The Dissolving Metal Reduction of an Alkyne

A lithium atom donates an electron to the ir bond of the alkyne. An electron pair shifts to one carbon as the hybridization states change to sp . 

The radical anion acts as a base and removes a proton from a molecule of ethylamine. 

A second lithium atom donates an electron to the vinylic radical. 

The mechanism for this reduction, shown in the preceding box, involves successive electron transfers from lithium (or sodium) atoms and proton transfers from amines (or ammonia). In the first step, a lithium atom transfers an electron to the alkyne to produce an intermediate that bears a negative charge and has an unpaired electron, called a radical anion. In the second step, an amine transfers a proton to produce a vinylic radical. Then, transfer of another electron gives a vinylic anion. It is this step that determines the stereochemistry of the reaction. The trawi-vinylic anion is formed preferentially because it is more stable the bulky alkyl groups are farther apart. Protonation of the trani-vinylic anion leads to the trans-alkene. 

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A MECHANISM FOR THE REACTION ] The Dissolving Metal Reduction of an Alkyne 322... 

This method is a very interesting counterpoint to the Lindlar reduction discussed in Section 19.3.3. Whereas Lindlar reduction of an alkyne gives a Z-alkene, dissolving metal reduction of an alkyne gives an -alkene. The reduction process can therefore be controlled, and either a Z- or an -alkene can be prepared. Assume that alkenes are not reduced to the alkane under the conditions described using Na or Li in ammonia or ethanolic ammonia. 

Na, or Li in liquid ammonia, for example) to reduce aromatic rings and alkynes. The dissolving metal reduction of enones by lithium metal in liquid ammonia is similar to these reactions—the C=C bond of the enone is reduced, with the C=0 bond remaining untouched. An alcohol is required as a proton source and, in total, two electrons and two protons are added in a stepwise manner giving net addition of a molecule of hydrogen to the double bond. 

Anti additions to alkenes typically result in a stepwise mechanism formation of a cationic cyclic intermediate such as a bromonium ion, followed by backside attack by a nucleophile to open up the ring. Such is the mechanism for the anti addition of Br2. The bromination reaction results in trans bromines since the second bromine (as Br ) has to come in from the opposite face as the first bromine (as Br+) in order to do an Sn2 attack on the bromonium ion. Other mechanisms involving the bromonium ion include reaction of an aikene with Br2/H20 (adds -Br and -OH anti) and Br2/ROH (adds -Br and -OR flnfi)-Treatment of an aikene with a peroxyacid in water forms an epoxide that undergoes a ring opening in situ to give a trans diol product. Trans stereoselectivity is also seen in the dissolving metal reduction of alkynes. 

Keeping in mind the mechanism for the dissolving metal reduction of alkynes to trans alkenes in Chapter 12, write a stepwise mechanism for the following reaction, which involves the conversion of an a,p-unsaturated carbonyl compound to a carbonyl compound with a new alkyl group on the a carbon. 

Dissolving-Metal Reduction of Aromatic Compounds and Alkynes. Dissolving-metal systems constitute the most general method for partial reduction of aromatic rings. The reaction is called the Birch reduction,214 and the usual reducing medium is lithium or sodium in liquid ammonia. An alcohol is usually added to serve as a proton source. The reaction occurs by two successive electron transfer/proto-nation steps. 

Reduction of an alkyne to an (E)-alkene can be achieved by treating the alkyne with lithium or sodium metal in ammonia at low temperatures (Following fig.). This is called dissolving metal reduction. 

The reduction of a carbon-carbon multiple bond by the use of a dissolving metal was first accomplished by Campbell and Eby in 1941. The reduction of disubstituted alkynes to c/ s-alkenes by catalytic hydrogenation, for example by the use of Raney nickel, provided an excellent method for the preparation of isomerically pure c -alkenes. At the time, however, there were no practical synthetic methods for the preparation of pure trani-alkenes. All of the previously existing procedures for the formation of an alkene resulted in the formation of mixtures of the cis- and trans-alkenes, which were extremely difficult to separate with the techniques existing at that time (basically fractional distillation) into the pure components. Campbell and Eby discovered that dialkylacetylenes could be reduced to pure frani-alkenes with sodium in liquid ammonia in good yields and in remarkable states of isomeric purity. Since that time several metal/solvent systems have been found useful for the reduction of C=C and C C bonds in alkenes and alkynes, including lithium/alkylamine, ° calcium/alkylamine, so-dium/HMPA in the absence or presence of a proton donor,activated zinc in the presence of a proton donor (an alcohol), and ytterbium in liquid ammonia. Although most of these reductions involve the reduction of an alkyne to an alkene, several very synthetically useful reactions involve the reduction of a,3-unsaturated ketones to saturated ketones. ... 

