Linear Extension of Carbaporphyrin Chromophores: Synthesis, Protonation, and Metalation of Anthro[2,3-b]carbaporphyrins: Evidence for 30π-Electron Aromatic Circuits in a Palladium(II) Complex.

Acid-catalyzed condensation of a naphtho[2,3-f]indane dialdehyde with a tripyrrane, followed by an oxidation step, afforded an anthro[2,3-b]-21-carbaporphyrin. The presence of a fused anthracene unit induced minor bathochromic shifts and did not significantly affect the aromatic characteristics of the carbaporphyrin core. Protonation led to the formation of a monocation with similar diatropic properties, but the dication generated in the presence of a large excess of trifluoroacetic acid had a weakened Soret band absorption and a broad absorption at 754 nm. Nucleus-independent chemical shift (NICS) calculations indicate that the dication is only weakly aromatic and possesses a 32-atom 30π electron delocalization pathway. Alkylation with methyl iodide and potassium carbonate gave a 22-methyl derivative that reacted with palladium(II) acetate to afford an aromatic palladium(II) complex. Upon heating, the methyl group migrated from the nitrogen to the internal carbon atom and the resulting complex exhibited diminished aromatic character. A comparison with related carbaporphyrin complexes without ring fusion or with benzo- or naphtho-fused units demonstrated that the diatropic character decreased with increasing conjugation. NICS calculations and anisotropy of induced current density (AICD) plots confirmed this trend and showed that the remaining aromatic properties of the anthrocarbaporphyrin complex were due to a 30π electron circuit that extends around the entire anthracene unit.

Aromatic Character and Relative Stability of Pyrazoloporphyrin Tautomers and Related Protonated Species: Insights into How Pyrazole Changes the Properties of Carbaporphyrinoid Systems.

Pyrazoloporphyrins (PzPs), which are porphyrin analogues incorporating a pyrazole subunit, are examples of carbaporphyrin-type structures with a carbon atom within the macrocyclic cavity. DFT calculations were used to assess a series of 17 PzP tautomers, nine monoprotonated species and four related diprotonated PzP dications. The geometries of the structures were optimized using M06-2X/6-311++G(d,p), and the relative stabilities computed with the cc-PVTZ functional. Nucleus independent chemical shifts, both NICS(0) and NICS(1)zz, were calculated, and the anisotropy of the induced current density (AICD) plots were generated for all of the species under investigation. The results for free base PzPs show that fully aromatic PzP tautomers are not significantly more stable than weakly aromatic cross-conjugated species. In addition, strongly aromatic structures with internal CH2's are much less stable, a feature that is also seen for protonated PzPs. The degree of planarity for the individual macrocycles does not significantly correlate with the stability of these structures. The results allow significant aromatic conjugation pathways to be identified in many cases, and provide insights into the aromatic properties of this poorly studied system. These investigations also complement experimental results for PzPs and emphasize the need for further studies in this area.

Synthesis of Chrysoporphyrins and a Related Benzopyrene-Fused System.

Reaction of 6-nitrochrysene with ethyl isocyanoacetate in the presence of a non-nucleophilic base gave a c-annulated pyrrole ethyl ester that was used to prepare chrysene-fused tripyrranes and a chrysopyrrole dialdehyde. Chrysene-fused tripyrranes were reacted with a pyrrole dialdehyde, but poor yields of chrysoporphyrins were obtained. However, condensation of the chrysopyrrole dialdehyde with a series of tripyrranes afforded excellent yields of chrysoporphyrins and an acenaphtho-chrysoporphyrin. Iron(III) chloride mediated oxidative cyclization of a dihexylchrysoporphyrin afforded a benzopyrene-fused porphyrin that exhibited a strongly red-shifted electronic absorption spectrum. DFT calculations show that both chrysoporphyrins and the benzopyrene-fused porphyrin have tautomers that possess 34π electron delocalization pathways that pass through the porphyrin nucleus and the fused polycyclic aromatic hydrocarbon (PAH) units. Protonation gave dications that favor 36-atom 34π electron circuits. c-Annulated pyrrole dialdehydes were also condensed with a carbatripyrrin to generate PAH-fused carbaporphyrins that retained fully aromatic properties.

Oxyquinoliziniporphyrins: Introduction of a Heterocyclic Dimension to Carbaporphyrinoid Systems.

