Traugott Sandmeyer (September 15, 1854 – April 9, 1922) was a Swiss chemist after whom the Sandmeyer reaction, which he discovered 1884, was named. Sandmeyer was born as the last of seven children and attended school in Aarau, studying to become a precision mechanic. His friend, J. Gustav Schmidt, studied chemistry at the Polytechnikum of Zurich (ETH), and their cooperation in conducting experiments led to Sandmeyer’s close contact with chemistry.
In 1882 Sandmeyer was made a chemistry lecturer at the ETH by Viktor Meyer. Meyer and Sandmeyer collaborated in studying the synthesis of thiophene, which Meyer had discovered earlier. When Meyer moved to the University of Göttingen, Sandmeyer followed, but then returned to Zürich after a year to work with Arthur Rudolf Hantzsch.
Sandmeyer began his career in the industry in 1888 with Johann Rudolf Geigy-Merian, who was the owner of the chemical factory J. R. Geigy & Cie (later Ciba Geigy, now Novartis). Sandmeyer was involved in the development of several dyes and invented a new synthesis for indigo.
What is Sandmeyer reaction?
The “Sandmeyer Reaction” is a versatile method for replacing the amine group of a primary aromatic amine with a number of different substituents. The amine is treated with “nitrous acid” (HNO2) under acidic conditions, which produces the diazonium ion. The diazonium can then undergo substitution reaction with various reactants, particularly copper(I) substrates. Although the substitution can be simplistically viewed as a direct ionic substitution
reaction (anion as a nucleophile, molecular N2 as a premier leaving the group), the actual mechanism is actually more complicated and involves radicals.
In an acid-base reaction such as
CH3CO2H + NH3 → CH3CO2– + NH4+
the N acts as a nucleophile (Greek for “loving the nucleus), the H acts as an electrophile (“loves electrons”), and the O that accepts the pair of electrons acts as a leaving group. The acid-base reaction is the simplest model for a substitution reaction, which is a reaction in which a σ bond between atom 1 and atom 2 is replaced by a σ bond between atom 1 and atom 3. Substitution reactions are incredibly important in organic chemistry, and the most important of these involve substitutions at C.
This substitution reaction, discovered in 1849, involves the nucleophilic O making a new bond to the electrophilic C, and the bond between the electrophilic C and the leaving group I breaking. Any Brønsted base can also act as a nucleophile, and any nucleophile can also act as a Brønsted base, but some compounds are particularly good bases and particularly poor nucleophiles, whereas some are particularly poor bases and particularly good nucleophiles.
Any Brønsted or Lewis acid can also act as an electrophile, but there are many electrophiles that are neither Brønsted nor Lewis acids (as in the example above). A haloalkane, e.g. CH3CH2Br, can in principle undergo either of two
polar reactions when it encounters a lone pair nucleophile, e.g. MeO–. First, MeO– might replace Br– at the electrophilic C atom, forming a new C–O bond and giving an ether as the product. This is a substitution reaction because the C–Br σ bond is replaced with a C–O σ bond.
Substitution reactions involve the replacement of one atom or group (X) by another (Y):
RA + B —> RB + A
Reactions of this type proceed by radical-chain mechanisms in which the bonds are broken and formed by atoms or radicals as reactive intermediates. This mode of bond-breaking, in which one electron goes with R and the other with X, is called homolytic bond cleavage:
R X + Y. – X . + R : Y
This is an example of a homolytic substitution reaction.
There are a large number of reactions, usually occurring in solution, that does not involve atoms or radicals but rather involve ions. They occur by heterolytic cleavage as opposed to homolytic cleavage of el~ctron-pair bonds.
In heterolytic bond cleavage, the electron pair can be considered to go with one or the other of the groups R and X when the bond is broken.
This method provides an effective route for the preparation of aromatic bromides and chlorides. Addition of cold aqueous solution of diazonium chloride to a solution of CuCl in HCl medium gives a sparingly soluble complex which is separated and heated to give aryl chloride or bromide by decomposition.
The Trifluoromethylating Sandmeyer Reaction
The presence of fluorine-containing substituents can impart favorable properties to organic molecules. On one hand, they increase the metabolic stability of important pharmaceutical compounds, thus reducing dosing rates in patients. On the other hand, they can improve switching times and broaden the working temperature ranges in LCD devices. Perhaps even more critical to supporting the basic needs of an evergrowing population, is the use of fluorine substituents to tune the rates and selectivities in agrochemical products, thus leading to both reduced quantities of material required and increasing the reliability and yield of the desired crop per unit area of precious arable land. Owing to these desirable benefits there has been a recent surge in interest to improve the range of methods available for introducing monofluoromethyl, difluoromethyl, and trifluoromethyl appendages to C, O, N, and S atoms, typically through a late-stage coupling or alkylation, and this has also necessitated the development of new reagents for permitting mild transformations.
Diazonium salts are readily prepared from aromatic amines (anilines) by treatment with nitrous acid in hydrochloric acid:
Ar NH2 + HONO/HCl —> ArN2+ Cl– + 2H2O
Diazonium salts are weak electrophiles and will react with aromatic rings bearing electronic rich substituents (usually OH or NR2) to give colored diazo compounds which form the basis of a huge dyestuff industry.
However, the formation of dyestuffs is again electrophilic substitution. Treatment of diazonium salts with cuprous chloride [Cu(I)Cl] or cuprous bromide [Cu(I)Br] or cuprous cyanide [Cu(I)CN] leads to aryl chlorides, bromides and cyanides respectively. Collectively, these reactions are named after the chemist who discovered them, Sandmeyer.
The mechanism of Sandmeyer reaction is believed to
involve radical intermediates:
ArN2+ X– + CuX —> Ar. + N2 + CuX2
Ar. + CuX2 —> ArX + CuX
A similar reaction occurs with KI (CuI is too insoluble for these reactions):
ArN2+ X– + I– —> Ar. + N2 + I. + X
Ar. + I. —> ArI
Analogous reactions (although mechanistically somewhat more complicated, they also appear to be radical reactions) also occur with NaNO2 and SO2:
ArN2+ X– + NaNO2 + cat. CuX —> ArNO2 + N2 + NaX
ArN2+ Cl– + SO2 + cat. CuCl/HCl —> ArSO2Cl + N2
Finally, the diazonium salts may also be reduced by a radical mechanism to give the parent hydrocarbon.
In the case when hypophosphorous acid (H3PO2) is used as the reductant the reaction proceeds through a phosphorus-centred radical.
All these reactions (except replacement of N2 by H) represent ways of making these aromatic compounds other than by electrophilic substitution. the scope of potential starting materials has been dramatically increased. The groups of Wang, Gooßen, and Fu have reported the CN to CCF3 transformation using a trifluoromethylating Sandmeyer reaction, as outlined herein. The general approach seeks to convert an aromatic amine into the requisite diazonium salt before treatment with a suitable metal and trifluoromethyl source.
Low temperatures were necessary to ensure good conversions and yields, which is likely a result of the relative instability of diazonium chloride salts, however diazo tetrafluoroborate salts, which are considered more stable (and typically isolable) were less reactive under these low-temperature conditions. The reaction procedure tolerates electron-withdrawing and electron-donating groups, vinyl and alkynyl substituents, as well as boronic esters and silyl moieties. Mechanistic studies were conducted and strongly suggest that the reaction does not operate by a radical mechanism. The authors hypothesize instead that high-valent silver species mediate an oxidative addition, reductive elimination pathway.
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