A modular autonomous flow reactor combining monitoring technologies with a feedback algorithm is presented for the synthesis of the natural product carpanone. The autonomous self-optimizing system, controlled via MATLAB, was designed as a flexible platform enabling an adaptation of the experimental setup to the specificity of the chemical transformation to be optimized. The reaction monitoring uses either online high pressure liquid chromatography (HPLC) or in-line benchtop nuclear magnetic resonance (NMR) spectroscopy. The custom-made optimization algorithm derived from the Nelder-Mead and golden section search methods performs constrained optimizations of black-box functions in a multidimensional search domain, thereby assuming no a priori knowledge of the chemical reactions. This autonomous self-optimizing system allowed fast and efficient optimizations of the chemical steps leading to carpanone. This contribution is the first example of a multistep synthesis where all discrete steps were optimized with an autonomous flow reactor.

Starting from either K2PtCl4 or K[PtCl3(C2H4)]•H2O (Zeise's salt), complexes (nBu4P)2[PtBr4] (1), nBu4P[PtBr3(C2H4)] (2), nBu4P[PtBr3(PhNH2)] (3), trans-[PtBr2(C2H4)-(PhNH2)] (4), cis-[PtBr2(C2H4)(PhNH2)] (5), and cis-[PtBr2(PhNH2)2] (6) have been obtained by efficient one-pot procedures. All have been fully characterized by microanalysis (C, H, N), multinuclear NMR spectrometry ( 1 H, 13 C, 195 Pt), UV-visible spectroscopy, and single crystal Xray diffraction. Compound 1 slowly loses Brin solution to yield (nBu4P)2[Pt2Br6] (1'), which has also been characterized crystallographically. The relative stability of the various compounds has been probed experimentally by NMR studies in several solvents and computationally by gas phase geometry optimizations followed by C-PCM calculations of the solvation effects in dichloromethane and aniline. The calculations also included the bis(ethylene) complexes [PtBr2(C2H4)2] in the trans (two different conformations 7 and 7') and cis (8) configurations.The solution experiments gave no evidence for a nucleophilic attack of aniline onto coordinated ethylene under mild conditions (T up to 68°C), setting a lower limit of 29 kcal mol -1 for the activation barrier of this process. Therefore, the relative energies computed for the other compounds suggest that all ethylene-containing complexes (2, 4, 5, 7 and 8) are viable candidates for the key nucleophilic addition step of the PtBr2-catalyzed ethylene hydroamination by aniline. Use of the isolated complexes 2, 4 or 5 in combination with nBu4Br as precatalysts for the ethylene hydroamination by aniline yields similar catalytic activities.