Noteworthy Chemistry

September 26, 2011

Use three catalysts to α,α-difluorinate carbonyl compounds. The value of fluorine in strategic sites on candidate drug molecules is well established. Chemists often choose fluorine to replace hydrogen at metabolically labile sites—frequently, positions adjacent to carbonyl groups.

T. Lecta and co-workers at Johns Hopkins University (Baltimore) observed that monocarbonyl compounds are difficult substrates for α-position fluorination because undesirable mixtures of mono- and difluorinated products are often produced. They now report a solution to this problem that uses a three-component catalyst for mild, one-pot conversion of acid chloride substrates to the corresponding α,α-difluorinated products. Acid chlorides are ideal substrates because they are inexpensive, they are readily available, and they have highly acidic α-positions that promote fluorination.

A key feature of this reaction is the synergistic effect of the three catalysts (see figure):

  • a tin-based Lewis acid (OTf is trifluoromethanesulfonate);
  • pyridine, which serves as a catalytic nucleophile and as a reagent; and
  • potassium tetrakis(pentafluorophenyl)borate (KBARF), which functions as an anionic phase transfer catalyst.

This system efficiently promotes the fluorination process when commercial Selectfluor is the fluorine source. (Selectfluor is 1-chloromethyl-4-fluoro-1,4-‍diazoniabicyclo‍[2.2.2]octane bis(tetrafluoroborate.)

A final component in the reaction mixture is a nucleophile such as aniline, which is used as a quenching agent for the acid chloride. The α,α-difluorinated product 1 forms in yields as high as 82%, although most other substrates give smaller yields. The authors expanded the scope of the reaction to form a variety of carboxylic acid derivatives by selecting appropriate nucleophilic quenching agents. This modification eliminates the need for prefunctionalized substrates.

The efficiency of Selectfluor in the three-catalyst system is limited by its poor solubility. The authors found that the presence of the anionic phase transfer catalyst leads to increased Selectfluor solubility in the MeCN reaction medium. The addition of KBARF improves the reaction rate, cleanliness, and yield. (Org. Lett. 2011, 13, Article ASAP DOI: 10.1021/ol2019295; W. Jerry Patterson)

Here’s a new way to make self-healing materials. J. S. Moore and colleagues at the University of Illinois at Urbana–Champaign explored the role of cohealing agents on polymers’ adhesion and self-healing properties in an epoxy matrix. They used dimethylnorbornene ester (DNE), which is copolymerizable and undergoes noncovalent interactions with the matrix, and dimethyl phthalate (DMP), which also exhibits noncovalent interactions, in concert with “healing” dicyclopentadiene (DCPD).

The authors copolymerized DCPD with DNE by using a second-generation Grubbs catalyst with no appreciable change in DCPD’s initial ring-opening metathesis polymerization kinetics. Incorporating small amounts of DNE increases the polymer’s glass-transition temperature. In lap-shear experiments conducted at 50 °C, blending with DMP reduces the polymer’s adhesion properties, whereas copolymerization with 10 wt% DNE enhances adhesion by ≈100%.

At a healing temperature of 50 °C, the 10 wt% DNE cohealing copolymer produces a peak load of ≈35 N, compared with a peak load of ≈12 N for DCPD alone. When the optimized DCPD–DNE blend is microencapsulated, the enhanced healing performance is preserved. The researchers emphasize the need for rapid initiation kinetics to maximize adhesion when a cohealing agent is used. (ACS Appl. Mater. Interfaces 2011, 3, 3072–3077; LaShanda Korley)

Prepare hyper–cross-linked polymers by click polymerization. Hyper–cross-linked polymers (HCLPs) are novel materials with desirable properties such as high mechanical strength, thermal stability, and chemical resistance. Their promising applications include absorbents, catalysts, and sensors. P. Sozzani, T. Muller, S. Bräse and coauthors at Karlsruhe Institute of Technology (Germany), Cynora GmbH (Eggenstein-Leopoldshafen, Germany), and the University of Milan-Bicocca (Italy) developed new HCLPs such as 1 with tetrahedral cores via an unconventional synthetic route based on click chemistry.

The click polymerization of tetrayne monomer 1,3,5,7-tetrakis‍(4-ethynylphenyl)adamantine and diazide monomer 1,4-diazidobenzene catalyzed by CuSO45H2O and sodium ascorbate in a DMSO–H2O mixture at 80 °C for 3 days gives 1 in quantitative yield. The polymer network is robust because of the rigidity of its adamantane, benzene, and triazole components. HCLP 1 efficiently captures CO2 at low pressures and temperatures. (New J. Chem. 2011 35, 1577–1581; Ben Zhong Tang)

The Appel reaction can be catalyzed by triphenylphosphine oxide. The Appel reaction is a phosphorus-mediated substitution reaction that converts an alcohol to a chloride with inversion of configuration. This reaction, however, requires stoichiometric amounts of phosphine, which makes the products difficult to purify. R. M. Denton and coauthors at the University of Nottingham (UK) and AstraZeneca R&D Charnwood (Loughborough, UK) devised a catalytic version of the Appel reaction.

