Unsubstituted Parent Research Articles

Theoretical Study of the Isotope Effect in Optical Rotation.

In this work, the isotope effect in optical rotation (OR) is examined by exploring structure-property relationships for H → D substitutions in chiral molecules. While electronic effects serve as the dominant source of optical activity, there is a non-negligible contribution from nuclear vibrations, which changes with isotopic substitution. We employ a test set of 50 small organic molecules: three-membered rings with varying heteroatoms (PCl, PH, S, NCl, NH, O, and NBr) and functional groups (Me, F), and simulations were run at the B3LYP/aug-cc-pVDZ level of theory. The objectives of this work are to determine locations of isotopic substitution that result in significant changes in the vibrational correction to the OR and to evaluate which vibrational modes and electronic response are the major contributors to the isotope effect. Molecules with more polarizable heteroatoms in the ring (e.g., S and P) have the largest change in the vibrational correction compared to the unsubstituted parent molecules. In many cases, isotopic substitution made to the hydrogens on the opposite side of the ring from the functional group provides the largest change in the OR. H/D wagging modes and C vibrations (for D-C centers) are the largest contributors to the isotope effect. This is explained with a molecular orbital decomposition analysis of the OR. The relevant vibrational modes affect the orbital transitions that are already significant at the equilibrium geometry. However, this effect is only large when polarizable heteroatoms are involved because the electron density surrounding them is diffuse enough to feel the subtle effect of change in mass due to isotopic substitution on the relevant vibrational modes.

Enhanced Catalytic Activity of Binuclear Oxidovanadium(IV) Bisbenzimidazole Linked Porphyrin Dimer for the Generation of Biologically Active 3,4-Dihydropyrimidinones and Their Corresponding Thiones.

Binuclear vanadyl(IV) porphyrin (V2BP), where two vanadium(IV) porphyrin macrocycles are linked through benzimidazole units at the β-positions, has been prepared and characterized with various techniques, such as UV-vis, Fourier transform-infrared, electron paramagnetic resonance, cyclic voltammetry, density functional transform calculations, and mass spectrometry. V2BP exhibits a red shift (Δλmax = 10 nm) in the Soret band as compared with unsubstituted parent vanadyl(IV) meso-tetraphenylporphyrin (VP). The synthesized binuclear vanadyl(IV) porphyrin (V2BP) has further been studied as a catalyst to explore a single-pot multicomponent Biginelli reaction producing biologically active 3,4-dihydropyrimidin-2-(1H)-one (DHPM)-based biomolecules and the corresponding thiones under solvent-free conditions and its catalytic activity has been compared with vanadyl(IV) meso-tetraphenylporphyrin (VP). Several reaction conditions, such as the amount of catalyst, time, solvent, and temperature, have been optimized to obtain the maximum yield of DHPMs or thiones. The synthesized β-functionalized V2BP porphyrin dimer manifests much higher conversion (84-95% yield) of DHPMs or the corresponding thiones under the optimized reaction conditions with high TON (4454-5037) and TOF (1113-1259 h-1) values for the one-pot multicomponent Biginelli reaction as compared to the literature. The catalyst exhibited excellent recyclability up to 10 cycles.

Effect of β-fluorinated porphyrin in changing selectivity for electrochemical O2 reduction

The development of catalytic systems that selectively convert O2 to water is required to progress fuel cell technology. As an alternative to platinum catalysts, derivatives of iron and cobalt porphyrin molecular catalysts provide one benchmark for catalyst design. However, the inclusion of these catalysts into homogeneous platforms remains a difficulty. Co-porphyrins have been studied as heterogeneous O2 reduction catalysts; however, they have not been explored much in homogeneous systems. Moreover, they suffer from poor selectivity for the desired four-electron reduction of O2 to H2O. Herein, we present two cobalt-based β-fluorinated porphyrin complexes (CoTPF8(OH)2 and CoTPF8(OH)4) and demonstrate applicability as effective catalysts for the oxygen reduction reaction. Using rotating ring-disk electrochemistry, the catalysts, CoTPF8(OH)2 and CoTPF8(OH)4, showed maximum Faradaic efficiency for H2O of 92 % and 97 %, respectively. DFT calculations suggest that the formation of a phlorin intermediate could occur before O2 reduction and that a stronger H2O2 binding in the cobalt-based β-fluorinated porphyrin species compared to the unsubstituted parent compound, CoTP(OH)2, was responsible for the observed experimental selectivity for H2O. These results reveal that the β-fluorinated porphyrin catalyst serves as a novel platform for investigating molecular electrocatalytic reactions.

