Rational Design, Synthesis, and Characterization of a Solid Δ9-Tetrahydrocannabinol Nanoformulation Suitable for "Microdosing" Applications.

Background: This article highlights the formulation of a solid Δ9-tetrahydrocannabinol (THC)-loaded ingestible prepared from pure THC distillate. Methods: A THC-containing ethanol-assisted cannabinoid nanoemulsion (EACNE) was created using a solvent displacement technique. Subsequently, the EACNE was converted to a solid powdery material while still retaining its THC potency, a format uniquely suited for "microdosing" applications. Results: EACNE had an average lipid droplet size of ∼190 nm, with a polydispersity index of 0.15, and an average droplet ζ potential of -49±10 mV. The nanoemulsion (NE) was colloidally stable for at least 6 weeks, with no meaningful change in cannabinoid potency over the experimental period, as determined by high-performance liquid chromatography analysis. The EACNE remained stable when subjected to physical stresses such as heat, freeze/thaw cycles, carbonation, dilution to beverage concentrations, high sucrose concentrations, and a pH range between 5 and 8. The microencapsulated EACNE demonstrated limited free-flowing behavior but was freely redispersible in water without any visible phase separation. Conclusions: We report the design, creation, and characterization of a THC NE generated without the use of specialized equipment, such as a microfluidizer or a high-pressure homogenizer. This emulsion could readily be converted to a water-redispersible powder. This embodiment is particularly suited for THC "microdosing," a practice that might decouple the health benefits of THC from its psychotropic effects.

A remarkably stable acyclic phosphamethine cyanine dye.

While cyanine dyes enjoy a multitude of uses in science and technology, their phosphorus analogues, phosphamethine cyanine dyes, have not yet found benchtop applications primarily because of their sensitivity to air and moisture. We are excited to report full characterization of an extraordinarily stable acyclic phosphamethine cyanine dye. Nitrile substituents on the N-heterocyclic framework afford air and water stability as well as resistance to methylation and sulfuration even under forcing conditions. Cyclic voltammetry confirms a high oxidation potential of the compound and computational investigations reveal stabilized orbitals. The unusual orbital stability appears to render the normally electron-rich PI site an extremely poor nucleophile and difficult to oxidize. From a practical perspective, this dye is prepared in a one-pot method under mild conditions.

Synthesis, characterization and stress-testing of a robust quillaja saponin stabilized oil-in-water phytocannabinoid nanoemulsion.

BACKGROUND: This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. [Formula: see text], a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Stress-testing was performed on this nanoemulsion in order to evaluate its chemical and colloidal stability under the influence of different environmental factors, encompassing both physical and chemical stressors. METHODS: Extensive optimization studies were conducted to arrive at an ideal nanoemulsion formulation. A coarse emulsion containing 16.6 wt% CBD-enriched cannabis distillate and 83.4 wt% carrier (soybean) oil dispersed in 10 wt% [Formula: see text] (1.5 wt% quillaja saponin) solution after 10 homogenization cycles at a pressure of 30,000 psi produced a stable nanoemulsion. This nanoemulsion was then subjected to the stress studies. RESULTS: The optimized nanoemulsion had an average droplet diameter of ca. 120 nm and average droplet surface ζ potentials of ca. -30 mV. It was imaged and characterized by a variety of protocols. It proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values ≤2 and moderately high salt concentrations (> 100 mM), however, destabilized the nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. CONCLUSIONS: Quillaja saponin stabilized cannabidiol(CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.

Triphosphenium salts: air-stable precursors for phosphorus(I) chemistry.

The chemistry of low-coordinate phosphorus-containing species is an area of intense interest in modern main group chemistry. While typical routes for accessing such species include pyrophoric phosphorus-centered precursors or harsh reducing agents, triphosphenium cations represent a more convenient and safer alternative. This Perspective summarizes the use of air- and moisture-stable triphosphenium salts of [dppeP]+ as a source of P+ ions for the generation of a variety of new and/or useful low-coordinate phosphorus-containing species. These range from phosphorus-rich oligomers to phosphamethine cyanine dyes. Special emphasis is placed on the electronic structure of the newly generated species as well as their subsequent reactivity.

The phosphinoboration of acyl chlorides.

This investigation examines the reactivity of phosphinoboronate esters Ph2PBpin (pin = 1,2-O2C2Me4) and Ph2PBcat (cat = 1,2-O2C6H4), as well as other phosphinoboron species, with various aryl and aliphatic acyl chlorides. These reactions proceed smoothly to give acyl phosphines of the type RC(O)PR'2 along with loss of a boron-chloride compound. In some cases, a second equivalent of the phosphinoboron species can add to the C[double bond, length as m-dash]O double bond at elevated temperatures to give the corresponding diphosphines RC(OBR''2)(PR'2)2. These ambiphilic diphosphines behave like substituted (1,1-bis(diphenylphosphino)methane) derivatives in a reaction of PhC(OBpin)(PPh2)2 (2a) with (η5-C9H7)Rh(η2-coe)2 (coe = cis-cyclooctene) affording the indenyl rhodium complex (η5-C9H7)Rh(PhC(OBpin)(PPh2)2) (3a) where the phosphines are bound to the metal centre in a κ2-P,P bidentate manner.

