Steric Strain Research Articles

The H2Sxmacropa Series: Increasing the Chemical Softness of H2macropa with Sulfur Atoms to Chelate Radiometals [213Bi]Bi3+ and [203Pb]Pb2+ for Radiopharmaceutical Applications.

The effects of replacing nitrogen with sulfur atoms in the 18-membered macrocycle of the H2macropa chelator on the binding affinity and stability of "intermediate" (radio)metal [203Pb]Pb2+ and [213Bi]Bi3+ complexes are investigated. The 1,4,10,13-tetraoxo-7,16-diazacyclooctadecane backbone was replaced with derivatives containing sulfur in the 1,4- or the 1,4,10,13-positions to yield the novel chelators H2S2macropa (N4O4S2) and H2S4macropa (N4O2S4), respectively. Trends on the nat/203Pb- and nat/213Bi-complex stability constants, coordination chemistry, radiolabeling, and kinetic inertness were assessed via potentiometric titrations, UV-vis spectroscopy, NMR spectroscopy, X-ray crystallography and density functional theory (DFT) calculations. 1H-207Pb NMR spectroscopy confirmed the involvement of backbone S and/or O donors in the metal coordination sphere. Overall, the trend demonstrated that increasing the softness of the donor atoms within the ligand backbone decreased the thermodynamic stability and kinetic inertness of both the Pb2+ and Bi3+ complexes. Conversely, DFT calculations with mock compounds dimethyl ether (DME) and dimethyl sulfide (DMS) demonstrated enhanced affinity of the S atom to both Pb2+ and Bi3+ with DMS compared to DME evinced by large ΔG° values for both Pb2+ and Bi3+ complexes. The decreased stability of Pb/Bi-Sxmacropa (x = 0, 2, 4) upon increased sulfur atom incorporation may be a result of the increased steric strain within the macrocyclic backbone upon sulfur atom introduction. Nonetheless, [203Pb]Pb2+ and [213Bi]Bi3+ labeling (pH = 7, 30 min reaction time; 10-4-10-8 M chelator) resulted in both S2macropa2- and macropa2- attaining similarly high radiolabeling efficiency. Meanwhile, S4macropa2- only possessed the ability to complex [213Bi]Bi3+. Both [203Pb][Pb(macropa)] and [203Pb][Pb(S2macropa)] remained greater than 97% intact when challenged against human serum over 72 h. The results of this study reveal the effects of incorporating sulfur donor atoms into macrocyclic chelators for [203Pb]Pb2+ and [213Bi]Bi3+ radiopharmaceuticals.

Substituent effects on first generation photochemical molecular motors probed by femtosecond stimulated Raman.

Unidirectional photochemical molecular motors can act as a power source for molecular machines. The motors operate by successive excited state isomerization and ground state helix inversion reactions, attaining unidirectionality from an interplay of steric strain and stereochemistry. Optimizing the yield of the excited state isomerization reaction is an important goal that requires detailed knowledge of excited state dynamics. Here, we investigate the effect of electron withdrawing and donating substituents on excited state structure and ultrafast dynamics in a series of newly synthesized first generation photochemical molecular motors. All substituents red-shift the absorption spectra, while some modify the Stokes shift and render the fluorescence quantum yield solvent polarity dependent. Raman spectra and density functional theory calculations reveal that the stretching mode of the C=C "axle" in the electronic ground state shows a small red-shift when conjugated with electron withdrawing substituents. Ultrafast fluorescence measurements reveal substituent and solvent polarity effects, with the excited state decay being accelerated by both polar solvent environment and electron withdrawing substituents. Excited state structural dynamics are investigated by fluorescence coherence spectroscopy and femtosecond stimulated Raman spectroscopy. The time resolved Raman measurements are shown to provide structural data specifically on the Franck-Condon excited state. The C=C localized modes have a different substituent dependence compared to the ground state, with the unsubstituted motor having the most red-shifted mode. Such measurements provide valuable new insights into pathways to optimize photochemical molecular motor performance, especially if they can be coupled with high-quality quantum molecular dynamics calculations.