Oxyquinoliziniporphyrins, novel carbaporphyrinoids that incorporate quinolizone units, were synthesized. These structures exhibit moderate diamagnetic ring currents that are greatly enhanced upon protonation. Addition of trifluoroacetic acid initially gave a monocation, but this was readily converted into a dicationic species. The aromatic character of the free base and protonated species was assessed by proton NMR, nucleus-independent chemical shift calculations, and anisotropy of induced ring current plots. Stable Ni(II) and Pd(II) complexes are also reported.

Synthesis of [1-13 C-5-12 C]-alpha-ketoglutarate enables noninvasive detection of 2-hydroxyglutarate.

Isocitrate dehydrogenase 1 (IDH1) mutations that generate the oncometabolite 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG) have been identified in many types of tumors and are an important prognostic factor in gliomas. 2-HG production can be determined by hyperpolarized carbon-13 magnetic resonance spectroscopy (HP-13 C-MRS) using [1-13 C]-α-KG as a probe, but peak contamination from naturally occurring [5-13 C]-α-KG overlaps with the [1-13 C]-2-HG peak. Via a newly developed oxidative-Stetter reaction, [1-13 C-5-12 C]-α-KG was synthesized. α-KG metabolism was measured via HP-13 C-MRS using [1-13 C-5-12 C]-α-KG as a probe. [1-13 C-5-12 C]-α-KG was synthesized in high yields, and successfully eliminated the signal from C5 of α-KG in the HP-13 C-MRS spectra. In HCT116 IDH1 R132H cells, [1-13 C-5-12 C]-α-KG allowed for unimpeded detection of [1-13 C]-2-HG. 12 C-enrichment represents a novel method to circumvent spectral overlap, and [1-13 C-5-12 C]-α-KG shows promise as a probe to study IDH1 mutant tumors and α-KG metabolism.

Telluracarbaporphyrins and a Related Palladium(II) Complex: Evidence for Hypervalent Interactions.

The reaction of a carbatripyrrin with a tellurophene dicarbinol in the presence of BF3·Et2O, followed by oxidation with DDQ, afforded the first example of a telluracarbaporphyrin. Although this system exhibits strongly aromatic characteristics, it is prone to air oxidation, giving rise to a hydroxy derivative that was characterized by X-ray crystallography. The initial telluracarbaporphyrin reacted with palladium(II) acetate to give a stable organometallic complex, and X-ray crystallography showed that the palladium cation was coordinated to all four atoms in the CNTeN core. An oxacarbatripyrrin was also reacted with a tellurophene dialcohol to give an air-stable porphyrin analogue with a CNTeO core. Nonmetalated telluracarbaporphyrins showed relatively short Te-N separations that strongly implied the involvement of hypervalent tellurium interactions. Furthermore, despite the presence of a very large tellurium atom, the tellurophene subunit is not strongly pivoted away from the mean macrocyclic plane as would be expected in the absence of these interactions. The aromatic properties of heterocarbaporphyrins were assessed by proton NMR spectroscopy, NICS calculations, and AICD plots. In addition, the relative stability of hydroxytelluraporphyrins in comparison to their tellurophene oxide tautomers was investigated and the aromatic characteristics of these oxidized structures were evaluated.

Synthesis of Azulitriphyrins(1.2.1) and Related Benzocarbatriphyrins.

Bis(pyrrolylmethyl)azulene dialdehydes underwent intramolecular McMurry coupling, and following oxidation with DDQ and addition of trifluoroacetic acid, gave aromatic azulitriphyrin cations. The proton NMR spectra for these contracted carbaporphyrinoids showed the internal CH upfield at ca. 2 ppm, while the bridging methine units appeared downfield between 8 and 10 ppm, demonstrating that the macrocycles possess significant 14π electron diamagnetic ring currents. Although protonated azulitriphyrins(1.2.1) proved to be very stable, the free base forms were unstable and could not be isolated. Treatment of an azulitriphyrin with KOt-Bu-t-BuOOH gave rise to oxidative ring contractions that afforded the first examples of benzocarbatriphyrins. These contracted porphyrinoids also exhibit aromatic ring currents, and the internal CH resonances shifted upfield to 0.5-0.7 ppm. Protonation afforded cations with slightly enhanced diatropic properties. Nucleus independent chemical shift and anisotropy of induced current density calculations confirmed that benzocarbatriphyrins are 14π electron delocalized aromatic systems that bypass the fused arene units.

Azulichlorins and Benzocarbachlorins Derived Therefrom.