DFT mechanistic study on the synthesis of 2-fluorinated allylic scaffolds via PdII-catalyzed defluorinative arylation of gem-difluorocyclopropanes with phenylboronic acids

DFT calculations were conducted to understand the mechanism details and the Z/E-, regio-, and chemoselectivities observed in the synthesis of 2-fluorinated allylic scaffolds through PdII-catalyzed defluorinative arylation of gem-difluorocyclopropanes with arylboronic acids. The reaction is determined to proceed sequentially through oxidative addition, β-F elimination, two consecutive transmetalations, and reductive elimination. The β-F elimination dictates the Z/E-selectivity, primarily influenced by steric effects, while the reductive elimination step controls the regioselectivities, driven by electronic effects. The second transmetalation process serves as the bottleneck process with a free energy barrier of 26.5 kcal/mol. The chemoselective preference for gem-difluorocyclopropane over its corresponding chloride and its unsubstituted parent is attributed to the stronger electron-withdrawing capability of the F substituent compared to Cl and H, which polarizes the C1-C3 bond more than chlorine or hydrogen, making it easier to break.

Pressure‐Dependent “Insulator–Metal–Insulator” Behavior in Sr‐Doped La3Ni2O7

AbstractRecently, superconductivity at high temperatures is observed in bulk La3Ni2O7−δ under high pressure. However, the attainment of high‐purity La3Ni2O7−δ single crystals remains a formidable challenge. Here, the crystal structure and physical properties of single crystals of Sr‐doped La3Ni2O7 synthesized at high pressure (20 GPa) and high temperature (1400 °C) are reported. Through single crystal X‐ray diffraction, it is shown that high‐pressure‐synthesized paramagnetic Sr‐doped La3Ni2O7 crystallizes in an orthorhombic structure with Ni─O─Ni bond angles of 173.4(2)° out‐of‐plane and 175.0(2)°and 176.7(2)°in plane. The substitution of Sr alters in band filling and the ratio of Ni2+/Ni3+ in Sr‐doped La3Ni2O7, aligning them with those of “La3Ni2O7.05”, thereby leading to significant modifications in properties under high pressure relative to the unsubstituted parent phase. At ambient pressure, Sr‐doped La3Ni2O7 exhibits insulating properties, and the conductivity increases as pressure goes up to 10 GPa. However, upon further increasing pressure beyond 10.7 GPa, Sr‐doped La3Ni2O7 transits back from a metal‐like behavior to an insulator. The insulator–metal–insulator trend under high pressure dramatically differs from the behavior of the parent compound La3Ni2O7−δ, despite their similar behavior in the low‐pressure regime. These experimental results underscore the considerable challenge in achieving superconductivity in nickelates.

Tailoring the Photophysical Properties of a Homoleptic Iron(II) Tetra N-Heterocyclic Carbene Complex by Attaching an Imidazolium Group to the (C∧N∧C) Pincer Ligand─A Comparative Study.