Relaxation of Steric Strains of TTR-Type Amyloid Fibril Inhibitors Radically Changes the Results of Their Virtual Screening

Relaxation of Steric Strains of TTR-Type Amyloid Fibril Inhibitors Radically Changes the Results of Their Virtual Screening

A Tale of Two Tails: Rotational Spectroscopy of N-Ethyl Maleimide and N-Ethyl Succinimide.

Broadband microwave spectra of N-ethyl maleimide (NEM) and N-ethyl succinimide (NES) have been recorded using chirped pulse Fourier transform microwave spectroscopy in the Ka-band (26.5-40 GHz). The spectra for both molecules were fit to a Watson A-reduced Hamiltonian in the Ir representation to obtain best fit experimental rotational constants (NEM: A0 = 2143.1988(29), B0 = 1868.7333(22), C0 = 1082.98458(36); NES: A0 = 2061.47756(14), B0 = 1791.73517(12), C0 = 1050.31263(11)), centrifugal distortion constants, and nuclear quadrupole coupling constants. While the heavy atoms of the five-membered ring of both molecules are planar, the ethyl chain has its terminal methyl group perpendicular to the ring. Along the relaxed potential energy curve for the ethyl dihedral angle (θ1 = C(6)-C(5)-N-C(4)), the ethyl group experiences significant steric strain when it is in the plane of the ring, associated with the interaction of the ethyl group with the two carbonyl oxygens. This leads to calculated barriers of θ1 = 1469 cm-1 and θ1 = 1680 cm-1 in N-ethyl maleimide and N-ethyl succinimide, respectively.

Helically Chiral π-Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States.

We report a synthetic approach to π-expanded [6]helicenes incorporating tropone and azocine units in combination with a 5-membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8-membered lactam, azocine, and amine units. As shown by X-ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high-performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near-infrared (NIR) absorption bands extending beyond 3000 nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Helically Chiral π‐Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States

AbstractWe report a synthetic approach to π‐expanded [6]helicenes incorporating tropone and azocine units in combination with a 5‐membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8‐membered lactam, azocine, and amine units. As shown by X‐ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high‐performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near‐infrared (NIR) absorption bands extending beyond 3000 nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Understanding the Role of Ligand Structure on Extraction of Neptunium by N-Pivot Tripodal Diglycolamides in an Ionic Liquid

ABSTRACT The extraction of Np4+ was studied by a series of N-pivot tripodal diglycolamides, with varying substituents (alkyl groups with varying branching and chain length) and varying spacer length, dissolved in an ionic liquid, i.e. [C4mim][Tf2N]. Out of a series of four ligands, L I (propylene spacer) and L II (ethylene spacer) differ only in the spacer length connecting the three diglycolamide units with the tripodal N platform. While L II – L IV have the same spacer length (ethylene spacer), but L II has a hydrogen atom, L III has methyl group, and L IV has isopropyl group as a substituent at the amidic N atom close to the central N atom. A reversal extraction mechanism of Np4+ was observed when the spacer chain length reduced from a propylene group in L I to an ethylene group in L II – L IV . While a cation-exchange mechanism was observed in case of L I , a solvation extraction mechanism was seen for the other three ligands with the extracted species being Np(NO3)2(L)2+ for L I , and [Np(NO3)4·L] for L II – L IV . The extraction efficiencies of Np4+ with L II – L IV were significantly affected by the nature of the alkyl substituents and follow the order: L II > L III > L IV . This trend in the extraction pattern affirms that the alkyl substitution at the amidic N atom creates steric strain in the ligand while complexing with the metal ion.

Stereospecific alkenylidene homologation of organoboronates by SNV reaction.

Concerted nucleophilic substitution, known as SN2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon-carbon and carbon-heteroatom bonds1. SN2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp3)-X bond (X = halogen or other leaving group), resulting in complete inversion of a stereocentre2. By contrast, the corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp2 vinyl electrophiles, namely concerted SNV(σ) reaction, is much rarer, and so far limited to carefully designed substrates mostly in ring-forming processes3,4. Here we show that concerted SNV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates. This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise. Further application to the synthesis of bioactive compounds containing multi-substituted alkenes is also demonstrated. Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction.

