A new postfunctionalization method was developed for the Anderson-type POM based on a nucleophilic substitution reaction occurring at an electrophilic sp3 hybridized carbon localized on the hybrid POM. Using this method, several types of different nucleophiles including primary and secondary amines, carboxylates, and thiolates were efficiently coupled to a chloride-functionalized Anderson-type POM in high yields and purity. The heterogeneous acetonitrile-Na2CO3 conditions were found to be superior over other bases and solvents for the coupling of amines and thiolates to the chloride-functionalized POM. Moreover, the addition of 1 equiv of tetrabutylammonium iodide as a catalyst drastically decreased the reaction times to 24 h for the complete coupling of amines and only a couple of hours for thiolates. In the case of carboxylic acids as substrates, using tetrabutylammonium hydroxide as the base for the reaction proved to be beneficial. This is because the resulting tetrabutylammonium carboxylates were found to be much more reactive than the corresponding sodium carboxylates and allowed homogeneous reaction conditions. Using sodium carbonate, only 25% of N-acetyl glycylglycine could be coupled after 24 h at 80 °C, while full conversion was achieved after the same reaction time when using tetrabutylammonium hydroxide as a base.