University:
Rutgers University Newark
Course:
CHEM 336 | Organic Chemistry ||
Academic year:

2024
Views:

179

Pages:

47
Author:

Mahitab S.

CHAPTER 24 Part 1 CATALYTIC CARBONCARBON BOND FORMATION ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • (24.1) • • • • (24.2) (24.3) (24.4) (24.5) • (24.6) Carbon-carbon bond-forming reactions from earlier chapters Organometallic compounds and catalysis Heck reaction (Nobel 2010) Catalytic allylic alkylation Palladium-catalyzed cross-coupling (Nobel 2010) Alkene metathesis (Nobel 2005) ©2018 Cengage Learning. All Rights Reserved. C—C Bond-Forming Reactions from Earlier Chapters • (1) Nucleophilic displacement of a leaving group by a carbon nucleophile (SN2-type) (C-X) • (i) Gilman (organocuprate) reagents if the leaving group is a halogen atom or tosylate • (ii) Grignard reagents, organolithium reagents, and Gilman reagents if the leaving group is the oxygen of an epoxide • (iii) Alkyne and cyanide anions • (iv) Enolate anion alkylations, acetoacetic ester synthesis and malonic ester synthesis • (v) Enamine alkylations ©2018 Cengage Learning. All Rights Reserved. C—C Bond-Forming Reactions from Earlier Chapters • (2) Nucleophilic addition to a carbonyl or a carboxyl group (C=O) • (i) Grignard reagents, organolithium reagents, and Gilman reagents • (ii) Alkyne and cyanide anions • (iii) Aldol reactions • (iv) Claisen and Dieckmann condensations • (v) Enamine acylations • (vi) Wittig reaction • Conjugate addition to α,β-unsaturated carbonyl compounds (R-CH=CH-C(O)R’) • Michael reaction ©2018 Cengage Learning. All Rights Reserved. C—C Bond-Forming Reactions from Earlier Chapters • (3) Pericyclic reactions • (i) Diels-Alder reaction • (ii) Claisen rearrangement and Cope rearrangement • (4) Aromatic substitution • (i) Friedel-Crafts alkylation and acylation of aromatics • (ii) Reaction of cyanide with aromatic diazonium compounds • (5) Carbene/carbenoid additions ©2018 Cengage Learning. All Rights Reserved. Organometallic Compounds important methyl ligands ©2018 Cengage Learning. All Rights Reserved. Organometallic Compounds • Key steps of the catalytic processes involve oxidative additions and reductive eliminations • Use of organometallic catalysts causes a net decrease in the number and quantity of waste (reagents, solvents, and purifications) necessary in an overall synthetic sequence • Green chemistry - Chemical field dedicated to designing chemical processes to decrease waste and toxic byproducts • Goal - To effectively use all atoms involved in a reaction ©2018 Cengage Learning. All Rights Reserved. Heck Reaction • Palladium-catalyzed reaction in which the carbon group of a haloalkene or haloarene is substituted for a vinylic hydrogen of an alkene (Ar-X + alkene) • Substitution is highly regioselective • Formation of the new C—C bond commonly occurs at the less substituted carbon of the double bond ©2018 Cengage Learning. All Rights Reserved. Heck Reaction • Substitution is highly stereoselective where an E or Z configuration is possible at the double bond of the product • E configuration is often formed almost exclusively ©2018 Cengage Learning. All Rights Reserved. Heck Reaction • Reaction is completely stereospecific with regard to the haloalkene • Configuration of the double bond in the haloalkene is preserved Cis ©2018 Cengage Learning. All Rights Reserved. shouldendwith E or 2 whenyoustartwith for z you Heck Reaction - Preparation of the Palladium Catalyst • Palladium(II) acetate, Pd(OAc)2, is the form of palladium most commonly added to the reaction • Catalytically active form of the metal is a complex of Pd(0) formed in situ by reduction of Pd(II) to Pd(0) • Reaction of Pd(0) with ligands, L, gives the actual Heck catalyst, PdL2, and Pd(0) is insoluble without the ligand • Common ligand used - Triphenylphosphine, (C6H5)3P ©2018 Cengage Learning. All Rights Reserved. Heck Reaction - The Haloalkane I O O • The