The authors treated Ph3PO with a stoichiometric amount of oxalyl chloride [(COCl)2] to prepare a halophosphonium salt, which acts as the halogen source. The alcohol and 85 mol% (COCl)2 are added to a mixture of a catalytic amount of Ph3PO (3‍–‍15 mol%) and 15 mol% (COCl)2 over 7 h at room temperature.

The authors demonstrated the inverted configuration of the products by optical rotation measurements and chiral GC. Alcohols such as 1-decanol and (S)-ethyl lactate react smoothly, but sterically hindered alcohols give low yields.

The bromination of alcohols is also possible by using LiBr as the bromine source; this was effective for aliphatic and benzylic secondary alcohols. The authors propose a mechanism (see figure) in which the release of CO and CO2 during the preparation of the halophosphonium salt is the driving force of the reaction. (J. Org. Chem. 2011, 76, 6749–6767; JosÉ C. Barros)

Is PMI a better measure of “greenness” than the E factor? C. Jimenez-Gonzalez and colleagues at GlaxoSmithKline (Research Triangle Park, NC), DSM Innovative Synthesis (Geleen, The Netherlands), and the ACS Green Chemistry Institute (Washington, DC) discuss the pros and cons of various “green yardsticks”. The E factor (kilograms of waste produced per kilogram of product) is a very good measure of the amount of waste produced during a process or synthesis, and it drives waste minimization in the pharmaceutical, fine chemical, and related industries. Process mass intensity (PMI, the total mass of materials in kilograms used per kilogram of product produced) is subtly different from the E factor because it incorporates the total amount of raw materials used.

Reducing the PMI of a process or synthesis reduces raw material cost and waste, but more importantly, the reduction has a beneficial global effect. A lower raw material requirement means that less of these compounds must be produced; this also reduces the waste generated to make them. The authors conclude that PMI is a superior mass-related metric for green chemistry than the E factor or atom economy, another measure frequently used to gauge the environmental impact of a process. (Org. Process Res. Dev. 2011, 15, 912–917; Will Watson)

Epoxy resins with polyisobutylene domains have enhanced mechanical properties. The use of cross-linked (thermoset) epoxy resins as engineering materials is limited by their inherent brittleness and poor resistance to crack propagation. These problems have historically been addressed by blending them with functionalized elastomers (liquid rubbers) to introduce phase separation in the cured matrix and provide increased toughness and energy dissipation.

R. Tripathy, U. Ojha, and R. Faust* at the University of Massachusetts Lowell devised a new route to toughened epoxies that is based on incorporating a telechelic or epoxy-terminated polyisobutylene elastomer such as 1. (In the structures in Figure 1, R represents the same long chain as in the position meta to it.) Among the advantages of this type of reactive elastomer is compatibility or homogeneity of the liquid elastomer with the uncured epoxy matrix resin. During curing, the phases in the elastomer completely separate, and rubber particles form in the nano- to micrometer range.

The authors’ initial experiments showed desired increases in fracture resistance at concentrations of 1 up to ≈15 wt%, but the toughness decreased dramatically at higher concentrations. Adding even higher levels of 1 caused the two liquid phases to become immiscible and led to a cured matrix with degraded fracture toughness and mechanical properties.

The authors modified the structure of 1 to incorporate oligo(tetramethylene oxide)s in a two-step process. This provided a more miscible reactive elastomer in the form of a liquid copolymer chain with epoxy termination (2).

Molecular weights (Mn) of the reactive elastomers were 1.6 or 2.6 kDa. They could be varied by changing the degree of polymerization of the poly‍(isobutylene) or poly‍(tetramethylene ether) segment.

The basic epoxy resin for this study was the diglycidyl ether of bisphenol A (3), which was blended with varying amounts of 2. This was followed by cross-linking or “curing” with aliphatic polyamine triethylenetetramine (4) to form modified epoxy matrix 5 (Figure 2). The authors describe the morphology of 5 as well-dispersed spherical rubber domains, with diameters of 1‍–‍3 μm as the level of 2 in the epoxy matrix approached 40 wt%.

The use of 5 showed an increase in fracture toughness from 0.75 to 1.65 MPa·m0.5 as the level of 2 increased. This excellent fracture toughness of 5 persisted even at levels of 2 up to 40 wt%. Even at these high elastomer contents, the mechanical properties and thermal stability of 5 remained sufficiently high to make it a useful engineering material.

These modified epoxy resins should be useful as stable, flexible, transparent cross-linked coatings with superior toughness properties. The authors note that materials prepared from 5 outperformed a commercial epoxy resin designed specifically for enhanced toughness. (Macromolecules 2011, 44, 6800–6809; W. Jerry Patterson)

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