All right guys. Now I want to take this concept one step further and talk about what happens to an enone after it's been reacted. Can it keep reacting? Turns out it can. Now we're going to talk about what's called conjugate addition of enones. Remember that enones are those alpha, beta, unsaturated products of Aldol reactions. Cool. Just before we even get started, I want to just give you a disclaimer that this topic is called a lot of different things. It's also called 1,2 versus 1,4 addition of enones. It's also called nucleophilic addition versus conjugate addition of carbonyls. Just letting you know that if you find it in your textbook or online, it's got a lot of different names but it's all the same concept. What the concept is that once an aldol condensation is completed and you make your enone, this is your enone, an electrophilic carbonyl still remains. You still have this very partial positive. Do you think that it has to stop reacting? No. This thing can react again. Not only that, not only is it susceptible to nucleophilic attack the way that a normal carbonyl would be. But now it actually has a second electrophilic region. How does that work? Because if you look at the resonance structure of this molecule, you could always push the electrons up to the O. That would give me a positive and a negative. That's just a resonance structure of a carbonyl. Another resonance structure would be now that we have this conjugated portion, we could move this double bond into here and then I could get the positive out here. That means that I have an electrophilic region at the 2 position. If you consider my oxygens to be 1, then at the 2 position, I have an electrophilic region. I have a 1, 2 electrophile. But I also have an electrophilic position at the 4 if you're going to consider my oxygen by 1. This would be a 1,4 electrophile. How do I know if I'm attacking with another nucleophile, how do I know if I'm going to attack the 1,2 or the 1,4? The 1,2 is what we call the nucleophilic addition. This is something you should be extremely familiar with because we've been doing this a lot. Nucleophilic addition. The 1,4 addition because it had to do with a conjugated compound that resonated, this is what we call conjugate addition. When I say 1,2 versus 1,4, that's the same thing as saying nucleophilic versus conjugate addition. The answer is it's complicated. It's going to depend on the nucleophiles. Specific nucleophiles are going to favor the nucleophilic addition, the 1,2. And specific nucleophiles, other nucleophiles are going to favor the 1,4. Let's just hash these out. Nucleophilic addition is actually going to be the minority of reactions because that conjugate position is very reactive. There are really only 2 reactions that I know of that are going to want to do this nucleophilic addition on an enone. That's going to be 1, Grignard's. Oh man. I'm forgetting, sorry guys. Grignards. Grignards. And 2 organolithiums. I'm going to put RLi. These are extremely strong nucleophiles that are going to go for this site just like always and we're going to wind up getting a substituted alcohol, except that the alcohol happens to have a double bond on it. Conjugate addition is going to be the majority of additions. Pretty much any other nucleophile besides a Grignard or an organometallic or an organolithium is going to attack here at the 4th spot. What I'm giving you here is specific versions of that. Let's just say you took a generic nucleophile. The product of a generic nucleophile attacking that 4th position would look like this. Notice that there's no more double bond. It's just going to be in that 4 position. Just so you know, some examples of general nucleophiles that could do this would be there are a lot of them. But specifically, CN negative is a very common example. Also a Gilman reagent, so it'll be R2CuLi. That's also called lithium dialkylcuprate or Gilman reagent. Notice that it's easy to confuse this with these guys but it's different. The lithium dialkylcuprate we've mentioned before is weaker than a normal organometallic. I'm going to expect it to add with my conjugate addition, not with my nucleophilic addition. Honestly, just make something up. There are a lot of different nucleophiles that could react there. 