Some isocyanides convey less offensive odours such as malt, natural rubber, creosote, cherry or old wood. Non-volatile derivatives such as tosylmethyl isocyanide do not have an odor. Toxicity While some isocyanides (e.g., cyclohexyl isocyanide) are toxic, others "exhibit no appreciable toxicity for mammals". Referring to ethyl isocyanide, toxicological studies in the 1960s at Bayer showed that "oral and subcutaneous doses of 500-5000 mg/kg can be tolerated by mice". Synthesis Many routes to isocyanides have been developed. From formamides Commonly, isocyanides are synthesized by dehydration of formamides. The formamide can be dehydrated with toluenesulfonyl chloride, phosphorus oxychloride, phosgene, diphosgene, or the Burgess reagent in the presence of a base such as pyridine or triethylamine. The formamide precursors are, in turn, prepared from amines by formylation with formic acid or formyl acetyl anhydride.or from the Ritter reaction of alkenes (and other sources of carbocations) and hydrogen cyanide. From dichlorocarbene In the carbylamine reaction (also known as the Hofmann isocyanide synthesis) alkali base reacts with chloroform to produce dichlorocarbene. The carbene then converts primary amines to isocyanides. Illustrative is the synthesis of tert-butyl isocyanide from tert-butylamine in the presence of catalytic amount of the phase transfer catalyst benzyltriethylammonium chloride. As it is only effective for primary amines this reaction can be used as a chemical test for their presence. Silver cyanide route Of historical interest but not often of practical value, the first isocyanide, allyl isocyanide, was prepared by the reaction of allyl iodide and silver cyanide. RI + AgCN → RNC + AgI Other methods Another route to isocyanides entails deprotonation of oxazoles and benzoxazoles in the 2-position. The resulting organolithium compound exists in chemical equilibrium with the 2-isocyanophenolate, which can be captured by an electrophile such as an acid chloride. Reactions Isocyanides have diverse reactivity. Isocyanides are stable to strong base (they are often made under strongly basic conditions), but they are sensitive to acid. In the presence of aqueous acid, isocyanides hydrolyse to the corresponding formamides: This reaction is used to destroy odorous isocyanide mixtures. Some isocyanides can polymerize in the presence of Lewis and Bronsted acids. Isocyanides participate in many multicomponent reactions of interest in organic synthesis, two of which are: the Ugi reaction and the Passerini reaction. Isocyanides also participate in cycloaddition reactions, such as the [4+1] cycloaddition with tetrazines. Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyls or gives stable