18.6 Examples of Transition-Metal-Catalyzed Reactions 845

Home , Coupling reaction, Heck reaction, Hydroformylation, Karl Ziegler, Suzuki reaction

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18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 845

PROBLEMS 18.14 A student has written the following ligand substitution reaction, claiming that it changes the oxidation state of the metal by one unit. What is wrong with this reasoning?

Cl_ Pd(PPh3)4 ClPd(PPh3)3 PPh3 + LT + 3 18.15 The Wilkinson catalyst chlorotris(triphenylphosphine)rhodium(I), ClRh(PPh3)3, brings about the catalytic hydrogenation of an alkene in homogeneous solution: R R

ClRh(PPh3)3 $CHA C) 2 RCH2CH2R (18.40) + HH) $ (a) Using the following mechanistic steps as your guide, draw structures of the transition- metal complexes involved in each step. Give the electron count and the metal oxidation state at each step.

1. oxidative addition of H2 to the catalyst 2. ligand substitution of one PPh3 by the alkene 3. 1,2-insertion of the alkene into a Rh H bond and readdition of the previously ex-

pelled PPh3 ligand L 4. reductive elimination of the alkane product to regenerate the catalyst (b) According to the known stereochemistry of the 1,2-ligand insertion and reductive elim-

ination steps, what would be the stereochemistry of the product if D2 were substituted for H2 in the reaction?

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS

A. The Heck Reaction In the Heck reaction, an alkene is coupled to an aryl bromide or aryl iodide under the inﬂuence of a Pd(0) catalyst.

H3C $ Pd P L Lc 34 CH3 (catalyst) CH3 (CH3CH2)3N % H2C A CH2 % HBr (18.41) CH C' N (solvent) i ++3 i neutralized by Br 18 h, 125 °C CH A CH % % 2 the (CH CH ) N (86% yield) 3 2 3

(The aryl substituents of the phosphine ligands used in the catalyst in this case are o-tolyl (that is, o-methylphenyl) groups rather than phenyl groups, but phenyl groups are also sometimes used.) The reaction is named for Richard F. Heck (b. 1931), who discovered the reaction in the early 1970s while a professor of chemistry at the University of Delaware. (A Japanese chemist, T. Mizoroki, simultaneously discovered the reaction, but it is generally known as the Heck reaction.) The Heck reaction has proven to be one of the most useful processes for form- ing carbon–carbon bonds to aromatic rings and even, occasionally, to vinylic groups. The mechanism of the Heck reaction is outlined in the following equations. You should identify the process or processes involved in each step (L tri-o-tolylphosphine ligands; the steps in Eq. 18.42b are numbered for reference). = 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 846

846 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

The actual catalytically active species is believed to be PdL2, which is formed by two lig- and dissociations:

L L L L L

L L L L L Pd L L Pd L L Pd L (18.42a) L L L L + L + The PdL2 thus generated enters into the catalytic cycle.

CH2

L L Ar (2) Ar

L L L L L (1) H2C CH2 H2C (3) L Pd Ar Br L Pd L Pd L + L L L Br L Br L +

CH2

ArCHCH2 L H H

L L L L L (4) CH (5) L L L Pd Pd L Pd L "H Ar (6) L Br L Br L Br

ArCH CH2 +

L H L

L L L (7) L Pd L L Pd HBr (18.42b) +reacts with L Br L (CH3CH2)3N 3

PROBLEM 18.16 Characterize each step of the mechanism in Eq. 18.42b in terms of the fundamental processes discussed in the previous section. Give the electron count and the oxidation state of the metal in each complex.

Another example of the Heck reaction illustrates two important aspects of the reaction.

I Pd(OAc)2 catalyst (CH3CH2)3N M HI (18.43) dimethylformamide + 15 h, 100 °C + reacts with (CH3CH2)3N cyclohexene iodobenzene (2-cyclohexenyl)benzene (excess) (72% yield)

First, the catalyst is not Pd(0), but rather a Pd(II) species. (Pd(OAc)2 is used because it is a con- venient and easily handled Pd derivative.) In some cases (typically with iodobenzenes as the aryl halides), the reaction can be run with Pd(II), but it is believed that the Pd(II) is reduced to Pd(0), perhaps by a few molecules of alkene that are converted into vinylic acetates; Pd(0) is the actual

catalyst. Addition of an oxidizable ligand such as PPh3 can also serve to reduce the Pd(II). Be- cause a very small amount of Pd is used, the by-products of these reactions are also formed in very small amounts. Second, the alkene double bond in the product is not at the site of coupling, but rather one carbon removed. What has happened here? 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 847

