A new electron-deficient aromatic-based coupling reagent, tetrafluorophthalonitrile (TFPN), designed according to the concept of dual coupling reagents, is developed to facilitate amide and peptide bond formation in a one-pot, two-step manner. This reaction proceeds through an aryl ester of carboxylic acids and a subsequent fluoride exchange of the generated aryl ester. The TFPN reagent is successfully used not only for electron-deficient or sterically hindered amides but also for peptide synthesis from natural and unnatural sterically hindered amino acids in excellent yield without racemization. Remarkably, the robustness of TFPN-mediated peptide formation is showcased incisively by the synthesis of the pentapeptide neurotransmitter Leu-enkephalin. Moreover, the synthesis of “difficult peptides”, N-methyl and α,α-disubstituted amino acid modification peptides and acyl carrier protein (ACP, 65-74), is achieved on a feasible solid support, suggesting that the TFPN coupling reagent is compatible with solid-phase peptide synthesis (SPPS). The TFPN reagent combines the advantage of coupling reagents and active esters while avoiding their disadvantage and inspires new ideas for the design of peptide coupling reagents. The bench stability, low cost, and ready availability of TFPN make it a practical choice for amides and peptides, especially for challenging amide and peptide bond formation.