Acid-catalyzed condensation of azulidipyrrane aldehydes with a dihydrodipyrrin carbaldehyde afforded the first examples of azulichlorins. These macrocyclic products were isolated in a monoprotonated form, and the free bases proved to be somewhat unstable. The monocations were strongly diatropic, and proton NMR spectroscopy showed the internal C-H at ca. -2 ppm. Addition of TFA gave the related dications, but these exhibited significantly reduced aromatic ring currents. Reaction of an azulichlorin with tert-butyl hydroperoxide and KOH in dichloromethane/methanol gave a benzocarbachlorin and two related aldehydes. The UV-vis spectrum for the benzocarbachlorin showed a split Soret band at 414 and 430 nm, together with a strong chlorin-like absorption at 684 nm. The proton NMR spectrum indicated that the carbachlorin is strongly aromatic and the internal C-H was observed at -4.64 ppm. Addition of TFA afforded a C-protonated dication with a significantly increased diatropic ring current. The proton NMR spectrum, NICS calculations, and AICD plots indicated that the system favors a 22π electron delocalization pathway that runs through the fused benzo unit. Addition of TFA to the benzocarbachlorin aldehydes primarily led to the formation of monocations, and the generation of C-protonated dications was no longer favored due to the presence of electron-withdrawing formyl moieties.

adj-Dicarbaporphyrinoid Systems: Synthesis, Spectroscopic Characterization, and Reactivity of 23-Carbabenziporphyrins.

A new family of adj-dicarbaporphyrinoids has been prepared using the "2 + 2" MacDonald methodology. Dibutylboron triflate catalyzed condensation of 3-iodo-4-methoxybenzaldehyde with an indene enamine afforded an iodofulvene aldehyde, and a related dimethoxyfulvene was similarly prepared in two steps from 2,4-dimethoxybenzaldehyde. Following protection as the corresponding dimethyl acetals, the iodofulvenes were metalated with Bu3MgLi at -100 °C and reacted with dimethylformamide to give the required fulvene dialdehyde intermediates. Acid-catalyzed condensation with three different dipyrrylmethanes afforded a series of benzo-23-carbabenziporphyrins in 52-70% yields. The proton nuclear magnetic resonance spectra for these adj-dicarbaporphyrinoids indicate that these macrocycles are slightly diatropic. Monoprotonation afforded cationic species with slightly larger aromatic ring currents, and under strongly acidic conditions, C-protonated dications were generated with substantial diatropic properties. The aromatic character of these structures was supported by nucleus-independent chemical shifts and anisotropy of induced current density calculations. The computational results indicate that the dications favor 23-atom 22π electron delocalization pathways. The benzo-23-carbabenziporphyrins were selectively oxidized with silver(I) acetate in dichloromethane-methanol to give stable nonaromatic structures with two additional methoxy substituents connected to sp3 hybridized bridging carbons. The intriguing reactivity and unique spectroscopic properties of benzo-23-carbabenziporphyrins make these novel structures promising candidates for further investigations.

1,2-(Bis)trifluoromethylation of Alkynes: A One-Step Reaction to Install an Underutilized Functional Group.

Modifying the electronic properties of olefins is the quintessential approach to tuning alkene reactivity. In this context, the exploration of trifluoromethyl groups as divergent electronic modifiers has not been considered. In this work, we describe a copper-mediated 1,2-(bis)trifluoromethylation of acetylenes to create E-hexafluorobutenes (E-HFBs) under blue light in a single step. The reaction proceeds with high yield and E/Z selectivity. Since the alkyne captures two trifluoromethyl groups from each molecule of bpyCu(CF3 )3 , mechanistic studies were conducted to illuminate the role of the reactants. Interestingly, E-HFBs exhibit remarkable stability to standard olefin functionalization reactions in spite of the pendant trifluoromethyl groups. This finding has significant implications for medicine, agroscience, and materials.

A microdroplet-accelerated Biginelli reaction: mechanisms and separation of isomers using IMS-MS.

Electrospray ionization (ESI) combined with ion mobility spectrometry (IMS) and mass spectrometry (MS) techniques is used to examine the Biginelli reaction in an ensemble of ions generated from droplets. We find evidence for rapid dihydropyrimidinone formation from condensation of ethyl acetoacetate, benzaldehyde, and urea on the very short timescales associated with the electrospray process (∼10 µs to ∼1.0 ms). Control bulk-solution reactions show no product formation even after several days. This implies that the in-droplet reaction rate is enhanced by an astonishing factor. Examination of the reaction conditions and characterization of the intermediates en route to product shows evidence for variations in the reaction mechanism. IMS separation shows that the Knoevenagel condensation intermediate from benzaldehyde and ethyl acetoacetate exists as both the cis- and trans-isomer, in a ∼5 to 1 ratio. We suggest that the dramatic acceleration arises because of increased reagent confinement as electrosprayed droplets shrink. The ability of IMS-MS to resolve intermediates (including isomers) provides a new means of understanding reaction pathways.