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 847

This sort of product, which occurs commonly with cyclic alkenes in the Heck reaction, is a direct consequence of the stereochemistry of certain steps in the mechanism. The insertion step (step 3 in Eq. 18.42b) must occur in a syn manner because the reaction is intramolecular. Hence, in the initially formed insertion complex, the Pd and the phenyl group become cis substituents on a cyclohexane ring.

the only b-hydride available for syn-elimination I

H L Pd" L H H L Pd (18.44) L H H "I H Pd and phenyl are cis

The subsequent b-elimination is also a syn process. Hence, only a hydride cis to the Pd is “el- igible” for elimination. When a noncyclic alkene is used in the Heck reaction, internal rotation is possible so that the hydride on the carbon at which insertion occurs can be eliminated.

Pd" Ph Pd" Ph L L syn internal H H insertion L rotation CCA H CC) ) H HH HH

Pd" H Pd" H syn L b-elimination L L H CC) ) Ph H Ph (18.45) CCA HH HH

When the starting material is a cyclic alkene, as in Eq. 18.43, an analogous internal rotation is prevented by the ring. The only cis b-hydride available for elimination is the one (shown in red in Eq. 18.44) on the other b-carbon. Elimination of this hydride yields an alkene in which the carbon at the insertion point—the one attached to the phenyl—is not part of the double bond, but is one carbon removed. We can summarize this in the following way, with the insertion point marked with an asterisk (*):

H H H HH* * syn syn Ph insertion H Ph b-elimination L Pd Ph L Pd L Pd H (18.46) L L L L L "I "I "I

When the Heck reaction is applied to unsymmetrically substituted alkenes, such as an

alkene of the form R CHACH2, two products are in principle possible, because insertion L 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 848

848 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

might occur at either of the alkene carbons. It is found that when the R group is phenyl, CO2R (ester), CN, or another relatively electronegative group, the aryl halide tends to react at the un- substituted carbon; that is, the product is R CHACH Ar, usually the E (or trans) stereoisomer. When R alkyl, mixtures of productsL are oftenL observed (Problem 18.17). =

PROBLEMS 18.17 When iodobenzene and propene are subjected to the conditions of the Heck reaction, two constitutionally isomeric products are formed. What are they? Why are two products formed? 18.18 What two sets of aryl bromide and alkene starting materials would give the following compound as the product of a Heck reaction?

H %

"C OCH3 C % ( % "H

18.19 The product of a Heck reaction is, like the starting material, an alkene. Why doesn’t a Heck reaction of the product compete with the reaction of the starting alkene? 18.20 What product is expected when cyclopentene reacts with iodobenzene in the presence of tri- ethylamine and a Pd(0) catalyst?

B. The Suzuki Coupling The Suzuki–Miayura coupling reaction (usually referred to as the Suzuki reaction or the Suzuki coupling) is a Pd(0)-catalyzed process in which an aryl or vinylic boronic acid (a

compound of the form RB(OH)2, where R an aryl or vinylic group) is coupled to an aryl or vinylic iodide or bromide in the presence of= a base, which is in many cases aqueous sodium hydroxide or sodium carbonate. The reaction can be used to prepare three types of compounds: biaryls—compounds in which two aryl rings are connected by a s bond; aryl-substituted alkenes; and conjugated alkenes. Eq. 18.47 illustrates the preparation of a biphenyl.

Pd(OAc)2 (0.3 mole %) PPh3 Na2CO3 NaOH + B(OH)2 + Br CH O propanol–water

phenylboronic acid p-bromobenzaldehyde

CH O ++Na Br B(OH)3 (18.47) boric acid 4-phenylbenzaldehyde (a biphenyl; 86% yield)

The Pd(0) catalyst can be Pd(PPh3)4, the same catalyst used in the Heck reaction, or the Pd(0) can be formed in the reaction ﬂask from Pd(OAc)2, a strategy that is also used in the Heck reaction, as in the preceding example. Eq. 18.48 shows the preparation of an aryl-substituted alkene. 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 849