We here report the synthesis of the homoleptic iron(II) N-heterocyclic carbene (NHC) complex [Fe(miHpbmi)2](PF6)4 (miHpbmi = 4-((3-methyl-1H-imidazolium-1-yl)pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) and its electrochemical and photophysical properties. The introduction of the π-electron-withdrawing 3-methyl-1H-imidazol-3-ium-1-yl group into the NHC ligand framework resulted in stabilization of the metal-to-ligand charge transfer (MLCT) state and destabilization of the metal-centered (MC) states. This resulted in an improved excited-state lifetime of 16 ps compared to the 9 ps for the unsubstituted parent compound [Fe(pbmi)2](PF6)2 (pbmi = (pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) as well as a stronger MLCT absorption band extending more toward the red spectral region. However, compared to the carboxylic acid derivative [Fe(cpbmi)2](PF6)2 (cpbmi = 1,1'-(4-carboxypyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)), the excited-state lifetime of [Fe(miHpbmi)2](PF6)4 is the same, but both the extinction and the red shift are more pronounced for the former. Hence, this makes [Fe(miHpbmi)2](PF6)4 a promising pH-insensitive analogue of [Fe(cpbmi)2](PF6)2. Finally, the excited-state dynamics of the title compound [Fe(miHpbmi)2](PF6)4 was investigated in solvents with different viscosities, however, showing very little dependency of the depopulation of the excited states on the properties of the solvent used.

Double axial stabilization of a carbenium ion via convergent PO → C+ tetrel bonding.

Our efforts in carbocation chemistry have led us to target examples of such species stabilized intramolecularly by tetrel bonding. Described here is an example of such a compound in which a triaryl carbenium is stabilized intramolecularly by two convergent PO → Ccarbenium interactions, as confirmed by structural studies. The formation of this new motif favorably impacts the reversibility of the first and second reduction of the carbenium center. It also has profound influence on the Lewis acidity of the carbenium center which is lower than that of the unsubstituted parent carbenium by seven orders of magnitude.

Synthese und Charakterisierung eines stabilen Nickelocenium‐Dikation‐Salzes

AbstractWir berichten über die Synthese und Charakterisierung der Nickelocenium‐Kationen [NiCp2]⋅+ und [NiCp2]2+ als deren [F‐{Al(ORF)3}2]− (Cp = C5H5; RF=C(CF3)3) Salze. Das diamagnetische [NiCp2]2+ ist das erste Beispiel für die Isolierung eines unsubstituierten Metallocen Dikations. Beide Salze wurden durch Reaktion von neutralem NiCp2 mit [NO]+[F‐{Al(ORF)3}2]− in 1,2,3,4‐Tetrafluorbenzol (4FB) erzeugt. Die Salze konnten durch Einkristall‐Röntgenbeugung charakterisiert werden, wobei kürzere Metall‐Ligand‐Bindungslängen für das höher geladene Salz gemessen wurden. Pulver‐Röntgenbeugung zeigte, dass die Salze phasenrein erhalten wurden. Cyclovoltammetrie in 4FB ergab quasi‐reversibel Redoxwellen bei −0.44 (0→1) und +1.17 V (1→2) gegen Fc/Fc+. Das 1H NMR von [NiCp2]2+ weist ein Singulett bei 8.6 ppm auf, während das paramagnetische [NiCp2]⋅+ deutlich Hochfeld auf −103.1 ppm verschoben ist.

Synthesis and Characterization of a Stable Nickelocenium Dication Salt.

We report the synthesis and characterization of the nickelocenium cations [NiCp2 ]⋅+ and [NiCp2 ]2+ as their [F-{Al(ORF )3 }2 ]- (Cp = C5 H5 ; RF =C(CF3 )3 ) salts. Diamagnetic [NiCp2 ]2+ represents the first example for the isolation of an unsubstituted parent metallocene dication. Both salts were generated by reacting neutral NiCp2 with [NO]+ [F-{Al(ORF )3 }2 ]- in 1,2,3,4-tetrafluorobenzene (4FB). The salts were characterized by single crystal X-ray diffraction (XRD), indicating shorter metal-ligand bond lengths for the higher charged salt. Powder XRD shows the salts to be phase pure, cyclic voltammetry in 4FB gave quasi reversible redox waves at -0.44 (0→1) and +1.17 V (1→2) vs Fc/Fc+ . The 1 H NMR of [NiCp2 ]2+ is a singlet at 8.6 ppm, whereas paramagnetic [NiCp2 ]⋅+ is significantly shifted upfield to -103.1 ppm.

