A tetrafunctional site-directed reagent for protein modification has the potential for introducing specific cross-links by reaction at two of its four reactive sites. The remaining reactive groups on the link within the protein an available for further reaction with added reagents. The first example of such a designed multifunctional crosslinker, 3,5,3’,5’-biphenyltetracarbonyl tetrakis(3,5-dibromosalicylate), BTDS (1), was prepared by treatment of the tetra tert-butyl ester with trifluoroacetic acid. The ester was from reaction of the acid chloride of biphenyl 3,5,3’,5’-tetracarboxylic acid with tert-butyl-3,5-dibromosalicylate. BTDS contains four anionic sites each adjacent to four electrophilic sites, The reaction of BTDS with deoxy human hemoglobin A generates in high yield the biphenyl bis carboxamide at the epsilon-amino of lysine-82 of each of the beta subunits (BBS-Hb). The remaining ester groups from the biphenyl cross-link are available iv react with other nucleophiles, This is demonstrated by efficient reaction with ethylenediamine. The use of multifunctional cross-linkers presents opportunities for introduction of probes and bioactive materials.