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 849

HH H H Pd(PPh3)4 B(OH)2 (4.5 mole %) CC KOH + CC (18.48) H2O/THF CH3 CH3O Br CH3 4-methoxybenzene- (Z)-1-bromo-1-propene boronic acid CH3O (Z)-1-methoxy-1-propenylbenzene (cis-anethole; 62% yield)

As this example illustrates, the coupling occurs with retention of alkene stereochemistry. You may have noticed that this is the type of compound that can be prepared by the Heck reaction. However, the Suzuki coupling avoids issues of regiochemistry that can sometimes occur with the Heck reaction. (See Problem 18.17, p. 848.) The importance of the Suzuki reaction has resulted in the commercial availability of many boronic acids and their derivatives. Two ways of preparing the required boron derivatives are, ﬁrst, the reaction of Grignard or organolithium reagent with trimethyl borate:

MgBr B(OCH3)3 MgBr B(OH)2

H3O + B(OCH3)3 + 3 CH3OH (18.49) H2O + Mg2+ + Br–

OCH3 OCH3 OCH3

In this reaction, the Grignard reagent, a strong Lewis base, donates electrons to the boron in a Lewis acid–base association. A reaction with aqueous acid results in formation of the boronic acid product. (See Problem 18.24, p. 851.) The analogous reaction can be used to form vinylic boronic acids from vinylic Grignard reagents. A second preparation of vinylic boronic acid derivatives is the hydroboration of 1-alkynes with catecholborane:

O H B O O CH CH CH CH C CH H B CC (18.50) 3 2 2 2 + THF O 1-hexyne CH3CH2CH2CH2 H catecholborane

This is essentially the same reaction discussed in Sec. 14.5B, in which hydroboration is car- ried out with disiamylborane. Recall that hydroboration occurs as a syn-addition. Both the catecholborane adducts and the disiamylborane adducts can be used in the Suzuki coupling. The following reaction illustrates both the use of vinylic catecholboranes and the formation of a conjugated alkene.

O HH HH H B Pd(PPh3)4 catalyst H CC Na+ CH CH O– O + CC 3 2 CC benzene CC Ph CH CH CH CH H Br Ph 3 2 2 2 CH3CH2CH2CH2 H (76% yield) (18.51) 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 850

850 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

The mechanism of the Suzuki coupling begins exactly like that of the Heck reaction (Eq.

18.42b, p. 846) with ligand dissociation to give a 14e_ complex, followed by oxidative addition of the aryl halide.

PPh3 PPh3 PPh3

PPh Pd PPh PPh Pd Ar Br PPh Pd Br 3 3 3 oxidative 3 – addition 14e , Pd(0) Ar PPh 3 – + 2 PPh3 16e , Pd(II) (18.52a) 18e–, Pd(0)

From this point on, the mechanism is not deﬁnitively established, but a reasonable sequence involves another ligand substitution in which the base displaces the halide ion:

PPh3 PPh3

PPh Pd Br ++OH PPh Pd OH Br 3 ligand 3 substitution Ar Ar (18.52b)

A Lewis acid–base association brings the boron into the coordination sphere of the metal:

PPh3 PPh3

.. .. B(OH) PPh3 Pd OH 2 Lewis acid–base PPh3 Pd O association B(OH)2 Ar R Ar R (18.52c)

This association results in a formal negative charge on boron. Remember, though, that carbon is more electronegative than boron; this means that carbon bears a signiﬁcant amount of the negative charge in this complex. In other words, the Lewis acid–base association of the oxy- gen with boron endows the carbon in the carbon–boron bond with signiﬁcant carbanion character. An intramolecular substitution of this “carbon anion,” a strong base, for the weaker base HO results in transfer of the R group to the metal. Reductive elimination then gives the cou- plingL product and provides the catalyst for another cycle.

PPh3 PPh3 PPh3

H PPh3 Pd O.. d– intramolecular PPh3 Pd R reductive PPh3 Pd + Ar R B(OH)2 ligand elimination regenerated coupling Ar substitution Ar Rd– catalyst product + B(OH)3 the carbon of the carbon–boron bond has carbanion character (18.52d) 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 851

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 851

The Suzuki coupling is named for Akira Suzuki (b. 1930), who is on the faculty of the Kirashiki Uni- versity of Science and the Arts in Kirashiki, Japan. Prof. Suzuki had spent two years as a postdoctoral fellow with Herbert C. Brown (the discoverer of hydroboration), where he was immersed in the organic chemistry of boron. His intellectual synthesis of transition-metal organometallic chemistry and organoboron chemistry led to the discovery in the mid-1970s of the reaction that bears his name, in collaboration with his student Norio Miyaura, while the two were at Hokkaido University in Japan. The Suzuki coupling has become a very important reaction in both academic and industrial settings.