Iminoboranes With Parent B=NH Entity: Imino Group Metathesis, Nucleophilic Reactivity and N-N Coupling.

While R2 C=N-R double bonds in organic imines are well established, the related iminoboranes R-B=N-R are either prone to oligomerization or can only be stabilized at sufficient steric congestion. In particular, the examples of unsubstituted parent B=N-H entity are rare. We demonstrate that the amino imidazoline-2-imine ligand system (HAmIm) not only gives rise to the isolation of a parent (AmIm)B=N-H iminoborane, but also to species of type (AmIm)B=N-SiMe3 with concomitant stabilization by lithium bromide. The double bond character in these systems is unambiguously corroborated by DFT calculations. The steric accessibility of the (AmIm)B=NH unit allows facile reactivity including metathesis reactions with C=O and C=S bonds, nucleophilic addition toward organic and organometallic carbonyl compounds, but also oxidative N-N coupling within a dimeric unit. Thus, the chemical behavior of the (AmIm)B=N-H and (AmIm)B=N-SiMe3 is distinctly different from that of organic imines.

Molecular pyramids - from tetrahedranes to [6]pyramidanes.

The study of 3D architectures at a molecular scale has fascinated chemists for generations. This includes molecular pyramids with all-carbon frameworks, such as trigonal, tetragonal and pentagonal pyramidal geometries. A small number of substituted tetrahedranes and all-carbon [4]-[5]pyramidanes have been experimentally generated and studied. Although the hypothetical unsubstituted parent [3]-[6]pyramidanes have only been explored computationally, the formal replacement of carbon vertices with isolobal main group element fragments has provided a number of examples of stable hetero[m]pyramidanes, which have been isolated and amply characterized. In this Review, we highlight the synthesis and chemical properties of [3]-[6]pyramidanes and summarize the progress in the development of chemistry of pyramid-shaped molecules.

Structure-affinity relationships of stereoisomers of norbenzomorphan-derived σ2R/TMEM97 modulators

The sigma 2 receptor (σ2R), which is identical to transmembrane protein 97 (TMEM97), is attracting increasing interest as a possible therapeutic target for various indications in neuroscience. In continuation of a program to identify novel compounds that bind with high affinity and selectivity to σ2R/TMEM97, we performed structure-affinity-relationship (SAfiR) studies of several sets of σ2R/TMEM97 ligands having a B-norbenzomorphan ring core. Binding data for σ2R/TMEM97 and σ1R of several enantiomeric pairs of piperazine-substituted norbenzomorphans show the (1S,5R)-enantiomers have affinities (Ki = 9–75 nM) for σ2R/TMEM97 that are 2–3-fold higher than their enantiomorphic (1R,5S)-analogs; however, there is no clear trend for selectivity for σ2R/TMEM97 vs σ1R. A series of N-alkyl piperazino (1S,5R)-norbenzomorphans was then evaluated, and with the exception of compounds having N-alkyl groups substituted with oxygen or amino groups at C (2) of an ethylene chain, Ki values for σ2R/TMEM97 are less than 25 nM, and several compounds have good selectivities (ca 7–16-fold) for σ2R/TMEM97 vs σ1R. Mono-substituted carbobenzyloxy analogs have Ki values for σ2R/TMEM97 comparable to the unsubstituted parent (Ki = ca 7–27 nM), but replacing the N-acyloxy group with N-acyl or N-arylsulfonyl groups provides analogs having lower affinity and selectivity. Some congeners with bioisosteric replacements of the piperazine group on the (1S,5R)-norbenzomorphan core have high affinity (Ki = <30 nM) for σ2R/TMEM97, but selectivities are modest. Computational docking studies for racemic pairs of piperazino norbenzomorphans show that individual (1S,5R)- and (1R,5S)-enantiomers adopt distinct poses upon binding to σ2R/TMEM97, whereas ligands belongingto the same enantiomeric series adopt closely similar binding poses. The protonated amino group in each of the enantiomorphic ligands engages in highly conserved salt bridges with Asp29 and cation-π interactions with Tyr150 that are the primary determinants of binding affinity. There is no correlation between any of the computational parameter outputs and Ki values, but this is unsurprising given the small energetic differences involved. Modeling also suggest sthat some compounds can extend deeper into σ2R/TMEM97 binding pocket forming salt bridges with Glu73.