2 specifically that I want to add to this list that are very important are the nucleophiles that are going to make a Michael reaction and a Stork enamine synthesis. Because it turns out that a Michael reaction is going to be a conjugated addition of an enone with an enolate. A Michael reaction specifically is when you use an enolate to attack that 4th position. Interesting. When you use an enolate to attack that 4th position, you're going to wind up getting even more carbons attached to each other. An enolate would be specifically a Michael reaction. A Michael reaction is a type of conjugate addition but it's only of enolates. Then we have Stork enamine synthesis. Stork enamine synthesis is when you use an enamine. Remember what an enamine looks like. Let's say a double bond, something like this. I'll make it a really flat cyclohexene there. When you use a Stork enamine synthesis, again, this can be a nucleophile. You can get electrons going down from the end. It can be a nucleophile and it can attack that 4th position. What's so cool about both of these reactions is that both the Michael reaction and the Stork and amine synthesis make the same exact thing. They make 1,5-dicarbonyls. Now 1,5-dicarbonyls might not sound like they're very special. It's like why is that so special? It's just random carbonyls in different places. But if you think about it, 1,5-dicarbonyls are special for one reason. They can cyclize. They can cyclize and self condense. Why? Because they like to form 6-membered rings. The rabbit hole is just getting deeper because now I'm telling you that the product of an aldol can react with stuff. Now I'm telling you that the product of an aldol can react with another aldol to make an aldol product that can cyclize through aldol. Obviously, there's a lot going on. These things can just keep on reacting and reacting. At some point, we've got to call it quits cause this could just go on forever. But there are a few more reactions that are specifically going to need 1,5-dicarbonyls that I want to teach you because most textbooks or professors don't really put it together, don't explain how the Michael reaction and the Stork enamine synthesis both really do the same exact thing to get to the 1,5-dicarbonyl. Other than that, you guys understand that your nucleophilic or your nucleophilic addition just happens with these 2 reagents. Everything else adds conjugate. Let's just add one more we forgot to put the enamine here. Enamine is another one we could use. Let's just put a random one, so just you guys can see that it's like everything. For example, N3 negative. Any nucleophile, pretty much any nucleophile could react at that 4 position and cause that reaction to happen. That being said, let's move on to the next video.
- 1. A Review of General Chemistry5h 5m
- Summary23m
- Intro to Organic Chemistry5m
- Atomic Structure16m
- Wave Function9m
- Molecular Orbitals17m
- Sigma and Pi Bonds9m
- Octet Rule12m
- Bonding Preferences12m
- Formal Charges6m
- Skeletal Structure14m
- Lewis Structure20m
- Condensed Structural Formula15m
- Degrees of Unsaturation15m
- Constitutional Isomers14m
- Resonance Structures46m
- Hybridization23m
- Molecular Geometry16m
- Electronegativity22m
- 2. Molecular Representations1h 14m
- 3. Acids and Bases2h 46m
- 4. Alkanes and Cycloalkanes4h 19m
- IUPAC Naming29m
- Alkyl Groups13m
- Naming Cycloalkanes10m
- Naming Bicyclic Compounds10m
- Naming Alkyl Halides7m
- Naming Alkenes3m
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- Naming Amines15m
- Cis vs Trans21m
- Conformational Isomers13m
- Newman Projections14m
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- Ring Strain8m