2,6-Bis(benzimidazol-2-yl)pyridine complexes of group 14 elements.

Treatment of MCl2 (M = Ge or Sn) with 2,6-bis(benzimidazol-2-yl)pyridine (G-BZIMPY, G = NBn, N(3,5-CF3)Bn, NAllyl and O) yielded the self-ionization products [G-BZIMPYMCl][MCl3] (1-6) in high yields (75-98%). Reduction reactions are examined and the nickel complexes 8 and 9 ([(NBn-BZIMPY)2Ni][MCl3]2) are isolated from the reaction of Ni(COD)2 with 1 and 2 respectively. [NBn-BZIMPYSnCl][SnCl3] shows a significantly stronger MLCT band in the UV-vis absorption spectrum than its germanium counterparts, with germanium complexes exhibiting negative solvatochromism that is not observed in tin complexes.

2,6-Bis(benzimidazol-2-yl)pyridines as more electron-rich and sterically accessible alternatives to 2,6-bis(imino)pyridine for group 13 coordination chemistry.

Treatment of GaCl3 with 2,6-bis(benzimidazol-2-yl)pyridine (G-BZIMPY, G = NBz, N(3,5-CF3)Bz, N-allyl and O) yielded the autoionization products [G-BZIMPYGaCl2][GaCl4] (1-4) in great yields. The Ga(iii) complex 1 was reduced to Ga(i) using K2[Fe(CO)4], resulting in the complex [(NBzBZIMPY)(Cl)Ga-Fe(CO)4] (7). GaCl3 and AlCl3 were complexed by the structurally similar bis(imino)pyridine (DIMPY) and the resulting complexes are compared to those of G-BZIMPY.

Diphosphoniodiphosphene Formation by Transition Metal Insertion into a Triphosphenium Zwitterion.

Treatment of two equivalents of the triphosphenium zwitterion L with sources of Ni0 and Pd0 form the mononuclear η2 -diphosphoniodiphosphene complexes 1 and 2. The reaction between L and [FeCp(CO)2 ]2 results in the binuclear µ-η1 :η1 -diphosphoniodiphosphene iron complex 3, which features an alternative bonding motif of the diphosphoniodiphosphene unit. The formation of these species has been confirmed by spectroscopic methods and single-crystal X-ray diffraction analysis, and their electronic structures have been elucidated using computational methods.

Synthesis of Heteroleptic Phosphorus(I) Cations by P+ Transfer.

Reported are general synthetic approaches for the syntheses of asymmetrically substituted phosphorus(I) cations by P+ transfer from [dppeP]+ (dppe = 1,2-bis(diphenylphosphino)ethane). The first method grants access to acyclic derivatives and is accomplished by the sequential substitution of dppe using first a sterically encumbered ligand which cannot form a stable homoleptic complex, followed by a second equivalent of a less sterically demanding ligand. The second method grants access to cyclic derivatives and utilizes asymmetric hybrid phosphine/N-heterocyclic carbene ligands. Interplay between the different ligand types and their stoichiometries relative to those of [dppeP]+ also allows for the isolation of symmetrical derivatives with pendant phosphines.

Synthesis of Heavy Dicyanamide Homologues from Air-Stable Precursors.

A convenient synthesis of dicyanophosphide and dicyanoarsenide anions is reported. These heavy homologues of the long-known and fundamentally important dicyanamide anion were formed through the nucleophilic displacement of bis(diphenylphosphino)ethane (dppe) from the pnictogen+ transfer agents [dppePn][BPh4 ] (Pn=P, As) by exposure to cyanide salts. The protocol requires three synthetic steps from commercially available materials and the [dppePn][BPh4 ] salts are remarkably temperature, air, and moisture stable. All products have been fully characterized by spectroscopic methods and by single-crystal X-ray diffraction, and the electronic structures of the DCPn anions have been assessed computationally.

Phosphonium-Templated Iodoplumbates.

A new family of iodoplumbates based on phosphonium cations have been synthesized and characterized via X-ray crystallography. Thermogravimetric analysis demonstrates that these materials have a remarkably high thermal stability and show potential for applications as organic-inorganic hybrid semiconductors. We also present the synthesis of three novel phosphonium salts and the crystallographic elucidation of these compounds.

Assessing the Ligand Properties of NHC-Stabilised Phosphorus(I) Cations.

The isolation and full characterisation of a series of cationic metal-carbonyl complexes bearing an N-heterocyclic carbene stabilised phosphorus(I) ligand are reported. Specifically, the mononuclear coordination complexes [LM(CO)5 ][BPh4 ] (M=Cr, Mo, W), [LFe(CO)4 ][BPh4 ] and the dinuclear complexes [LMn2 (CO)8 ][BPh4 ] and [LCo2 (CO)6 ][BPh4 ], in which L=[bis(1,3,4,5-tetramethylimidazol-2-ylidene)phosphanide]+ , have all been isolated in the solid state and structurally confirmed by single-crystal X-ray diffraction. The dicationic platinum complex trans-[L2 PtCl2 ][BPh4 ]2 is also reported and fully characterised. The donor ability of [L]+ has been assessed by IR spectroscopy of its metal-carbonyl complexes and by using DFT calculations. The results suggest that [L]+ is a weak π-acceptor with moderate donor strength and thus it bridges the gap that exists between phosphines and amines in terms of ligand properties. Collectively, these molecules represent the first crystallographically characterised cationic metal-carbonyl derivatives of a PI -centred ligand and are a rare collection of cationic metal-carbonyl complexes.

