaction: they use organic compounds of calcium to replace hydrides to make benzocycloalkylation without the use of more conventional electrophilic groups such as chlorides This surprising and serendipitous reaction demonstrates the unusual nucleophilic properties of calcium bound carbon Calcium not only breaks the defense of benzene ring, but also breaks the iron rule in the previous textbooks It is a subversive discovery Synthesis route of compound 6-9 (source: Science) Hill explained that the reason why organic calcium compounds can overcome various limitations and dominate the nucleophilic alkylation reaction is that calcium ion complexes can attack benzene nucleophilically, and can also reduce the electron density of the electron enriched aromatic ring, so that the next alkyl substituents can be transferred to the benzene ring, and the redundant hydrogen atoms can be removed from the ring, so as to To produce aromatic derivatives, such as ethylbenzene, having a linear alkane chain According to the crystal structure (source: Science) hill of compounds 6 and 7, it is a complete coincidence to find this abnormal chemical behavior of calcium At that time, Wilson was studying the reaction between calcium hydride and terminal alkenes to form alkyl calcium complexes But the reaction was slow, so he decided to heat it to 60 ° C to accelerate Unexpectedly, the reaction produced alkylbenzene They soon realized that it was the reaction between alkylcalcium in the reactor and benzene as the reaction solvent that could form alkylbenzene Hill and his colleagues are very confused They think the abnormal nucleophilic attack is either the experiment is polluted or the operation is faulty, or it will be a breakthrough discovery Maron and his team calculated and analyzed the response, confirming Hill's hunch Monitoring of the benzocycloalkylation reaction (source: Science) although Hill acknowledges that at present the reaction may have limited use for organic synthesis At present, organic calcium compounds are more sensitive to air, and there may be many limitations in large-scale use But based on the application of calcium, developing more organic calcium compounds and studying their applicability to this reaction may bring more surprises Now synthetic chemists need to be involved to expand the use of this method to see if it can be applied to other aromatic molecules such as toluene and naphthalene Because aromatic compounds play a very important role in modern chemistry, the application potential of this reaction is very huge Paper link: http://science.sciencemag.org/content/358/6367/1168 corresponding author: http://www.bath.ac.uk/chemistry/contacts/academics/michael_hill/