Distal scaffold flexibility accelerates ligand substitution kinetics in manganese(I) tricarbonyls: flexible thianthrene versus rigid anthracene scaffolds.

This work investigates the effect of molecular flexibility on fundamental ligand substitution kinetics in a pair of manganese(I) carbonyls supported by scaffold-based ligands. In previous work, we reported that the planar and rigid, anthracene-based scaffold with two pyridine 'arms' (Anth-py2, 2) serves as a bidentate, cis donor set, akin to a strained bipyridine (bpy). In the present work, we have installed a more flexible and dynamic scaffold in the form of thianthrene (Thianth-py2, 1), wherein the scaffold in the free ligand exhibits a ∼130° dihedral angle in the solid state. Thianth-py2 also exhibits greater flexibility (molecular motion) in solution compared with Anth-py2, as evidenced by longer 1H NMR T1 times Thianthy-py2 (T1 = 2.97 s) versusAnth-py2 (T1 = 1.91 s). Despite the exchange of rigid Anth-py2 for flexible Thianth-py2 in the complexes [(Anth-py2)Mn(CO)3Br] (4) and [(Thianth-py2)Mn(CO)3Br] (3), respectively, nearly identical electronic structures and electron densities were observed at the Mn center: the IR of 3 exhibits features at 2026, 1938 and 1900 cm-1, nearly identical to the features of the anthracene-based congener (4) at 2027, 1936 and 1888 cm-1. Most importantly, we assessed the effect of ligand-scaffold flexibility on reactivity and measured the rates of an elementary ligand substitution reaction. For ease of IR study, the corresponding halide-abstracted, nitrile-bound (PhCN) cations [(Thianth-py2)Mn(CO)3(PhCN)](BF4) (6) and [(Anth-py2)Mn(CO)3(PhCN)](BF4) (8) were generated in situ, and the PhCN → Br- back-reaction was monitored. The more flexible 3 (thianth-based) exhibited ∼3-4× faster ligand substitution kinetics (k25 C = 22 × 10-2 min-1, k0 C = 43 × 10-3 min-1) than the rigid analogue 4 (anth-based: (k25 C = 6.0 × 10-2 min-1, k0 C = 9.0 × 10-3 min-1) on all counts. Constrained angle DFT calculations revealed that despite large changes in the thianthrene scaffold dihedral angle, the bond metrics of 3 about the metal center remain unchanged; i.e. the 'flapping' motion is strictly a second coordination sphere effect. These results suggest that the local environment of molecular flexibility plays a key role in determining reactivity at the metal center, which has essential implications for understanding the reactivity of organometallic catalysts and metalloenzyme active sites. We propose that this molecular flexibility component of reactivity can be considered a thematic 'third coordination sphere' that dictates metal structure and function.

Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins.

The strategic redesign of microbial biosynthetic pathways is a compelling route to access molecules of diverse structure and function in a potentially environmentally sustainable fashion. The promise of this approach hinges on an improved understanding of acyl carrier proteins (ACPs), which serve as central hubs in biosynthetic pathways. These small, flexible proteins mediate the transport of molecular building blocks and intermediates to enzymatic partners that extend and tailor the growing natural products. Past combinatorial biosynthesis efforts have failed due to incompatible ACP-enzyme pairings. Herein, we report the design of chimeric ACPs with features of the actinorhodin polyketide synthase ACP (ACT) and of the Escherichia coli fatty acid synthase (FAS) ACP (AcpP). We evaluate the ability of the chimeric ACPs to interact with the E. coli FAS ketosynthase FabF, which represents an interaction essential to building the carbon backbone of the synthase molecular output. Given that AcpP interacts with FabF but ACT does not, we sought to exchange modular features of ACT with AcpP to confer functionality with FabF. The interactions of chimeric ACPs with FabF were interrogated using sedimentation velocity experiments, surface plasmon resonance analyses, mechanism-based cross-linking assays, and molecular dynamics simulations. Results suggest that the residues guiding AcpP-FabF compatibility and ACT-FabF incompatibility may reside in the loop I, α-helix II region. These findings can inform the development of strategic secondary element swaps that expand the enzyme compatibility of ACPs across systems and therefore represent a critical step toward the strategic engineering of "un-natural" natural products.

CNS and CNP Iron(II) Mono-Iron Hydrogenase (Hmd) Mimics: Role of Deprotonated Methylene(acyl) and the trans-Acyl Site in H2 Heterolysis.