Tuning the Photophysical Properties and Photostability of Bis(naphthobipyrrolylmethene) Derived BODIPY via Functionalization.

A series of NIR absorbing and emitting, naphthobipyrrole derived BODIPY dyes are reported. These dyes possess different functional groups viz. -CHO, -CN, -NO2 , -Br and Ph at its α,α'-positions. All the derivatives were characterized thoroughly via various spectroscopic means as well as single-crystal X-ray structural analyses. Impacts of functionalization on its photophysical properties as well as photostability were evaluated. For instance, incorporation of the phenyl moieties at the α, α'-positions by Suzuki coupling of the dibromo-derivative 4 with phenyl boronic acid led to substantial bathochromic shift in absorption (762 vs 727 nm) and emission (778 vs 744 nm) relative to the unsubstituted parent dye VI. Theoretical calculations have been performed by ground state optimization to evaluate the electronic transitions which supports experimental observation.

Triple Thorpe-Ingold Effect in the Synthesis of 18-Membered C3 Symmetric Lactams Stacking as Endless Supramolecular Tubes.

Three C3 symmetric macrolactams were very efficiently cyclized from their linear precursors. Adequately located substituents are responsible for the enhancement of reactivity that is not observed in the unsubstituted parent. DFT calculations show that the properly folded cyclization precursor, the reactive conformer, is more populated than other conformers, leading to a decrease of free energy of activation. The crystal structure of the ring substituted with three very bulky esters indicates that tubular stacking is preserved.

Synthesis and Spectroscopic Characterization of the Four Complete Series [(C5XnH5‐n)Fe(CO)2R] (X= Cl, Br; R= Me, Ph; n= 1–5). Molecular and Crystal Structures of [(C5X5)Fe(CO)2R

AbstractThe complete series of chloro‐ and bromo‐cyclopentadienyl carbonyl complexes [(C5XnH5‐n)Fe(CO)2R] (n=1–5, R=Me, Ph) could be prepared from the unsubstituted parent compounds via a sequence of lithiations and electrophilic halogenations. All four pentahaloyclopentadienyl complexes were studied by X‐ray diffraction and show an interplay of weak intermolecular X…X, X…O and X…H interactions.

Effect of chemical structure on the microbial nitrification inhibition and copper corrosion inhibition properties of azole compounds