PROBLEMS 18.21 Complete the following Pd(0)-catalyzed Suzuki reactions by giving the coupling product. For parts (b) and (c), include the stereochemistry of the products.

(a) B(OH)2 Br +

2-naphthaleneboronic acid (b) B(OH)2 H CH3 + CC CH3O Br H

H B(OH)2 H CH2CH2CH2OH

18.22 Provide two different reaction sequences that could be used to synthesize 4-methoxy- 3´-methylbiphenyl. Both sequences, however, should start with both p-bromoanisole and m-bromotoluene.

H3C H3C

OCH3 fromBr and CH3O Br

4-methoxy-3´-methylbiphenyl m-bromotoluene p-bromoanisole

18.23 Give two different pairs of starting materials that could be used to prepare the following compound by a Suzuki coupling.

CH3

Ph CC HH

18.24 Draw a curved-arrow mechanism for the last (acid hydrolysis) step of Eq. 18.49. 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 852

852 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

C. Alkene Metathesis Certain ruthenium(IV) catalysts bring about a reaction in which two alkenes are “sliced apart” at their double bonds, and the parts reassembled, to give new alkenes.

HO HOCH2 CH2OH G2 ruthenium catalyst (2 mole %) CH3O CH2CH CH2 + CC CH2Cl2 HH eugenol cis-2-buten-1,4-diol

CH3O CH2 H

C C + HO CH2CH CH2 allyl alcohol H CH2OH (E)-4-(4-hydroxy-3-methoxyphenyl)-2-buten-1-ol 80% yield (18.53)

This remarkable reaction is an example of alkene metathesis, also called oleﬁn metathesis.

e A metathesis reaction (pronounced m -ta˘´-the -sı˘s, from the Greek, meta change, thesis place) can be represented in general as follows: = =

AB++CCD A BD (18.54)

You are probably familiar with some inorganic examples of metathesis reactions, such as the reaction of silver nitrate with sodium chloride:

AgNO3 ++Na Cl AgCl Na NO3 (18.55) silver(I) sodium silver(I) sodium nitrate chloride chloride nitrate

In an alkene metathesis, the groups at each end of the double bonds are interchanged. For example, the reaction in Eq. 18.53 has the following form:

R´ H R R R´ R R H C C + CC C C + C C (18.56) H H H H H H H H

For a metathesis reaction of two unsymmetrical alkenes, ten alkenes (not counting stereoiso- mers) can be formed. (See Problem 18.25.) However, the usual applications of this reaction are typically not this complex. A number of transition-metal catalysts have been developed for alkene metathesis. These catalysts are base on tungsten, molybdenum, and especially ruthenium. The two most widely used laboratory catalysts are the ruthenium-based catalysts G1, which stands for the Grubbs ﬁrst-generation catalyst, and G2, the Grubbs second-generation catalyst. The structures of 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 853

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 853

P(Cy)3 Cl .. Ru CH Ph P(Cy)3 = P Cl benzylidene group P(Cy)3 Grubbs G1 catalyst (a)

Mes = mesityl group = Mes NNMes .. NHC CH3 Cl Cl Ru CH Ph Ru CH Ph

H3C Cl Cl .. P(Cy)3 CH3 P(Cy)3 abbreviated structure Grubbs G2 catalyst for the G2 catalyst (b)

Figure 18.6 The structures of two ruthenium catalysts for alkene metathesis and their abbreviated structures. Cy is the abbreviation for the cyclohexyl group, and Mes is the abbreviation for the mesityl, or 2,4,6-trimethylphenyl, group.The unusual ligand in G2 is a stabilized carbene (see Eq. 18.57), and it is abbreviated NHC (for “Nitrogen Hete- rocycle-stabilized Carbene”). Formal charges in the NHC ligand are conventionally not shown. A key aspect of these catalysts is the ruthenium–carbon double bond.

these catalysts are shown in Fig. 18.6. Although we need not go into detail here, the design of these catalysts was an evolutionary process that involved a consideration of steric and elec- tronic effects of the ligands in light of the reaction mechanism (which we’ll discuss below), as well as some outright fortuitous discoveries! Ruthenium catalysts can be easily handled in the laboratory, and, as Eq. 18.53 illustrates, they can be used in the presence of alcohols, phenols, and other functional groups. The molybdenum and tungsten catalysts are much more air-sensitive and less tolerant of other functional groups. The ruthenium–carbon double bond plays an important role in the operation of these catalysts. The rather unusual NHC ligand in the G2 catalyst, when “dissociated” from the metal, is actually a carbene (a molecule containing divalent carbon; Sec. 9.8). Most carbenes are very

unstable, but this carbene is highly stabilized by resonance.

