Applications of 2-(Bromoalkyl)Benzaldehydes in Bioconjugation

-hydroxysuccinimide (NHS) esters for the selective modification of lysine and N-terminal amines, but most existing methods require auxiliary reagents or suffer from poor stability. We introduce 2-(bromoalkyl)benzaldehydes as a versatile class of reagents that react directly with primary amines in aqueous media without catalysts or reducing agents. The imine of the ortho-bromomethylbenzaldehyde undergoes rapid intramolecular cyclization to form isoindoles, enabling tandem coupling to maleimides through a Diels-Alder reaction and thereby labeling of proteins and oligonucleotides, albeit with limited stability in buffer. In contrast, ortho-bromoethyl analogues form stable isoquinolinium intermediates and the reagents exhibit markedly improved aqueous stability compared to NHS esters. Incorporation of alkyne or azide handles further allows CuAAC and SPAAC coupling, including a one-pot copper-free DNA-antibody conjugation. This modular platform enables mild, efficient, and durable labeling of proteins, oligonucleotides, and antibodies, providing a reagent-economical and broadly applicable strategy for bioconjugation in targeted therapeutics, molecular imaging, and nanoscale engineering.