Azoles are a class of nitrogen-containing heterocyclic compounds that are widely used as metal corrosion inhibitors in different industrial processes and consumer products. These compounds are severely inhibitory towards microorganisms responsible for nitrification and can impair the efficiency of biological nitrogen removal in wastewater treatment plants. This study assessed the effect of chemical structure on the toxicity of simple azole compounds towards microbial nitrification with the aim of identifying substitution patterns leading to decreased inhibition. Nitrification inhibition by the widely used azoles, pyrazole and 1,2,4-triazole, and several of their derivatives with dimethyl-, diethyl-, carbonyl-, amino substituent groups was studied. The results indicated that, while pyrazole and 1,2,4-triazole were severely inhibitory towards nitrification, addition of dimethyl- and diethyl-substituents greatly lowered the toxicity response of these compounds. The fifty percent inhibition concentrations (IC50) of pyrazole and 1,2,4-triazole were very low, 0.07 and 0.11 mg L−1, respectively, indicating a high level of inhibition. In contrast, nitrification inhibition by the dimethyl- and diethyl-substituted azoles was at least 30–700 times lower compared to the unsubstituted parent compounds, and in the best case, 3,5-diethyltriazole was found to be completely non-toxic. Preliminary evaluation of the corrosion inhibition efficiency of the alkyl-substituted azole compounds under alkaline conditions was conducted electrochemically. All the azoles tested were able to inhibit copper corrosion to a significant extent. For the pyrazoles, the corrosion inhibition performance improved with the addition of dimethyl- and diethyl-substituents. The inhibition efficiency by pyrazole, 3,5-dimethylpyrazole and 3,5-diethylpyrazole was 71.5, 77.6 and 85.0%, respectively, with respect to the control with no inhibitor. In the case of triazoles, the corrosion inhibition efficiency was slightly lower for the alkyl-substituted triazoles (77.7% for 3,5-dimethyl-1,2,4-triazole and 82.9% for 3,5-diethyl-1,2,4-triazole) than for the unsubstituted 1,2,4-triazole (89.6%). An important implication of these results is the possibility of replacing conventional azole compounds by their non-toxic substituted counterparts in industrial applications. This would prevent inhibition of microbial nitrification without compromising the efficacy of the azoles as inhibitors of copper corrosion.

Platinum(II)-Substituted Phenylacetylide Complexes Supported by Acyclic Diaminocarbene Ligands.

We introduce phosphorescent platinum aryl acetylide complexes supported by tert-butyl-isocyanide and strongly σ-donating acyclic diaminocarbene (ADC) ligands. The precursor complexes cis-[Pt(CNtBu)2(C≡CAr)2] (4a-4f) are treated with diethylamine, which undergoes nucleophilic addition with one of the isocyanides to form the cis-[Pt(CNtBu)(ADC)(C≡CAr)2] complexes (5a-5f). The new compounds incorporate either electron-donating groups (4-OMe and 4-NMe2) or electron-withdrawing groups [3,5-(OMe)2, 3,5-(CF3)2, 4-CN, and 4-NO2] on the aryl acetylide. Experimental HOMO-LUMO gaps, estimated from cyclic voltammetry, span the range of 2.68-3.61 eV and are in most cases smaller than the unsubstituted parent complex, as corroborated by DFT. In the ADC complexes, peak photoluminescence wavelengths span the range of 428 nm (2a, unsubstituted phenylacetylide) to 525 nm (5f, 4-NO2-substituted), with the substituents inducing a red shift in all cases. The phosphorescence E0,0 values and electrochemical HOMO-LUMO gaps are loosely correlated, showing that both can be reduced by either electron-donating or electron-withdrawing substituents on the aryl acetylides. The photoluminescence quantum yields in the ADC complexes are between 0.044 and 0.31 and the lifetimes are between 4.8 and 14 μs, a factor of 1.8-10× higher (for ΦPL) and 1.2-3.6× longer (for τ) than the respective isocyanide precursor (ΦPL = 0.014-0.12, τ = 2.8-8.2 μs).

Tracking historical sources of polycyclic aromatic compounds (PACs) in dated lake sediment cores near in-situ bitumen operations of Cold Lake, Alberta

Most bitumen in the Alberta oil sands (Canada) is extracted by thermal in-situ recovery. Despite the widespread use of in-situ bitumen extraction, little information is available on the release of petroleum hydrocarbons by this method to adjacent land and water. Here we analyzed the composition and abundance of parent and alkylated polycyclic aromatic compounds (PACs) in 11 radiometrically-dated lake sediment cores collected near in-situ operations at Cold Lake Alberta to assess potential petroleum contamination sources to surrounding lakes over the past century. Like open-pit mining areas, alkylated PACs in Cold Lake sediments were elevated compared to unsubstituted parent PACs and increased coeval with the onset of bitumen extraction in the area. Diagnostic ratios and pyrogenic indices showed that PAC sources to these lake sediments were dominantly pyrogenic, likely from historic forest fires, however they shifted to more petrogenic sources coeval with expanding oil sands extraction at Cold Lake. PACs in sediment from regional lakes are weakly correlated to their proximity to in-situ oil wells, once corrected for lake area. These results suggest that in-situ operations, via diesel-fueled vehicular emissions and the combustion of natural gas for steam generation, are a source of PACs to nearby lakes, but PACs did not exceed Canadian sediment quality guidelines for the protection of aquatic life.