.. ..

Mes NNMes Mes NNMes Mes NN.. Mes

......

resonance structures for the NHC ligand divalent carbon

Mes NNMes .. hybrid structure for the NHC ligand (18.57) 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 854

854 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

For electron-counting purposes, the NHC and PCy3 ligands are L-type ligands, the chlorines are X-type ligands, and the benzylidene group is a 2X ligand because it has two bonds to the ruthenium. You should verify that both catalysts are 16-electron complexes (Eq. 18.28) and that the oxidation state of ruthenium (Eq. 18.22) is formally Ru(IV). In many cases, the catalysts bring some or all of the possible alkenes into equilibrium. In such cases, the practical use of alkene metathesis requires the application of Le Châtelier’s principle. For example, in Eq. 18.53, one of the starting materials, cis-2-buten-1,4-diol, is used in excess. Use of an excess of this diol is practical because it is cheap, and because both it and the by-product allyl alcohol are readily separated from the desired product. One of the most important applications of alkene metathesis is for closing rings, and it can be used to close medium- and large-sized rings.

O G1 catalyst O (2 mole %) + H C CH (18.58) benzene 2 2 H2C Ph Ph

(72 % yield) H2C

In this and many other ring-closing applications, the by-product is ethylene, which bubbles out of the reaction mixture, thus driving the equilibrium towards the product—Le Châtelier’s principle in operation again. The mechanism of alkene metathesis, which we’ll illustrate for Eq. 18.56 using the G2 cat-

alyst, starts with loss of the PCy3 ligand by ligand dissociation. Because ruthenium in the resulting complex has 14 electrons, it can accept two electrons from another ligand, in this case one of the alkenes. Let the alkene RCHACHR be present in large excess; because of its con- centration, it is more likely to interact with the catalyst.

NHC NHC NHC

RCH CHR Cl2Ru CHPh Cl2Ru CHPh Cl2Ru CHPh (18.59a) – a 14e complex RCH CHR

P(Cy) .. 3 – + P(Cy)3 a 16e complex

Then follows a key step in alkene metathesis, a cycloaddition to form a metallacycle (a cyclic compound in which the metal occupies a ring position). This reaction is essentially a ligand insertion (p. 842).

cycloaddition cycloreversion NHC NHC NHC NHC CHPh Cl2Ru CHPh Cl2Ru CHPh Cl2Ru Cl2Ru + RCH CHPh (18.59b) CHR very minor RCH CHR RCH CHR RCH RCH by-product a metallacycle

As shown in this equation, the metallacycle then breaks down in the opposite sense by a cycloreversion (the reverse of a cycloaddition) to give a new alkene, which contains the benzylidene group. This becomes a very minor by-product, because the catalyst (and thus the benzylidene group) is typically present in 1 or 2 mole percent of the reactants. This process leaves the catalyst “primed” with the RCHA group. 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 855

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 855

The cycloaddition–cycloreversion process is now repeated. It is most probable that the process will occur with the alkene used in Eq. 18.59b, because this alkene is in excess; but the reaction with this alkene results in no change. (Be sure to demonstrate this point to yourself.)

However, occasionally a molecule of the other alkene R´CHACH2 will bind to the catalyst, and this produces a metathesis product.

NHC NHC NHC

Cl2Ru CH2 Cl2Ru CH2 Cl2Ru CH2 + RCH CHR´ (18.59c) first RCH CHR´ RCH CHR´ metathesis product

This leaves the catalyst with a ACH2 group. This catalyst molecule is most likely to react with the alkene in excess, and when that happens, the second metathesis product (which is allyl alcohol in Eq. 18.53) is formed, and the catalyst is again primed with a ACHR group.