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- A-Values17m
- Decalin7m
- 5. Chirality3h 39m
- Constitutional Isomers vs. Stereoisomers9m
- Chirality12m
- Test 1:Plane of Symmetry7m
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- R and S Configuration43m
- Enantiomers vs. Diastereomers13m
- Atropisomers9m
- Meso Compound12m
- Test 3:Disubstituted Cycloalkanes13m
- What is the Relationship Between Isomers?16m
- Fischer Projection10m
- R and S of Fischer Projections7m
- Optical Activity5m
- Enantiomeric Excess20m
- Calculations with Enantiomeric Percentages11m
- Non-Carbon Chiral Centers8m
- 6. Thermodynamics and Kinetics1h 22m
- 7. Substitution Reactions1h 48m
- 8. Elimination Reactions2h 30m
- 9. Alkenes and Alkynes2h 9m
- 10. Addition Reactions3h 18m
- Addition Reaction6m
- Markovnikov5m
- Hydrohalogenation6m
- Acid-Catalyzed Hydration17m
- Oxymercuration15m
- Hydroboration26m
- Hydrogenation6m
- Halogenation6m
- Halohydrin12m
- Carbene12m
- Epoxidation8m
- Epoxide Reactions9m
- Dihydroxylation8m
- Ozonolysis7m
- Ozonolysis Full Mechanism24m
- Oxidative Cleavage3m
- Alkyne Oxidative Cleavage6m
- Alkyne Hydrohalogenation3m
- Alkyne Halogenation2m
- Alkyne Hydration6m
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- 11. Radical Reactions1h 58m
- 12. Alcohols, Ethers, Epoxides and Thiols2h 42m
- Alcohol Nomenclature4m
- Naming Ethers6m
- Naming Epoxides18m
- Naming Thiols11m
- Alcohol Synthesis7m
- Leaving Group Conversions - Using HX11m
- Leaving Group Conversions - SOCl2 and PBr313m
- Leaving Group Conversions - Sulfonyl Chlorides7m
- Leaving Group Conversions Summary4m
- Williamson Ether Synthesis3m
- Making Ethers - Alkoxymercuration4m
- Making Ethers - Alcohol Condensation4m
- Making Ethers - Acid-Catalyzed Alkoxylation4m
- Making Ethers - Cumulative Practice10m
- Ether Cleavage8m
- Alcohol Protecting Groups3m
- t-Butyl Ether Protecting Groups5m
- Silyl Ether Protecting Groups10m
- Sharpless Epoxidation9m
- Thiol Reactions6m
- Sulfide Oxidation4m
- 13. Alcohols and Carbonyl Compounds2h 17m
- 14. Synthetic Techniques1h 26m
- 15. Analytical Techniques:IR, NMR, Mass Spect6h 50m
- Purpose of Analytical Techniques5m
- Infrared Spectroscopy16m
- Infrared Spectroscopy Table31m
- IR Spect:Drawing Spectra40m
- IR Spect:Extra Practice26m
- NMR Spectroscopy10m
- 1H NMR:Number of Signals26m
- 1H NMR:Q-Test26m
- 1H NMR:E/Z Diastereoisomerism8m
- H NMR Table21m
- 1H NMR:Spin-Splitting (N + 1) Rule17m
- 1H NMR:Spin-Splitting Simple Tree Diagrams11m
- 1H NMR:Spin-Splitting Complex Tree Diagrams8m
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- NMR Integration18m
- NMR Practice14m
- Carbon NMR4m
- Structure Determination without Mass Spect47m
- Mass Spectrometry12m
- Mass Spect:Fragmentation28m
- Mass Spect:Isotopes27m
- 16. Conjugated Systems6h 13m
- Conjugation Chemistry13m
- Stability of Conjugated Intermediates4m
- Allylic Halogenation12m
- Reactions at the Allylic Position39m
- Conjugated Hydrohalogenation (1,2 vs 1,4 addition)26m
- Diels-Alder Reaction9m
- Diels-Alder Forming Bridged Products11m
- Diels-Alder Retrosynthesis8m
- Molecular Orbital Theory9m
- Drawing Atomic Orbitals6m
- Drawing Molecular Orbitals17m
- HOMO LUMO4m
- Orbital Diagram:3-atoms- Allylic Ions13m
- Orbital Diagram:4-atoms- 1,3-butadiene11m
- Orbital Diagram:5-atoms- Allylic Ions10m
- Orbital Diagram:6-atoms- 1,3,5-hexatriene13m
- Orbital Diagram:Excited States4m
- Pericyclic Reaction10m
- Thermal Cycloaddition Reactions26m
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- Thermal Electrocyclic Reactions14m
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- Cumulative Electrocyclic Problems25m
- Sigmatropic Rearrangement17m
- Cope Rearrangement9m
- Claisen Rearrangement15m
- 17. Ultraviolet Spectroscopy51m
- 18. Aromaticity2h 31m
- 19. Reactions of Aromatics: EAS and Beyond5h 1m
- Electrophilic Aromatic Substitution9m
- Benzene Reactions11m
- EAS:Halogenation Mechanism6m
- EAS:Nitration Mechanism9m