Characterization of Deformational Isomerization Potential and Interconversion Dynamics with Ultrafast X-ray Solution Scattering.

Dimeric complexes composed of d8 square planar metal centers and rigid bridging ligands provide model systems to understand the interplay between attractive dispersion forces and steric strain in order to assist the development of reliable methods to model metal dimer complexes more broadly. [Ir2 (dimen)4]2+ (dimen = para-diisocyanomenthane) presents a unique case study for such phenomena, as distortions of the optimal structure of a ligand with limited conformational flexibility counteract the attractive dispersive forces from the metal and ligand to yield a complex with two ground state deformational isomers. Here, we use ultrafast X-ray solution scattering (XSS) and optical transient absorption spectroscopy (OTAS) to reveal the nature of the equilibrium distribution and the exchange rate between the deformational isomers. The two ground state isomers have spectrally distinct electronic excitations that enable the selective excitation of one isomer or the other using a femtosecond duration pulse of visible light. We then track the dynamics of the nonequilibrium depletion of the electronic ground state population─often termed the ground state hole─with ultrafast XSS and OTAS, revealing a restoration of the ground state equilibrium in 2.3 ps. This combined experimental and theoretical study provides a critical test of various density functional approximations in the description of bridged d8-d8 metal complexes. The results show that density functional theory calculations can reproduce the primary experimental observations if dispersion interactions are added, and a hybrid functional, which includes exact exchange, is used.

Multifaceted effects of ring fusion on the stability of charged dialkoxyarene redoxmers

Due to their almost unlimited scalability, redox flow batteries can make versatile and affordable energy storage systems. Redox active materials (redoxmers) in these batteries largely define their electrochemical performance, including the life span of the battery that depends on the stability of charged redoxmers. In this study, we examine the effects of expanding the π-system in the arene rings on the chemical stability of dialkoxyarene redoxmers that are used to store positive charge in RFBs. When 1,4-dimethoxybenzene is π-extended to 1,4-dimethoxynaphthalene, a lower redox potential, improved kinetic stability, and longer cycling life are observed. However, when an additional ring is fused to make 9,10-dimethoxyanthracene, the radical cation undergoes rapid O-dealkylation possibly due to increased steric strain that drives methoxy out of the arene plane thus breaking the π-conjugation with O 2p orbitals. On the other hand, the planar structure of 1,4-dimethoxynaphthalene may facilitate second-order reactions of radical cations leading to their neutralization in the bulk. Our study suggests that extending the π-system changes reactivity in multiple (sometimes, opposite) ways, so lowering the oxidation potential through π-conjugation to improve redoxmer stability should be pursued with caution.

Fluorine-Containing Poly(Fluorene)-Based Anion Exchange Membrane with High Hydroxide Conductivity and Physicochemical Stability for Water Electrolysis.