Alkynes can also be reduced to alkenes by using either sodium or lithium metal in liquid ammonia or in low-molecular-weight primary or secondary amines. The alkali metal is the reducing agent and, in the process, is oxidized to M, which dissolves as a metal salt in the solvent for the reaction. Reduction of an alkyne to an alkene by lithium or sodium in liquid ammonia, NH3(Z), is stereoselective it involves mainly anti addition of two hydrogen atoms to the triple bond. 

In the previous section, we explored the conditions that enable the reduction of an alkyne to a cis aUtene. Alkynes can also be reduced to trans alkenes via an entirely different reaction called dissolving metal reduction ... 

The mechanism of the Birch reduction is similar to that for dissolving metal reduction of alkynes (p. 452), and starts in the same way, with a transfer of an electron from the metal to one of the empty antibonding orbitals of benzene. The product is a resonance-stabilized radical anion (Fig. 13.67). 

What can we do if we want the tra s-alkene rather than the ds-isomer from alkyne reduction This can be accomplished using a dissolving metal reduction. When an alkali metal such as sodium is added to liquid ammonia, it is ionized to give solvated electrons (these are blue, but that s a story for the physical chemists...). One electron is added to the alkyne to give a radical anion (Figure 11.94). Because electrons repel each other, the orbitals containing the lone pair and the odd electron are on opposite sides of the triple bond. The lone pair is protonated by the solvent then a further electron and proton are added to complete the process. Thus, 4-octyne is cleanly reduced to fraKS-4-octene. 

Although catalytic hydrogenation is a convenient method for preparing cis alkenes from alkynes, it cannot be used to prepare trans alkenes. With a dissolving metal reduction (such as Na in NH3), however, the elements of H2 are added in an anti fashion to the triple bond, thus forming a trans alkene. For example, 2-butyne reacts with Na in NH3 to form rram-2-butene. 

For reduction, relevant data from polarographic and cyclic voltammetric experiments are summarized in Tables 1 and 2, respectively. For the results in Table 1 the variety of solvents and reference electrodes used makes comparisons difficult. It is clear, however, that even with the activation of a phenyl substituent (entries 6,7,9-14) reduction occurs at very cathodic potentials. In this context it is worth noting that in aprotic solvents at ca. — 3 V vs. S.C.E.) it becomes difficult to distinguish between direct electron transfer to the alkyne and the production of the cathode of solvated electrons. Under the latter conditions the indirect electroreductions show many of the characteristics of dissolving metal reductions (see Section II.B). Even at extreme cathodic potentials it is not clear that an electron is added to the triple bond the e.s.r. spectra of the radical anions of dimesitylacetylene and (2,4,6,2, 4, 6 -hexa-r-butyldiphenyl)acetylene have been interpreted in terms of equal distribution of the odd electron in the aromatic rings . 

Both disubstituted alkynes (Chapter 3.3, this volume) and isolated terminal double bonds may be reduced by alkali metals in NH3, but isolated double bonds are usually stable to these conditions. However, 16,17-secopregnanes (10 equation 8) afford mixtures of cyclization products (11) and (12) in 61% to 80% yield with Na naphthalenide-THF, Na-NHs-THF, Na-THF or Li-NHs-THF. With Na-NHa-THF-r-butyl alcohol, a 91% yield of a 72 28 mixture of (11) (12) (R = Me) is obtained. This type of radical cyclization of alkenes and alkynes under dissolving metal reduction conditions to form cyclopentanols in the absence of added proton donors is a general reaction, and in other cases it competes with reduction of the carbonyl group. Under the conditions of these reactions which involve brief reaction times, neither competitive reduction of a terminal double bond nor an alkyne was observed. However, al-lenic aldehydes and ketones (13) with Li-NHs-r-butyl alcohol afford no reduction products in which the diene system survives. ... 