We report syntheses and H2 activation involving model complexes of mono-iron hydrogenase (Hmd) derived from acyl-containing pincer ligand precursors bearing thioether (CNSPre) or phosphine (CNPPre) donor sets. Both complexes feature pseudo-octahedral iron(II) dicarbonyl units. While the CNS pincer adopts the expected mer-CNS (pincer) geometry, the CNP ligand unexpectedly adopts the fac-CNP coordination geometry. Both complexes exhibit surprisingly acidic methylene C-H bond (reversibly de/protonated by a bulky phenolate), which affords a putative dearomatized pyridinate-bound intermediate. Such base treatment of Fe-CNS also results in deligation of the thioether sulfur donor, generating an open coordination site trans from the acyl unit. In contrast, Fe-CNP maintains a CO ligand trans from the acyl site both in the parent and dearomatized complexes (the -PPh2 donor is cis to acyl). The dearomatized mer-Fe-CNS was competent for H2 activation (5 atm D2(g) plus phenolate as base), which is attributed to both the basic site on the ligand framework and the open coordination site trans to the acyl donor. In contrast, the dearomatized fac-Fe-CNP was not competent for H2 activation, which is ascribed to the blocked coordination site trans from acyl (occupied by CO ligand). These results highlight the importance of both (i) the open coordination site trans to the organometallic acyl donor and (ii) a pendant base in the enzyme active site.

Substituent effects of N4 Schiff base ligands on the formation of fluoride-bridged dicobalt(ii) complexes via B-F abstraction: structures and magnetism.

We report the synthesis of two fluoride bridged cobalt(ii) dimers - [Co(µ-F)(pnN4-PhCl)2(OH2)(MeCN)](BF4)3 (1) and [Co(µ-F)2(pnN4-PhCl)2](BF4)2 (2) - and related complexes derived from propyl-bridged N4 Schiff base plus pyridine ligands. Notably, the bridging fluoride ion(s) emanate from B-F abstraction processes on the BF4 anions in the starting salt, [Co(H2O)6](BF4)2. Two types of bridging motifs are generated - mono-bridged (µ-F) or di-bridged (µ-F)2- synthetically differentiated by the absence or presence of pyridine, respectively, during metalation. The synergistic roles of pyridine and the (ClPh)N4 ligand in promoting B-F abstraction were clarified by the isolation and crystallization of the simple tetrakis-pyridine monomeric complex [Co(py)4(MeCN)2](BF4)2 (4) [no B-F abstraction]; subsequent addition of the (ClPh)N4 ligand to 4 resulted in formation of the dimeric, di-bridged complex 2. Omission of pyridine during metalation resulted in formation of the mono-bridged dimer 1. The bulky chlorophenyl substituents were obligate for B-F abstraction, as metalation of the unsubstituted N4 ligand resulted in the non-fluoride-bridged dimer, [Co(pnN4)3](BF4)4 (3). In magnetic studies, complexes 1 (µeff = 6.24µB, 298 K) and 2 (µeff = 7.70µB, 298 K) both exhibit antiferromagnetic (AFM) coupling, but to different extents. Temperature-dependent magnetic susceptibility measurements (SQUID, 2 → 300 K) reveal that the linearity of the mono-fluoride bridge in 1 [∠Co-F-Co = 159.47(11)°] results in very strong AFM coupling (J = -14.9 cm(-1)). In contrast, the more acute Co2F2 diamond core [∠Co-F-Co = 98.8(2)°, 99.1(2)°] results in a smaller extent of AFM coupling (J = -2.97 cm(-1)). Overall, the results indicate the 'non-innocence' of the BF4 counterion in cobalt(ii) chemistry, and dimers 1 and 2 affirm the effect of the geometry of the bridging fluoride ion(s) in determining the extent of AFM coupling.

"Criss-crossed" dinucleating behavior of an N4 Schiff base ligand: formation of a µ-OH,µ-O2 dicobalt(III) core via O2 activation.

We report the synthesis and structural characterization of a dicobalt(III) complex with a µ-OH,µ-O2 core, namely µ-OH,µ-O2-[Co(enN4)]2(X)3 [1(ClO4)3 and 1(BF4)3]. The dinuclear core is cross-linked by two N4 Schiff base ligands that span each cobalt center. The formally Co(III)-Co(III) dimer is formed spontaneously upon exposure of the mononuclear Co(II) complex to air and exhibits a ν(O-O) value at 882 cm(-1) that shifts to 833 cm(-1) upon substitution with (18)O2. The CV of 1(BF4)3 exhibits a reversible {Co(III)-Co(III)}↔{Co(III)-Co(IV)} redox process, and we have investigated the oxidized {Co(III)-Co(IV)} species by EPR spectroscopy (g = 2.02, 2.06; S = 1/2 signal) and DFT calculations.