NHC NHC NHC

Cl2RuCH2 Cl2Ru CH2 Cl2Ru + RCH CH2 (18.59d) second RCH CHR RCH CHR RCH metathesis product

catalyst enters another cycle (Eq. 18.59c)

The sequence in Eqs. 18.59c–d continues repeatedly until the limiting reactant is exhausted. It is conceivable that, as the product builds up, it might undergo metathesis with itself. However, self-metathesis is largely avoided in this example because one of the starting materials is used in excess, and it intercepts the catalyst almost every time. In other words, if the product enters into the metathesis sequence and is split by the catalyst, the fragments are most likely intercepted by the alkene present in excess; and such a reaction either gives back that same alkene or the desired product. When it is impractical to use one alkene in excess or to exploit Le Châtelier’s principle in some other way, self-metathesis of the product can be a problem. However, this potential com- plexity of alkene metathesis is mitigated by the fact that different alkenes undergo metathesis at greatly different rates. Alkene metathesis is very sensitive to the steric environment of the alkene double bonds. For example, 2-methylpropene (isobutylene) does not undergo self-

metathesis, presumably because the interaction of two (CH3)2CA fragments with the catalyst results in severe van der Waals repulsions (that is, steric congestion) with the bulky catalyst ligands.

H3C CH3 H3C CH3 self-metathesis C CH2 + H2C C C C + H2C CH2 (18.60)

H3C CH3 H3C CH3 two molecules of isobutylene not formed

(Isobutylene can be used as a metathesis partner with less crowded alkenes, however.) In fact, the metathesis catalysts were designed to emphasize such differences in alkene reactivity. 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 856

856 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

Alkene metathesis plays a major role in the synthesis of complex organic molecules, and it is used industrially with increasing frequency in such diverse applications as alkene synthesis, polymer synthesis, and pheromone synthesis. Because ruthenium catalysts can be used in aqueous solution, they are providing options for “green chemistry”—chemistry that is envi- ronmentally friendly. The importance of alkene metathesis was recognized with the 2005 Nobel Prize in Chemistry, which was shared by three chemists: Robert H. Grubbs (b. 1942) of the California Institute of Technology, who developed the ruthenium catalysts; Richard R. Schrock (b. 1945) of the Massachusetts Institute of Technology, who developed molybdenum- based metathesis catalysts; and Yves Chauvin (b. 1930) of the Petroleum Institute of France, who ﬁrst proposed the reaction mechanism.

PROBLEMS 18.25 Show that the equilibrium mixture produced by alkene metathesis of two completely different alkenes with the following general structures contains ten different alkenes. (Assume that all alkenes have trans stereochemistry.) R1 H R3 H CC + CC H R2 H R4

18.26 Give the structure of the major product formed in each case when the reactant(s) shown undergo alkene metathesis in the presence of an appropriate ruthenium catalyst.

(a) CH2OH

(R)-H2C CHCH2CHCH2CH2CH CH2 a compound with 7 carbons

(b) H3C a compound with 11 carbons H3C

(large excess)

18.27 Suggest an alkene metathesis reaction that would yield each of the following compounds as a major product. (a) OH (b) CO2H H3C H citronellol (oil of roses)

18.28 Draw structures analogous to those in Eqs. 18.59a–d for the catalytic intermediates formed in the conversion of 1,7-octadiene to cyclohexene and ethylene catalyzed by the G2 catalyst. 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 857

18.6 EXAMPLES OF TRANSITION-METAL-CATALYZED REACTIONS 857

The three coupling reactions presented in this section are additional examples of reactions that can be used to form carbon–carbon bonds. Here is a list of such reactions that we have en- countered up to this point: 1. the addition of carbenes and carbenoids to alkenes (Sec. 9.8) 2. the reaction of Grignard reagents with ethylene oxide and lithium organocuprate reagents with epoxides (Sec. 11.4C) 3. the reaction of acetylenic anions with alkyl halides or sulfonate esters (Sec. 14.7B) 4. the Diels–Alder reaction (Sec. 15.3) 5. Friedel–Crafts alkylation and acylation reactions (Secs. 16.4E–F) 6. the Heck and Suzuki coupling reactions (Secs. 18.6A–B) 7. alkene metathesis (this section)

D. Other Examples of Transition-Metal-Catalyzed Reactions One of the most important transition-metal catalysts in commerce is a catalyst formed from