- EAS:Friedel-Crafts Alkylation Mechanism6m
- EAS:Friedel-Crafts Acylation Mechanism5m
- EAS:Any Carbocation Mechanism7m
- Electron Withdrawing Groups22m
- EAS:Ortho vs. Para Positions4m
- Acylation of Aniline9m
- Limitations of Friedel-Crafts Alkyation19m
- Advantages of Friedel-Crafts Acylation6m
- Blocking Groups - Sulfonic Acid12m
- EAS:Synergistic and Competitive Groups13m
- Side-Chain Halogenation6m
- Side-Chain Oxidation4m
- Reactions at Benzylic Positions31m
- Birch Reduction10m
- EAS:Sequence Groups4m
- EAS:Retrosynthesis29m
- Diazo Replacement Reactions6m
- Diazo Sequence Groups5m
- Diazo Retrosynthesis13m
- Nucleophilic Aromatic Substitution28m
- Benzyne16m
- 20. Phenols55m
- 21. Aldehydes and Ketones: Nucleophilic Addition4h 56m
- Naming Aldehydes8m
- Naming Ketones7m
- Oxidizing and Reducing Agents9m
- Oxidation of Alcohols28m
- Ozonolysis7m
- DIBAL5m
- Alkyne Hydration9m
- Nucleophilic Addition8m
- Cyanohydrin11m
- Organometallics on Ketones19m
- Overview of Nucleophilic Addition of Solvents13m
- Hydrates6m
- Hemiacetal9m
- Acetal12m
- Acetal Protecting Group16m
- Thioacetal6m
- Imine vs Enamine15m
- Addition of Amine Derivatives5m
- Wolff Kishner Reduction7m
- Baeyer-Villiger Oxidation39m
- Acid Chloride to Ketone7m
- Nitrile to Ketone9m
- Wittig Reaction18m
- Ketone and Aldehyde Synthesis Reactions14m
- 22. Carboxylic Acid Derivatives: NAS2h 51m
- Carboxylic Acid Derivatives7m
- Naming Carboxylic Acids9m
- Diacid Nomenclature6m
- Naming Esters5m
- Naming Nitriles3m
- Acid Chloride Nomenclature5m
- Naming Anhydrides7m
- Naming Amides5m
- Nucleophilic Acyl Substitution18m
- Carboxylic Acid to Acid Chloride6m
- Fischer Esterification5m
- Acid-Catalyzed Ester Hydrolysis4m
- Saponification3m
- Transesterification5m
- Lactones, Lactams and Cyclization Reactions10m
- Carboxylation5m
- Decarboxylation Mechanism14m
- Review of Nitriles46m
- 23. The Chemistry of Thioesters, Phophate Ester and Phosphate Anhydrides1h 10m
- 24. Enolate Chemistry: Reactions at the Alpha-Carbon1h 53m
- Tautomerization9m
- Tautomers of Dicarbonyl Compounds6m
- Enolate4m
- Acid-Catalyzed Alpha-Halogentation4m
- Base-Catalyzed Alpha-Halogentation3m
- Haloform Reaction8m
- Hell-Volhard-Zelinski Reaction3m
- Overview of Alpha-Alkylations and Acylations5m
- Enolate Alkylation and Acylation12m
- Enamine Alkylation and Acylation16m
- Beta-Dicarbonyl Synthesis Pathway7m
- Acetoacetic Ester Synthesis13m
- Malonic Ester Synthesis15m
- 25. Condensation Chemistry2h 9m
- 26. Amines1h 43m
- 27. Heterocycles2h 0m
- Nomenclature of Heterocycles15m
- Acid-Base Properties of Nitrogen Heterocycles10m
- Reactions of Pyrrole, Furan, and Thiophene13m
- Directing Effects in Substituted Pyrroles, Furans, and Thiophenes16m
- Addition Reactions of Furan8m
- EAS Reactions of Pyridine17m
- SNAr Reactions of Pyridine18m
- Side-Chain Reactions of Substituted Pyridines20m
- 28. Carbohydrates5h 53m
- Monosaccharide20m
- Monosaccharides - D and L Isomerism9m
- Monosaccharides - Drawing Fischer Projections18m
- Monosaccharides - Common Structures6m
- Monosaccharides - Forming Cyclic Hemiacetals12m
- Monosaccharides - Cyclization18m
- Monosaccharides - Haworth Projections13m
- Mutarotation11m
- Epimerization9m
- Monosaccharides - Aldose-Ketose Rearrangement8m
- Monosaccharides - Alkylation10m
- Monosaccharides - Acylation7m
- Glycoside6m
- Monosaccharides - N-Glycosides18m
- Monosaccharides - Reduction (Alditols)12m
- Monosaccharides - Weak Oxidation (Aldonic Acid)7m
- Reducing Sugars23m
- Monosaccharides - Strong Oxidation (Aldaric Acid)11m
- Monosaccharides - Oxidative Cleavage27m
- Monosaccharides - Osazones10m
- Monosaccharides - Kiliani-Fischer23m
- Monosaccharides - Wohl Degradation12m
- Monosaccharides - Ruff Degradation12m
- Disaccharide30m
- Polysaccharide11m
- 29. Amino Acids3h 20m
- Proteins and Amino Acids19m
- L and D Amino Acids14m
- Polar Amino Acids14m
- Amino Acid Chart18m
- Acid-Base Properties of Amino Acids33m
- Isoelectric Point14m