Improving the hydroxide conductivity and dimensional stability of anion exchange membranes (AEMs) while retaining their high alkaline stability is necessary to realize the commercialization of AEM water electrolysis (AEMWE). A strategy for improving the hydroxide conductivity and dimensional stability of AEMs by inserting fluorine atoms in the core structure of the backbone is reported, which not only reduces the glass transition temperature of the polymer due to steric strain, but also induces distinct phase separation by inducing polarity discrimination to facilitate the formation of ion transport channels. The resulting PFPFTP-QA AEM with fluorine into the core structure shows high hydroxide conductivity (>159 mS cm-1 at 80°C), favorable dimensional stability (>25% at 80°C), and excellent alkaline stability for 1000h in 2m KOH solution at 80°C. Moreover, the PFPFTP-QA is used to construct an AEMWE cell with a platinum group metal (PGM)-free NiFe anode, which exhibits the current density of 6.86 A cm-2 at 1.9V at 80°C, the highest performance in Pt/C cathode and PGM-free anode reports so far and operates stably for over 100h at a constant current of 0.5 A cm-2.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp3-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD)2 or in situ reduction of Ni(II) salts. However, Ni(COD)2 is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.This Account chronicles the development of air-stable Ni(0) precursors as replacements for Ni(COD)2 or in situ reduction. Based on Schrauzer's seminal discovery of Ni(COD)(DQ) as an air-stable zerovalent organonickel complex, our research laboratories at Scripps Research and Bristol Myers Squibb have developed a class of precatalysts based on the Ni(COD)(EDD) (EDD = electron-deficient diene) framework, relying on the steric and electronic properties of the supporting diene to render the metal center stable to air, moisture, and even silica gel but reactive to ligand substitution and redox changes.The stable Ni(0) complexes can be accessed through ligand exchange with Ni(COD)2, through reduction of Ni(acac)2 using DIBAL-H, or electrochemically via cathodic reduction of Ni(acac)2 to Ni(COD)2, followed by addition of an EDD ligand in one pot. As a toolkit, the complexes demonstrate reactivity that is equivalent or enhanced compared to Ni(COD)2, catalyzing C-C and C-N cross-couplings, Miyaura borylations, C-H activations, and other transformations. Since the initial report on Ni(COD)(DQ), its reactivity in C(sp2)-CN activation, metallophotoredox, and electric field-induced cross-coupling have also been demonstrated.By incorporating the precatalyst toolkit into reaction discovery campaigns, our laboratories have been able to perform C(sp3)-S(alkyl) couplings and metallonitrenoid carboamination, both of which represent challenging transformations that were inaccessible with traditional phosphine, nitrogen, or electron-deficient olefin ligands. Computational and experimental studies demonstrate how the quinone ligands are hemilabile, adopting η1(O)-bound geometries to relieve steric strain or stabilize transition states and intermediates; redox-active, able to transiently oxidize the metal center; and electron-withdrawing or -donating, depending on metal oxidation state and coordination geometry. These studies show how the ligands enable key steps in catalysis beyond imparting air-stability.Since our report documenting the catalytic activity of Ni(COD)(DQ), many other laboratories have also observed unique reactivity with this precatalyst. Ni(COD)(DQ) was found to offer superior reactivity to Ni(COD)2 in C-N cross coupling to form N,N-diaryl sulfonamides and in preparation of biaryls from aryl halides and benzene through a Ni-mediated, base-assisted homolytic aromatic substitution.

Nitro-Enabled Atroposelective Dynamic Kinetic Resolution of 2-Arylindoles by Phase-Transfer Catalysis.

This study presents the atroposelective alkylation of 2-arylindoles catalyzed by a substituted cinchonium salt as a phase-transfer catalyst. Under the optimized reaction conditions, various substrates are employed to yield products with high enantioselectivity. The presence of an ortho-nitro group at the aromatic ring is essential for high atroposelectivity, because it facilitates favorable interactions between the catalyst and substrate. The origin of the enantioselectivity reveals favorable π-π interactions for both enantiomers and unfavorable steric strains for undesired enantiomers.

THERMOKINETIC DIMENSIONS OF RARE EARTH COMPLEXES OF ANTIPYRALDEHYDE SCHIFF BASES

Thermogravimetric investigations of rare earth complexes [Ln(3MPMAFA)2(NO3)3] and [Ln(4MPMAFA)2(NO3)3] have been performed. All the complexes have two decomposition stages, with the formation of the respective lanthanide oxide, Ln2O3, as the final residue. Using the Coats-Redfern approach, the kinetic aspects for each decomposition stage were assessed from the TG data. The lowering of the steric strain of intermediate molecules is due to the higher entropy of activation of the second phase decomposition than the first stage. The entropy of activation has positive values, which means that the decomposition products have lower-ordered structures than the initial constituents, which causes the reactions to proceed more quickly than normal. Using the many mechanistic equations proposed by Satava, the mechanisms for the decomposition reactions were computed.

Tetraquinolines; four linked quinoline units or porphyrinoids.