most common organic halides used are aryl, heterocyclic, benzylic, and vinylic iodides and bromides (sp2 or lack βincrease hydrogen). Iodides are generally the most reactive. I > Br down thecolumn • Haloalkanes with β-hydrogen are rarely used because they undergo β-elimination to form alkenes • Triflates (trifluoromethanesulfonates, CF3SO2O—), which are easily prepared by treating an alcohol with trifluoromethanesulfonyl chloride, are excellent substrates (OTf) ©2018 Cengage Learning. All Rights Reserved. Heck Reaction - The Haloalkane • a Pdl Halide or triflate (RX) reacts with PdL Rx by oxidative addition to give a square planar Pd(II) species, which is the reaction intermediate 2 squareplanet • A wide range of functional groups may be present elsewhere in the organic halogen compound or alkene without reacting themselves or affecting the reaction (highly chemoselective) ©2018 Cengage Learning. All Rights Reserved. Heck Reaction - The Alkene, Base, and Solvent Required not • The alkene • Reactivity of the alkene is a function of steric crowding feminine about the C=C bond • Greater the degree of substitution on the double bond, slower the reaction and the lower the yield of the product • The base • Commonly used bases are tertiary amines such as triethylamine, or sodium or potassium acetate, or sodium hydrogen carbonate (Et3N, NaOAc, KOAc, NaHCO3) • The solvent • Polar aprotic solvents such as DMF, CH3CN, and DMSO or aq MeOH can be used ©2018 Cengage Learning. All Rights Reserved. Mechanism of the Heck Reaction • Step 1: Formation of the catalyst, PdL2 • A two-electron reduction of Pd(II) to Pd(0) accompanied by its complex formation with two molecules of a ligand, L, gives the Heck catalyst ©2018 Cengage Learning. All Rights Reserved. Mechanism of the Heck Reaction • Step 2: The catalytic cycle (important) 13 spggaregygide pd o pl I aside prladiam and H areonthesame ©2018 Cengage Learning. All Rights Reserved. side Example 24.1 - Heck Reaction • Complete these Heck reactions HYUN EYES ©2018 Cengage Learning. All Rights Reserved. Example 24.1 - Heck Reaction • In (a), 1-iodohexene has the E configuration, and this double bond retains its configuration in the product • Furthermore, the C=C bond adjacent to the ester in the product now has the possibility for cis,trans isomerism • The Heck reaction is highly stereoselective, and this double bond has the more stable E configuration as well • In (b), the major product is (E)-1,2-diphenylethene ©2018 Cengage Learning. All Rights Reserved. Heck Reaction - Alternative Pattern • Usual pattern in a Heck reaction of acyclic alkenes • Replacement of a hydrogen on the double bond with an organo group • If the organopalladium group attacks the double bond so that the R-group is bonded to a carbon that lacks a hydrogen (or if the only syn hydrogen is on a neighboring carbon), the double bond shifts away from the original position to ©2018 Cengage Learning. All Rights Reserved. Heck Reaction - Chiral Ligand • Can give chiral products in significant enantiomeric excess (ee) • Because of the chiral ligand, the activation energy for the transition state in the syn addition to the alkene is different depending on which side of the alkene the metal complex approaches ©2018 Cengage Learning. All Rights Reserved. Problem 24.9 - Heck Reaction • The following reaction involves two sequential Heck reactions • Draw the structural formula for each organopalladium intermediate formed in the sequence and show how the final product is formed ©2018 Cengage Learning. All Rights Reserved. Problem 24.9 - Heck Reaction Final ©2018 Cengage Learning. All Rights Reserved. Catalytic Allylic Alkylation • When the alkyl group is allylic, metals can catalyze the reaction • Common catalysts - PdL4 and PdCl2 • Stereochemistry at the carbon with the leaving group is retained • The leaving groups can be a halogen as with SN2 reactions, but this catalytic reaction