TiCl3 and (CH3CH2)2AlCl, called the Ziegler–Natta catalyst. This catalyst brings about the polymerization of ethylene and other alkenes at 25 Cand1atmpressure.Althoughfree-radical polymerization of ethylene (Sec. 5.7) is very important,° the Ziegler–Natta polymerization of ethylene accounts for most of the polyethylene produced; the resulting high-density polyethylene has different properties from the low-density polyethylene produced by free-radical processes. The discoverers of this catalyst, the German chemist Karl Ziegler (1898–1973) and the Italian chemist Giulio Natta (1903–1979) shared the 1963 Nobel Prize in Chemistry for their work. Although the mechanism of the polymerization has been hotly debated, the following sequence is one possibility: Cl Cl H CA CH Cl" Ti CH CH 2 2 Cl" Ti CH CH 2 3 ligand 2 3 1,2-ligand insertion LLformed from association LL (CH3CH2)2AlCl H2CA CH2 and TiCl3 Cl Cl

H2CA CH2 Cl" Ti CH2CH2CH2CH3 ligand Cl" Ti CH2CH2CH2CH3 LL association LL H2CA CH2 (18.61)

Continuation of the insertion–ligand-association sequence gives the polymer. It is believed that titanium brings about this reaction because a d1 metal cannot undergo b-elimination. (b- Elimination requires some ﬁlled metal d orbitals for reasons that we haven’t discussed.) The tendency toward b-elimination of other metals would terminate the reaction. Hydroformylation is another commercially important process that involves a transition- metal catalyst, in this case a tetracarbonylhydridocobalt(I) catalyst. Propionaldehyde, for example, is produced by the hydroformylation of ethylene. (This is sometimes called the oxo process.) O

HCo(CO)4 H CA CH H CO CH CH CH (18.62) 2 2 2 100–120 °C 3 2 ++ ethylene propionaldehyde

This process involves, among other things, a 1,2-insertion reaction of ethylene and a 1,1-insertion reaction of carbon monoxide (Problem 18.29). 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 858

858 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

Yet another important transition-metal-catalyzed reaction is the homogeneous catalytic hydrogenation of alkenes using a soluble rhodium(I) catalyst called the Wilkinson catalyst,

ClRh(PPh3)3. This reaction was explored in Problem 18.15 (p. 845). And let’s not forget catalytic hydrogenation (Secs. 4.9A and 14.6A), an extremely important reaction that occurs over carbon-supported transition metals such as Ni, Pd, and Pt. The mechanism of catalytic hydrogenation is not deﬁnitively known, but it is not hard to imagine that the mechanism might involve oxidative additions and insertions much like those that take place on the Wilkinson catalyst. Many aspects of transition-metal chemistry are beyond the scope of an introduction. How does the chemist design a catalytic system and choose a catalyst? What inﬂuences the choice of ligands and solvents? These questions are sometimes addressed with a certain degree of empiricism, but the bases for the answers to these questions are becoming better understood.

PROBLEM 18.29 Suggest a mechanism for the oxo reaction (Eq. 18.62) involving intermediates that are con- sistent with the 16- and 18-electron rules.

18.7 ACIDITY OF PHENOLS

A. Resonance and Polar Effects on the Acidity of Phenols Phenols, like alcohols, can ionize.

(18.63) O H H2O O _ H3O| cLL2 + 2 cL 2 3 + 2 2 2 2 phenol phenoxide ion (phenolate ion) The conjugate base of a phenol is named, using common nomenclature, as a phenoxide ion or, using substitutive nomenclature, as a phenolate ion. Thus, the sodium salt of phenol is called sodium phenoxide or sodium phenolate; the potassium salt of p-chlorophenol is called potassium p-chlorophenoxide or potassium 4-chlorophenolate.

Phenols are considerably more acidic than alcohols. For example, the pKa of phenol is 9.95, but that of cyclohexanol is about 17. Thus, phenol is approximately 107 times more acidic than an alcohol of similar size and shape. OH OH 12 12 M M i `

pKa ≈10 ≈17

Recall from Fig. 3.2, p. 113, that the pKa of an acid is decreased by stabilizing its conjugate base. The enhanced acidity of phenol is due to stabilization of its conjugate-base anion. Further Exploration 18.2 Resonance Effects What is the source of this enhanced stability? First, the phenolate anion is stabilized by on Phenol Activity resonance:

O _ O _ O O 12 3 1 3 1 3 1 3 M 2 ( ( ( (18.64) r _ t a _ 3 3 resonance structures for the phenoxide anion