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Potassium cation solvated by the cyclic polyether, 18-crown-6 [18-membered ring; 6 oxygen atoms]. Each of the ethano groups is in a staggered conformation with each of the O-C-C-O dihedral angles at ~60^o [gauche]. For a dynamic version, click here. Note that the six oxygen atoms occupy the same spatial arrangement as do the six carbon atoms in chair cyclohexane. The discovery of the crown ethers by Charles Pedersen of DuPont earned him a share in the 1987 Nobel Prize in Chemistry. For potassium ion complexed with a cryptand, click here.

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1. Nonactin is a 32-membered ring ionophore comprised of four similar units. Assign R,S - configurations to nonactin and determine whether or not it is optically active. Explain. Nonactin (NONACTIve; meso) is optically inactive. It is a tetrolide comprised of four subunits, two of each. Each subunit is an enantiomer of the other. They are shown in Fig. 1 as blue and green enantiomers alternating positions in the 32-membered ring. Fig.2 shows the products from hydrolysis of nonactin, 2 moles of racemic nonactic acid. There is another meso compound derived from 2 moles of racemic nonactic acid. Can you draw it? [Use Ns(+) and Ns(-) as the two enantiomers.] How do you use any combination of four enantiomers [2+2, 3+1, 4+0] to prepare two racemic "nonactins"? For more information click here and here.

Fig. 1 Fig. 2

2. Cartoon A represents the cross-linking of a disulfide bond in hair. This property gives hair its natural curl or an artificial "permanent wave". When a solution of ammonium thioglycolate at alkaline pH is applied to the hair, it goes straight to form a dithiol (cartoon B) and disulfide C, which is water soluble and is rinsed away. To restore the curl, the hair is washed with a mild oxidant. Provide a mechanism for the formation of B and C from A, and the formation of A from B. At pH 9.5 ammonium thioglycolate is in equilibrium with ammonia and the carboxylate and the thiolate carboxylate. It is this species that behaves as a nucleophile to reduce the disulfide bonds in hair and form a new, water soluble disulfide C. Hydrogen peroxide reforms the disulfide A, putting the "bounce" back.

3. Forty years ago I was a young assistant professor working with a safety expert. We were cleaning up the departmental "chemical morgue". [The morgue was a repository for chemicals that were no longer needed by a researcher and were available to others in the department.] I came across a large bottle of diphenyl ether that was totally solid. Upon informing my associate, he panicked and claimed that the ether bottle (glass, plastic cap) was old; it had totally formed peroxides. As a result, he insisted that we should not handle the bottle but rather call the bomb squad. Your thoughts? How would you test for peroxides? ["Very carefully" is a necessary but not sufficient answer!]

For an ether to form a peroxide, the carbon adjacent to the oxygen must bear a hydrogen (sp3). Diphenyl ether does not have such a hydrogen. What hydrogens it does have (sp2) have too high a BDE (110 kcal/mol) to react with oxygen. In addition, diphenyl ether has mp. 63oC, a solid at room temperature. Since the bottle is glass and the cap plastic, cautious opening of the container is possible. [If an ether is in a metal can with a metal top, any rust could cause an explosion upon opening the cap.] Use a non-metallic spatula to remove a sample. Dissolve it in aqueous alcohol. Test with starch iodide paper. Any peroxide will turn the paper blue.

 

4. Neosporol (1), which is shown in two views, was successfully synthesized from racemic ketone 2, whose synthesis is well beyond the scope of this question. The immediate problem was to convert ketodiol 2 into triol 3. [The fact-oid-s have been altered slighted to facilitate the question. (J. Am. Chem. Soc., 1993, 115, 2581) ] When an excess of methyllithium was used to convert the ketone function of 2 into the tertiary alcohol of 3, only ketodiol 2 was recovered upon aqueous workup. A Jmol structure of neosporol is provided. Move the structure around to compare it with the two views of neosporol 1.

	Neosporol (How to manipulate Jmol structures)  (Larger Version)

 

a) What is the minimum amount of methyllithium required in this reaction? Explain? Methyllithium reacts with each of the alcohols and the ketone. Three equivalents of methyllithium.

b) What events occurred prior to aqueous work up? [Hint: Generally, organolithium and Grignard reagents undergo addition to ketones but they are also the conjugate bases of weak acids. pK_a's] What was the fate of the ketone group? Rather than undergoing addition to the ketone, the methyllithium acted as a base, abstracting a hydrogen atom adjacent to the ketone [pK_a = 20] forming a ketone enolate. The enolate is stable until it is protonated in the aqueous workup.

When methyl magnesium bromide was employed, both 2 and a mixture of the diastereomers of 3 were obtained. Complete conversion of 2 to 3 (5/1 mixture of diastereomeric tertiary alcohols) was effected cleanly with the cerium reagent, CH₃CeCl₂.

c) Draw the structures of the two diastereomers of 3, i.e., provide stereochemistry in structure 3.] See 3a and 3b below from addition of the organometallic reagent to either face of the ketone.

d) Provide conditions and a mechanism for the conversion of 3 to 1. Is it necessary to separate the diastereomers of 3 prior to forming 1? See above. A proton can protonate any of the oxygen atoms of 3a and 3b. The only productive event is protonation of the tertiary alcohol, which leads to a tertiary carbocation. The carbocation is captured by an intramolecular S_N1 reaction followed by loss of a proton to form 1. No separation of 3a and 3b is required.