N-Directed fluorination of unactivated Csp3-H bonds.

Site-selective fluorination of aliphatic C-H bonds remains synthetically challenging. While directed C-H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C-H fluorination of Csp3-H bonds. By converting primary amines to adamantoyl-based fluoroamides, site-selective C-H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes. Computational studies revealed a unique reaction coordinate for the catalytic process and offer an explanation for the high site selectivity.

Stereoinversion of Unactivated Alcohols by Tethered Sulfonamides.

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides. Starting from enantioenriched alcohols, the intramolecular variant proceeds with stereoinversion to produce enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines, without prior derivatization of the alcohol or solvolytic conditions.

Tropylium and Porphyrinoid Character in Carbaporphyrinoid Systems. Relative Stability and Aromatic Characteristics of Azuliporphyrin and Tropiporphyrin Tautomers, Protonated Species, and Related Structures.

DFT studies have been carried out on 46 azuliporphyrin (AzP) and tropiporphyrin (TrP) tautomers, cations, and dications. The structures were minimized using DFT-B3LYP/6-311++G(d,p), and the relative stabilities of the tautomers for each series were computed with M06-2X and B3LYP-D3 functionals. Nucleus independent chemical shifts, both NICS(0) and NICS(1) zz, were calculated for both the center of the macrocycles and the individual pyrrolic and carbocyclic subunits. In addition, anisotropy of induced current density (AICD) plots were generated for all of the species under investigation. The results provided insights into the favored conjugation pathways and aromatic properties of these important carbaporphyrinoid systems. The π delocalization pathways for AzP were complex, and contrary to previous speculations, there was no evidence for tropylium characteristics in the favored free base structure. The global diatropicity of AzP was found to increase with increasing solvent polarity, in agreement with experimental observations. TrP was shown to be planar and to possess a large global diamagnetic ring current. However, NICS calculations and AICD plots indicated that the cycloheptatrienyl components of the two most favored TrP tautomers have paratropic characteristics. These results are not fully consistent with the proton NMR spectra for TrPs. A dihydroTrP and a Diels-Alder adduct were investigated, and these showed exceptionally large shielding effects with NICS(1) zz values of -36.53 and -36.92 ppm, respectively, in agreement with experimental results. A silver(III) complex of tropiporphyrin was also examined, and this showed no paratropic character for the seven-membered ring, although in this case, the system was found to be severely twisted. Overall, the results provide important information about the electronic properties of AzP and TrP tautomers, as well as for related protonated species, and complement the extensive experimental studies that have been conducted on these systems.

Aqueous Benzylic C-H Trifluoromethylation for Late-Stage Functionalization.

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

Synthesis of Expanded Porphyrinoids with Azulene and Indene Subunits and an opp-Dioxadicarbaporphyrin from Fulvene Carbinols and a Dioxacarbatripyrrin.

In an attempt to prepare quatyrin derivatives, which are hydrocarbon analogues of the porphyrins, azulene-appended fulvene carbinols were self-condensed in the presence of BF3·Et2O. Although these investigations failed to give structures related to quatyrin, expanded porphyrin analogues were obtained instead. In dichloromethane, the major macrocyclic product consisted of three fulvene units, but when chloroform was used as the reaction solvent, a tetrafulvene macrocycle was isolated. Self-condensation of a furan-appended fulvene alcohol gave trace amounts of an opp-dioxadicarbaporphyrin. An alternative route to this novel system was developed where a dioxacarbatripyrrin was condensed with an indene dialdehyde in the presence of HBr. The heterodicarbaporphyrinoid proved to have strong globally aromatic properties as assessed by 1H NMR spectroscopy, anisotropy of induced current density, and NICS calculations. In the presence of excess trifluoroacetic acid, an unstable aromatic cation was formed by C-protonation of an indene subunit. This species was also highly diatropic, and the 1H NMR spectrum gave an unusually high Δδ value of 17.46 ppm.

Naphtho[2,3- b]carbaporphyrins.