is useful with esters, most commonly acetate, OAc, as the leaving group ©2018 Cengage Learning. All Rights Reserved. Example 24.3 - Allylic Alkylation • Write the products of the following reactions age NII soi CH 44 1 5 4co H3 z ©2018 Cengage Learning. All Rights Reserved. coechz Example 24.3 - Allylic Alkylation • As stated above, the reaction occurs with retention of stereochemical configuration at the carbon with the acetate leaving group • Consequently, in order to write the products, simply replace the acetate with the enolate, writing a C—C bond between the enolate carbon and the carbon that bears the acetate ©2018 Cengage Learning. All Rights Reserved. Catalytic Cycle of Allylic Alkylation Notarial ©2018 Cengage Learning. All Rights Reserved. Catalytic Allylic Alkylation - Stereochemical and Regiochemical Issues • Several steps in the catalytic cycle are stereoselective • Result in the ability to control the configuration at chiral carbons • In the following example, Y is an electron-withdrawing group (double inversion) ©2018 Cengage Learning. All Rights Reserved. Catalytic Allylic Alkylation - Stereochemical and Regiochemical Issues • Reaction is regioselective • Nucleophilic attack occurs at the less substituted end of the η3-allyl complex regardless of the initial position of the leaving group ©2018 Cengage Learning. All Rights Reserved. Palladium-Catalyzed Cross-Coupling • Catalytic cross-coupling reaction • Reaction wherein a C—C bond is formed in a catalytic fashion between alkyl, aryl, alkenyl, or alkynyl groups • Involves a transmetallation step • Transmetallation: Interchange of ligands between two metals or metalloids • Example: R—Pd + R′—M → R′—Pd + R—M o Pdi • Catalytic cycle of cross-coupling yes pay ©2018 Cengage Learning. All Rights Reserved. firedog dativeaddition synaddition Synelimination Reductive elimination Palladium-Catalyzed Cross-Coupling - Suzuki Coupling • Uses an borane compound (R-BY2) and an alkenyl, aryl, or alkynyl halide or triflate (RX) as the carbon sources (examples next slide) BV I • Bromides and iodides are the most commonly used halides, and haloalkanes can sometimes be used but are subject to elimination • Boron compound can be a borane, a borate ester, or a boric acid • Boranes can be prepared from alkenes or alkynes by hydroboration • Borates are made from aryl or alkyl lithium compounds and trimethyl borate (B(OMe)3 + R-Li) ©2018 Cengage Learning. All Rights Reserved. Palladium-Catalyzed Cross-Coupling - Suzuki Coupling end substituted Less attack open Mali • Examples ©2018 Cengage Learning. All Rights Reserved. Table 24.1 - Suzuki Coupling Examples Where One of the Organoboron Compounds Couples with One of the Coupling Reagents ©2018 Cengage Learning. All Rights Reserved. Palladium-Catalyzed Cross-Coupling - Suzuki Coupling • Mechanism • Starts with an oxidative addition, followed by transmetallation in which the substituent on the borane replaces the ligand on the palladium, followed by a reductive elimination of the palladium to form the new C—C bond ©2018 Cengage Learning. All Rights Reserved. Example 24.4 - Suzuki Coupling • Show how the following penicillin analog can be prepared from the indicated starting material and any other necessary compounds • Solution ©2018 Cengage Learning. All Rights Reserved. Palladium-Catalyzed Cross-Coupling - Stille Coupling • Involves the use of a vinyl or aryl tin reagent, called a stannane, as the transmetallating agent • Coupling with another vinyl or aryl group leads to the creation of conjugated dienes or an alkenylarene • Coupling occurs with regioselectivity and retains the stereochemistry from the reactants to the products ©2018 Cengage Learning. All Rights Reserved. Example 24.5 - Stille Coupling • When a conjugated diene is the desired product in a reaction, a Stille (or Suzuki) coupling is a logical choice to invoke during the synthesis • Write the correct stannane