Because free cysteine rarely occurs on protein surface, it is an excellent choice for chemoselective modification. Under basic condition, the cysteine residues will be deprotonated to generate a thiolate nucleophile, which will react with soft electrophiles, such as maleimides and iodoacetamides (shown in the first two reactions in Figure 2 below). As a result, a carbon-sulfur bond is formed. Another modification of cysteine residues involves the formation of disulfide bond (shown in the third reaction in Figure 2). The reduced cysteine residues react with exogenous disulfides, generating new a disulfide bond on the protein. An excess of disulfides is often used to drive the reaction, such as 2-thiopyridone and 3-carboxy-4-nitrothiophenol. Electron-deficient alkynes were demonstrated to selectively react with cysteine residues of proteins in the presence of other nucleophilic amino acid residues. Depending on the alkyne substitution, these reactions can produce either cleavable (when alkynone derivatives are used), or hydrolytically stable bioconjugates (when 3-arylpropiolonitriles are used; the last reaction below in Figure 2).