Acid-catalyzed condensation of a benzo[ f]indane dialdehyde with a tripyrrane, followed by an oxidation step, afforded the first example of a naphtho[2,3- b]-21-carbaporphyrin. This π-extended porphyrinoid system is strongly aromatic and gave a porphyrin-like UV-vis spectrum with a Soret band at 432 nm. Protonation with TFA gave a monocation, but under highly acidic conditions a C-protonated dication was generated. Reaction of the naphthoporphyrin with ferric chloride produced a 21-chloro derivative. Alkylation with methyl iodide and potassium carbonate gave a 22-methyl derivative, and this reacted with palladium(II) acetate to afford a palladium(II) complex in which the internal methyl group had migrated from a nitrogen to a carbon atom. Treatment of the naphthocarbaporphyrin with silver(I) acetate generated the corresponding silver(III) complex. In naphtho[2,3- b]-21-carbaporphyrin and many of its derivatives, the aromatic conjugation pathways appear to bypass the naphthalene unit, and for this reason the UV-vis spectra were little affected. However, the diprotonated dication and the palladium(II) complex have aromatic pathways that pass through the naphthalene moiety, and this leads to large bathochromic shifts for these species. The results provide insights on the influence of fused aromatic units on the reactivity, spectroscopic properties, and aromatic characteristics of carbaporphyrinoid systems.

Palladium-Catalyzed Divergent Arylation of Triazolopyridines: A Computational Study.

The mechanisms for new palladium-catalyzed divergent reactions of triazolopyridines were investigated by means of DFT calculations. Previously, it was observed experimentally that cross-coupling at the C7-position of triazolopyridines occurred when a strong base was used, whereas the reaction could be diverted to the C3-position if a weak base was employed. Calculations suggest that a strong base, such as tert-butoxide, can easily deprotonate C7-H, independent of the palladium metal, and deliver the preactivated substrate to palladium, which can reductively eliminate the final product. Without a strong base, the palladium(II) center reacts with the ring-opened diazo imine isomer of triazolopyridine to initially form a palladium(II)-carbene intermediate, which undergoes migratory insertion followed by ß-hydride elimination to afford a 1,1-disubstituted alkene.

Accurate Thermochemistry for Organic Cations via Error Cancellation using Connectivity-Based Hierarchy.

Connectivity-Based Hierarchy (CBH) is an effective error-cancellation scheme for the determination of chemically accurate thermochemical properties of a variety of organic and biomolecules. Neutral molecules and open-shell radicals have already been treated successfully by this approach utilizing inexpensive computational methods such as density functional theory. Herein, we present an extension of the method to a new class of molecules, specifically, organic cations. Because of the presence of structural rearrangements involving hydrogen migrations as well as unusual structures such as bridged cations, the application of the standard CBH protocol to a test set of 25 cations leads to significant errors due to ineffective bond-type matching. We propose an adjusted protocol to overcome such limitations to achieve highly effective error cancellation. The modified CBH methods, in conjunction with a wide range of density functionals, reproduce G4 energies for the test set of organic cations accurately within 1-2 kcal/mol at a reduced computational cost.

Pyreniporphyrins: Porphyrin Analogues That Incorporate a Polycyclic Aromatic Hydrocarbon Subunit within the Macrocyclic Framework.

The first examples of porphyrin analogues incorporating pyrene units are reported. Acid-catalyzed condensation of a pyrene dialdehyde with a tripyrrane, followed by oxidation with DDQ, afforded a polycyclic aromatic hydrocarbon (PAH)-porphyrin hybrid in 38% yield. Pyreniporphyrin proved to be devoid of global aromatic character, but upon protonation aromatic mono- and dicationic species were generated. In the proton NMR spectrum for the dication, the internal CH was shifted upfield to approximately +3 ppm. NICS calculations and ACID plots confirmed the diatropic nature of these structures. Pyreniporphyrin reacted with palladium(II) acetate to give excellent yields of a palladium(II) complex that showed weakly diatropic properties. Treatment of the pyrene dialdehyde with phenylmagnesium bromide generated a dicarbinol that reacted with excess pyrrole in the presence of boron trifluoride etherate to give a tripyrrane analogue. Lewis acid catalyzed ring closure with a thiophene dialcohol in 2% ethanol-dichloromethane afforded a tetraphenylthiapyreniporphyrin in 31% yield. This porphyrinoid was nonaromatic in the free-base form but showed significant diatropicity upon protonation. These results demonstrate that PAH-porphyrin hybrids are easily accessible, and this strategy may allow the incorporation of even larger aromatic subunits.