Many times in organic chemistry, a reaction involves polar or charged and nonpolar reagents. The challenge to the practicing organic chemist then becomes finding an appropriate solvent that will dissolve both reactive species. Let’s say we wanted to carry out an SN2 reaction with 1-chlorobutane and potassium cyanide to form pentanenitrile. If we mix an aqueous solution of potassium iodide with a solution of the nonpolar alkyl halide in a nonpolar solvent, the solutions will separate into two distinct phases because the two solutions are immiscible. The reaction will be unable to occur. Chemists have discovered a solution: phase-transfer catalysts. Although many classes of phase-transfer catalysts exist, the one of particular interest here are crown ethers.
What does a crown ether look like? (see below) Crown ethers are cyclic polymers with the repeating unit [–CH2CH2O-]n .The most important crowns are the tetramers (n=4), pentamers (n=5), and hexamers (n=6). The nomenclature is as such: the first number preceding the word crown indicates the number of total atoms that comprise the ring, and the second number following the word crown indicates the total number of oxygen atoms. Because crown ethers are chemically inert, they can form coordinate covalent bonds with selective cations without reacting with it. Most importantly, each crown ether has a unique cavity diameter. The cavity diameter ultimately dictates which cation can reside within the crown. For example, -Crown-5 selectively binds Na+ over other cations because the ionic diameter of Na+ is 1.80Å while the accommodating cavity diameter is between 1.7-2.2Å. Once the cation has given up its hydration shell, the lone pairs of oxygen coordinate with Na+. Similarly, -crown-4 binds with exclusively Li+, while -crown-6 binds solely to K+.
How do these crown ethers work as phase-transfer catalysts? Crown ethers are soluble in nonpolar solvents because the perimeter of the crown is mainly composed of C-H bonds. They also are soluble in water because of the electronegative oxygens. In our example reaction above, we can choose to employ -crown-6 as these bind selectively to K+. Once this binding has occurred in the aqueous phase, the crown can then be translocated into the alkyl halide phase. Importantly, the counterion of the potassium salt, in this case the cyanide group, also will follow the crown to the nonpolar solvent, where it will an unstoppable nucleophile because it will not be solvated! Once the displacement SN2 has occurred, the freshly generated Cl- will then follow the crown back to the aqueous phase. Holistically, crown ethers are shuttles between the two phases that shunt the polar or charged nucleophile, in this case cyanide, to the nonpolar solvent containing the alkyl halide, thereby acting as phase-transfer catalysts.
It has not eluded me that these crowns can be of great biological importance. Because of their ability to selectively bind certain electrolytes over others, ethers can disrupt the precisely maintained concentrations of electrolytes inside and outside a cell, or any membrane enclosed compartment for that matter. It’s not surprising that nature beat us to the chase—analogs of crown ethers already exist. One of the most elegant analogs I’ve come across is the small, modified peptide Valinomycin, extracted from several Streptomyces strains. Here is its structure:
It mainly consists of D and L-Valine, D-hydroxyvaleric acid, and L-lactic acid all linked via amide and ester bridges. Partial free rotation in the sigma bonds permit a different conformation, but, once a cation occupies the cavity and coordinates with the carbonyl oxygens, the above conformation is locked. It turns out that valinomycin is highly selective for K+. Once K+ is bound, the valinomcyin-K+ complex will diffuse down K+’s electrochemical gradient. Diffusion through the lipid bilayer is permitted as the outside facing R chains are nonpolar. Once electrolyte concentrations become abnormal, osmotic imbalances as well as electrical forces can induce many sequences that result in cell death.
At a cursory glance, it’s easy to see how we can use crown ether analogs to fight pathogenic microorganisms. A deeper look veils many questions and problems, in which the answers and solutions can earn the holder wild sums of money as well as fame. The most glaring problem with crown ether analogs is their lack of selectivity between human cells and invasive prokaryotes. What stops these analogs from dissipating electrochemical gradients generated by our very own cells? We must firstly find a way to limit cytotoxicity to strictly pathogens. I will share my own ideas as to how we can accomplish this in a latter article! Other questions we must address are how will these ethers be metabolized by the liver or kidney? What will be the resulting metabolites and will they be injurious? What will be the mechanism of elimination? How long will its half-life last? Will there be serious collateral damage as there is with cancer drugs? What are some other side-effects? What is the optimal route of introduction into systemic circulation: oral, intravenous, hypodermal, intramuscular, or rectal among others? What will it’s bioavailability be? Once these barriers are overcome, I think it would be a spectacular bet to invest in a company that is on the verge of generating this new, potential class of antibiotics, as this class of antibiotics is far different from those in existence today (Beta-lactams, quinolones, etc).
If these crowns excite you, check out a class of compounds called cryptands, for which the Nobel Prize in Chemistry in 1987 was awarded!
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