The mechanism of dissolving metal reductions depends on the nature of the solvent and the nature of the substrate. The proposed mechanism for the reduction of dialkylacetylenes by sodium in HMPA in the presence of a proton donor is illustrated in equation (18). The addition of an electron to the triple bond of (45) is proposed to produce the rran -sodiovinyl radical (46), or the corresponding radical anion (47), which undergoes protonation by the added alcohol to produce the radical (48). Further reduction of (48) by sodium produces the rrans-sodiovinyl compound (49), which on protonation produces the trans-a -kene (50). In the absence of a proton donor, the reduction of (45) with sodium in HMPA results in the formation of a mixture of cis- and trans-2- and 3-hexenes. Control studies showed that the isomerization products 2- and 3-hexene are not formed by rearrangement of the cis- or frans-3-hexenes. It was concluded that the starting alkyne (45) acts as a reversible proton donor reacting with an intermediate anion or radical anion to produce the delocalized anion (51) which is then protonated to produce the al-lene (52). Reduction of the allene (52), or further rearrangement to the alkyne (53) followed by reduction, then leads to the formation of the mixture of the cis- and trans-2- and 3-hexenes (equation 19). ... 

Catalytic hydrogenation of an enone would not be chemoselective if an isolated double bond were also present in the molecule. However, isolated double bonds are inert to dissolving metal reduction. On the other hand, a variety of functional groups are reduced with alkali metals in liquid ammonia. These include alkynes, conjugated dienes, allylic, or benzylic halides and ethers. 

The two hydrogen atoms add to the opposite faces of the alkene (i.e. anti-addition) using sodium in liquid ammonia. This dissolving metal reduction produces a solvated electron, which adds to the alkyne to produce a radical anion (bearing a negative charge and an unpaired... 

The alkyne was then reduced to an E alkene by a dissolving metal reduction, a step which also hydrolysed the five-membered heterocycle. The next step, an epoxidation, is needed to install the third of the chiral centres at the left-hand end of penarisidlne. However, hydrogen-bond directed epoxidation of this allylic alcohol would be expected to give the syn product shown, which has the wrong relative stereochemistry between the brown OH group and the epoxide. 

Dissolving metal reductions works very well with aldehydes and ketones, but alkenes are not readily reduced under the same conditions. For example, 1-hexene is reduced to hexane in only 41% yield with Na/MeOH/liquid NHg.14 Alkynes, on the other hand, are reduced to alkenes in good yield using dissolving metal conditions, and the experimental evidence shows that the -alkene is the major product. In a typical example, 4-octyne (60) is treated with sodium in liquid ammonia, and oct-4 -ene (64) is isolated in 90% yield. None of the Z-alkene is observed in this reaction. The reaction with sodium in liquid ammonia is an electron transfer process similar to that observed with ketones and aldehydes, but how is the E geometry of the alkene product explained ... 

A ketone or aldehyde is reduced to an alcohol by reaction with sodium or lithium metal in liquid ammonia, in the presence of ethanol. This is called a dissolving metal reduction and it proceeds by an alkoxy-radical known as a ketyl 21, 22, 46, 49. Alkynes are reduced to E-alkenes under dissolving metal conditions. Benzene is reduced to a cyclohexadiene under the same conditions 23, 28, 33, 37, 41, 48. 

Alkynes can be reduced to either a cis or trans alkene. Catalytic hydrogenation of an alkyne using a poisoned catalyst (H2, Lindlar catalyst) results in the syn addition of one equivalent of H2 to give a cis alkene product. Dissolving metal reduction (Li, NH3) of an alkyne produces the corresponding trans alkene. This strategy is well suited for synthesizing monosubstituted alkenes and disubstituted alkenes with a specific stereochemistry. 

Thus, by the proper choice of reagents and reaction conditions, it is possible to reduce an alkyne to either a ds-alkene (by catalytic reduction or hydroboration-protonolysis) or to a frans-alkene (by dissolving-metal reduction). 

A dissolving metal reduction will convert an alkyne into a trans alkene. The reaction involves an intermediate radical anion and employs fishhook arrows, which indicate the movement of only one electron. 

When hydrogenation is performed in the presence of a poisoned catalyst (such as Lindlar s catalyst), the alkyne is reduced to a cis alkene. When R is used as the catalyst, the alkyne is reduced aU the way to an alkane. Treatment of the alkyne with sodium in liquid ammonia affords a trans alkene (dissolving metal reduction), as shown here ... 

The product is a tmns alkene, which can be made from an alkyne. So the last step of our synthesis might be a dissolving metal reduction to convert the alkyne below into the product. This alkyne can be made from acetylene and 1-bromobutane via alkylation processes ... 

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