Tetraquinolines (TEQs) have been recently synthesized and proposed to be a new member of the porphyrinoid family with highly distorted, nonplanar, geometries. In this contribution by studying several molecules, closely related to TEQs, we have suggested that the origin of the nonplanarity of TEQs and their counterparts is a combination of steric strain and the propensity of the molecules to avoid antiaromaticity. The tendency of TEQs to coordinate with doubly charged metal ions can be interpreted in terms of their transition from potential antiaromaticity to nonaromaticity. Even metal-coordinated TEQs do not sustain diatropic ring currents. Although full planarization is not possible because of steric strain, doubly oxidized TEQs and their counterparts sustain moderate global diatropic ring currents and partially planarize. The nature of current density in the molecules is studied in the light of Steiner-Fowler selection rules.

Quantifying defects in carbon nanotubes undergoing prolonged electrochemical cycling with Raman phase map

Electrically conducting graphitic carbon materials are ubiquitous constituents of electrocatalysts and electrochemical energy storage materials. During electrolysis and electrochemical charge-discharge cycles, the carbon matrix is subjected to chemical stress due to drastic changes in the redox environment, the formation of reactive intermediate species and to steric strain caused by intercalation of counter ions. These factors trigger the formation of defects in the graphitic lattice, leading to scattering the charge carriers, thereby reducing the carrier mobility. It is of utmost importance to reliably monitor the graphitic lattice to maintain the integrity of the material and recognize the nature of defects. We have applied statistical Raman measurement technique in conjunction with Raman phase map and Raman ellipse to monitor and quantify the formation of point and line defects in functionalized carbon nanotubes. We also demonstrate how the Raman ellipse in combination with ID/ID′ is a new and powerful analytical tool which can serve to deduce the correct defect generation process in a graphitic lattice exposed to stress during electrochemical cycling. Thus, a deep mechanical insight by “simple” optical spectroscopy can be captured through our proposed Raman phase map analysis.

Intermolecular interaction-controlled novel azo dyes for use in the high-performance color conversion layers of microdisplays

We synthesized four novel red azo dyes for use in a low-temperature-cured white organic light-emitting diode color conversion layer. The various substituents were introduced into the synthesized dyes to induce steric strain within the base compound for enhancing their solubility. All synthesized dyes exhibited excellent maximum absorption peaks at 521 nm, and AR4, in particular, displayed the highest molar absorptivity of 42 500. Via optimal mixing, the synthesized dyes were used to form red color resists for use in microdisplay color conversion layers. As a white backlight was applied to the optimized spin-coated films, the AR3 and AR4 films, with large dihedral angles between their substituents and diazonium planes, exhibited excellent color coordinates and transmittances, as intermolecular aggregation was inhibited. The color resists fabricated using the AR3 and AR4 dyes also displayed clear micropatterning results, confirming their high compatibility with low-temperature curing binders for use in future display production.

Directed C−H Allylation of Aromatic Carboxamides with Allyl Aryl Ethers under Cp*Co(III)‐Catalysis

AbstractThe Cp*Co(III) C−H allylation of (hetero)arenes with allyl aryl ethers has been developed using an amide as directing group (24 examples). DFT calculations have shed light on the mechanistic course and reactivity pattern, showing that strong electron releasing groups favour the reaction by reducing the activation barrier of the rate‐determining C−H activation step. However, the steric strain can increase the energy of the migratory insertion step to the point of completely preventing the reaction, as in the case of the 3,5‐dimethylbenzamide. The obtained allylated compounds have been transformed into a variety of interesting heterocyclic and carbocyclic structures, such as isoquinolones and isochromanones.

Construction of Functionalized ortho‐Naphthoquinone Methides via Site‐Selective Ring Opening of 1‐Siloxy‐1,4‐epoxy‐1,4‐dihydronaphthalenes

Abstract1‐Siloxy‐4‐(benzyloxy)methyl‐1,4‐epoxy‐1,4‐dihydronaphthalenes, generated from benzynes and furans, underwent automatic site‐selective ring opening because of the synergetic effect of the steric strain of the 1,4‐epoxy moiety and the electron‐donating ability of the siloxy group on the acetal structure to afford the precursors of ortho‐naphthoquinone methides (o‐NQMs). Subsequent Lewis acid‐facilitated o‐NQM formation and annulation with olefins afforded multi‐fused heterocycles. Notably, the consecutive hexacyclic skeleton of rubioncolin B was constructed via solvent‐dependent regioselective annulation of naphthofuran derivatives.