Accessing multimetallic complexes with a phosphorus(i) zwitterion.

We present the synthesis of a zwitterionic triphosphenium molecule, tBu(C5H2)(PPh2)2PI (L), which can act as a single- or multidentate ligand with group 6, 7, 8 and 9 metal carbonyl complexes. Group 6, [M(CO)5L] complexes are formed under photolytic conditions, where the metal is bound at the P(i) center. In the case of Mo(CO)6, the bimetallic complex [M(CO)5LMo(CO)3] is generated, which features bonds to both the phosphorus(i) center and the cyclopentadienyl moiety of the molecule. Interestingly, group 7 and 9 metal carbonyl dimers generate bimetallic complexes in the form [M2(CO)nL], where both metal centers are bound at the phosphorus(i) center. A detailed analysis of these molecules is provided, including X-ray diffraction, multinuclear NMR, infrared spectroscopy and computational investigations.

Preparation and Reactivity of a Triphosphenium Bromide Salt: A Convenient and Stable Source of Phosphorus(I).

We present herein the optimized synthesis of a triphosphenium bromide salt. Apart from being a versatile metathesis reagent, this unusually stable low-valent-phosphorus-containing compound acts as a useful P+ transfer agent. Unlike traditional methods employed to access low-coordinate phosphorus species which usually require pyrophoric phosphorus-containing precursors (white phosphorus, Tris(trimethylsilyl)phosphine, etc.), or harsh reducing agents (alkali metals, potassium graphite, etc.), the current approach does not involve pyrophoric or explosive reagents and can be done on large scales (>20 g) in excellent yields by undergraduates with basic air-free synthetic training. The bromide counter ion is readily exchanged with other anions such as tetraphenyl borate (described herein) using typical salt metathesis reagents to obtain materials with desired properties and reactivities. The versatility of this P+ transfer approach is exemplified by the reactions of these triphosphenium precursors with an N-heterocyclic carbene and an anionic bisphosphine, each of which readily displace the neutral bisphosphine to give an NHC-stabilized phosphorus(I) cation and a phosphorus(I) containing zwitterion, respectively.

Convenient Preparation and Detailed Analysis of a Series of NHC-Stabilized Phosphorus(I) Dyes and Their Derivatives.

A safe, convenient, and P-atom-efficient synthesis of N-heterocyclic-carbene- (NHC-) stabilized phosphorus(I) bromide salts is reported that involves P(+) transfer from an easily prepared triphosphenium precursor. The resulting family of phosphamethine cyanine dyes featuring N,N'-dialkyl-substituted 4,5-dimethylimidazole-2-ylidenes ((R)NHC(Me)) and benzimidazole-2-ylidenes ((R)NHC(B)) (R = Me, Et, iPr) have been fully characterized. We found that increasing N-alkyl group size causes increased twisting of the carbene fragments from the C-P-C plane, which decreases the magnitude of hyperconjugation between the π-type lone pair on phosphorus and the carbene fragments. This decrease is manifested as changes in the (31)P NMR chemical shifts, magnitudes of the P-C coupling constants, and electronic spectra of the cations. The reactivities of these ions toward various oxidants are reported: Oxidation by sulfur generates dithiophosphinium salts, protonation or methylation gives dicationic phosphines, and coordination to 1 or 2 equiv of gold(I) chloride results in mono or bimetallic complexes, respectively.

A simple route to phosphamethine cyanines from S,N-heterocyclic carbenes.

Although salts of thiazolium cations are known, many readily prepared iodide salts have eluded spectroscopic and structural characterization; herein, data for a variety of such salts are reported. It has been demonstrated that thiazolium cations can be deprotonated to generate S,N-heterocyclic carbenes and their "electron rich olefin" dimers, but use of the former has been largely overshadowed by that of the more common N-heterocyclic carbenes. We report herein that the deprotonation of thiazolium iodides and their subsequent reaction with a conveniently prepared triphosphenium precursor grants phosphamethine cyanine cations with solid-state geometry and electronic structure unlike those of NHC-stabilized cations. Protection of the phosphorus atom in such ions with elemental sulfur provides an air- and moisture-stable dithiophosphinium salt.

Remarkably stable chelating bis-N-heterocyclic carbene adducts of phosphorus(i) cations.

A convenient one-pot synthesis of chelating bis-N-heterocyclic carbene-ligated P(I) salts is described. The solid state structures of these remarkably stable phosphamethine cyanine dyes with various N-alkyl groups and counter-anions are reported, and initial reactivity results are discussed.