starting material and a vinyl iodide reactant that would couple with Pd(0) catalyst to give the following product ©2018 Cengage Learning. All Rights Reserved. Example 24.5 - Stille Coupling • To consider the proper starting materials for a Stille coupling, dissect the central C—C bond of the diene into two parts in a retrosynthetic fashion • One reactant should be a vinyl iodide (or triflate) and the other reactant a stannane ©2018 Cengage Learning. All Rights Reserved. Palladium-Catalyzed Cross-Coupling Reactions Sonogashira Coupling • Involves transmetallation of an alkynyl-Cu(I) species to Pd followed by coupling to an aryl or vinyl iodide or triflate • The Cu(I) alkynyl complex is created in situ by the reaction of a terminal alkyne with CuI in the presence of triethylamine CUI ©2018 Cengage Learning. All Rights Reserved. Example 24.6 - Sonogashira Coupling • Two Sonogashira coupling reactions can be used to make unsymmetrical diaryl alkynes by first using trimethylsilylacetylene • The trimethylsilyl protecting group can be removed by addition of fluoride (usually tetrabutylammonium fluoride, see Section 11.6) • Show how such a sequence of reactions can be used to construct the following product when one reactant is phenyl iodide s ©2018 Cengage Learning. All Rights Reserved. Example 24.6 - Sonogashira Coupling • Sonogashira coupling conditions using trimethylsilylacetylene give phenyl acetylene in the presence of Cu and Pd catalysts after deprotection using fluoride • Another such coupling using the aryl iodide reactant shown gives the product ©2018 Cengage Learning. All Rights Reserved. Alkene Metathesis (Nobel Prize 2005) • Reaction in which two alkenes interchange carbons attached to their double bonds • Catalysts: Ru-carbene complexes • Certain carbenes with strongly electron-donating substituents are particularly stable • Their stability can be enhanced further by adding sterically bulky substituents that hinder self-reactions • Stable carbenes are ligands for certain metals that are catalysts for the alkene metathesis reaction (Ru = ruthenium) ©2018 Cengage Learning. All Rights Reserved. Alkene Metathesis - Types • Cross-metathesis: If the reaction involves two 2,2-disubstituted alkenes of the type R2C=CH2, the products are ethylene and a new alkene • Loss of gaseous ethylene drives the reaction to the right, giving a single alkene as product • Ring-closing alkene metathesis: A useful variant of this reaction uses a starting material in which both alkenes are in the same molecule • The product obtained is a cycloalkene ©2018 Cengage Learning. All Rights Reserved. Alkene Metathesis - Catalyst • A particularly useful alkene metathesis catalyst consists of ruthenium complexes with a nucleophilic carbene and another carbenoid ligand, C6H5CH=[M], where [M] is the metal with its ligands ©2018 Cengage Learning. All Rights Reserved. Alkene Metathesis - Ligands • Carbene = divalent carbon atom, 6 electron valence shell • Example: cyclic carbene that is stable enough to isolate (IMes), the large 2,4,6-trimethylphenyl substituents protect the carbene from attack by electrophiles or oxygen • The compounds are nucleophiles and excellent ligands for certain transition metals Singlet carbene = spin-paired Triplet carbenes (two unpaired electrons) IMes ©2018 Cengage Learning. All Rights Reserved. Alkene Metathesis - Mechanism • Key step: Addition of a metallocarbenoid to the alkene to give a four-membered metallacycle • Metallacycle is unstable and can either revert to starting material or eliminate an alkene in the opposite direction to give a new alkene • Addition is NOT regioselective • Involves catalysis ©2018 Cengage Learning. All Rights Reserved. Example 24.7 - Ring-Closing Metathesis • Show how the following compound can be prepared from an acyclic diene • Solution • Ring-closing alkene metathesis gives the product in one step ©2018 Cengage Learning. All Rights Reserved.