Comprehensive Computational Investigation of the Barton-Kellogg Reaction for Both Alkyl and Aryl Systems.

The course of the Barton-Kellogg (BK) reaction for alkyl- and aryl-substituted substrates has been investigated at the DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D/def2-TZVPP level of theory, with results compared to available experimental kinetic data. Through comparison with the unsubstituted parent system, the preference for the formation of 1,3,4-dihydrothiadiazole over the isomeric 1,2,3-dihydrothiadiazole was observed to result from reduced steric repulsion in the relevant transition-state structure. Nitrogen extrusion [retro-(3 + 2)-cycloaddition] from the intermediate dihydrothiadiazole was found to be the rate-determining step. The barrier for this process was, however, significantly lower for aromatic substrates, which is consistent with the difficulty in isolating aryl-substituted dihydrothiadiazoles. The electronic structure of the transient thiocarbonyl ylide was also investigated, highlighting the contradictory results from wave-function theory- and density functional theory-based methods. Correlation of unrestricted natural orbital eigenvalues with previous experimental models suggested that the dipole intermediates possess low diradical character and are therefore considered to be closed-shell species. Exergonic conrotatory electrocyclization of the dipole led to sterically congested thiirane products, even for very bulky systems (di-t-butyl). These results complement the recent work of Mlostoń et al. Finally, DLPNO-CCSD(T)//ωB97X-D was found to be a reliable method for estimating the feasibility of the BK reaction, which should assist experimentalists in the selection of viable substrates.

Attenuation of the Reaction of Michael Acceptors with Biologically Important Nucleophiles.

β-Elimination of drugs tethered to macromolecular carbamates provides a platform for drug half-life extension. However, the macromolecular Michael acceptor products formed upon drug release can potentially react with biological amines and thiols and may raise concerns about safety. We desired to mitigate this possibility by developing linkers that have predictable rates of β-elimination but suppressed rates of nucleophilic addition to their Michael acceptor products. We prepared Michael acceptor products of β-eliminative linkers that contained a methyl group at the Cβ carbon or a gem-dimethyl group at the Cγ carbon and studied the kinetics of their reactions with the most prevalent biological nucleophiles-amine and thiol groups. Aza-Michael reactions with glycine are slowed about 20-fold by methylation of the β-carbon and 175-fold with a gem-dimethyl group at the γ-carbon. Likewise, addition of the glutathione thiol to γ-gem-dimethyl Michael acceptors was retarded 7-24-fold compared to parent unsubstituted linkers. It was estimated that in an in vivo environment of ∼0.5 mM macromolecular thiols or ∼20 mM macromolecular amines-as in plasma-the reaction half-life of a typical Michael acceptor with a γ-gem-dimethyl linker could exceed 3 years for thiols or 25 years for amines. We also prepared a large series of γ-gem-dimethyl β-eliminative linkers and showed excellent structure-activity relationships of elimination rates with corresponding unsubstituted parent linkers. Finally, we compared the first-generation unsubstituted and new gem-dimethyl β-eliminative linkers in a once-monthly drug delivery system of a 39 amino acid peptide. Both linkers provided the desired half-life extension of the peptide, but the Michael acceptor formed from the gem-dimethyl linker was much less reactive. We conclude that the γ-gem-dimethyl β-eliminative linkers provide high flexibility and greatly reduce potential reactions of Michael acceptor products with biologically important nucleophiles.