- Amino Acid Synthesis: HVZ Method12m
- Synthesis of Amino Acids: Acetamidomalonic Ester Synthesis16m
- Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis13m
- Synthesis of Amino Acids: Strecker Synthesis13m
- Reactions of Amino Acids: Esterification7m
- Reactions of Amino Acids: Acylation3m
- Reactions of Amino Acids: Hydrogenolysis6m
- Reactions of Amino Acids: Ninhydrin Test11m
- 30. Peptides and Proteins2h 42m
- Peptides12m
- Primary Protein Structure4m
- Secondary Protein Structure17m
- Tertiary Protein Structure11m
- Disulfide Bonds17m
- Quaternary Protein Structure10m
- Summary of Protein Structure7m
- Intro to Peptide Sequencing2m
- Peptide Sequencing: Partial Hydrolysis25m
- Peptide Sequencing: Partial Hydrolysis with Cyanogen Bromide7m
- Peptide Sequencing: Edman Degradation28m
- Merrifield Solid-Phase Peptide Synthesis18m
- 32. Lipids 2h 50m
- 34. Nucleic Acids1h 32m
- 35. Transition Metals5h 33m
- Electron Configuration of Elements45m
- Coordination Complexes20m
- Ligands24m
- Electron Counting10m
- The 18 and 16 Electron Rule13m
- Cross-Coupling General Reactions40m
- Heck Reaction40m
- Stille Reaction13m
- Suzuki Reaction25m
- Sonogashira Coupling Reaction17m
- Fukuyama Coupling Reaction15m
- Kumada Coupling Reaction13m
- Negishi Coupling Reaction16m
- Buchwald-Hartwig Amination Reaction19m
- Eglinton Reaction17m
Conjugate Addition - Online Tutor, Practice Problems & Exam Prep
Enones, formed from aldol condensation, can undergo further reactions through conjugate addition, also known as 1,4-addition. This involves nucleophiles attacking the electrophilic carbon at the 4-position, while strong nucleophiles like Grignard reagents favor 1,2-addition. Common nucleophiles for conjugate addition include cyanide and lithium dialkylcuprate. Notably, Michael reactions and Stork enamine synthesis are specific cases of conjugate addition that yield 1,5-dicarbonyls, which can cyclize to form six-membered rings, showcasing the dynamic reactivity of enones in organic synthesis.
Once an aldol condensation is completed and we make our enone, an electrophilic carbonyl still remains. Enones specifically have two electrophilic regions on them. I guess that means there's more to the story...
1,2 vs 1,4 Addition
Video transcript
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More setsHere’s what students ask on this topic:
What is conjugate addition in organic chemistry?
Conjugate addition, also known as 1,4-addition, is a reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This process involves the nucleophile attacking the electrophilic carbon at the 4-position, resulting in the addition across the conjugated system. This type of addition is common with nucleophiles like cyanide (CN-) and lithium dialkylcuprate (R2CuLi). Conjugate addition is significant in organic synthesis as it allows for the formation of complex molecules, such as 1,5-dicarbonyls, which can further cyclize to form six-membered rings.
What is the difference between 1,2-addition and 1,4-addition in enones?
1,2-Addition and 1,4-addition refer to the positions where nucleophiles attack an enone. In 1,2-addition, the nucleophile attacks the carbonyl carbon (position 2), leading to the formation of a substituted alcohol. This type of addition is favored by strong nucleophiles like Grignard reagents (RMgX) and organolithiums (RLi). In contrast, 1,4-addition, or conjugate addition, involves the nucleophile attacking the β-carbon (position 4) of the enone. This is favored by weaker nucleophiles such as cyanide (CN-) and lithium dialkylcuprate (R2CuLi), resulting in the addition across the conjugated system.
What are some common nucleophiles used in conjugate addition reactions?
Common nucleophiles used in conjugate addition reactions include cyanide (CN-), lithium dialkylcuprate (R2CuLi), and enamines. These nucleophiles are less reactive compared to strong nucleophiles like Grignard reagents and organolithiums, making them suitable for attacking the β-carbon (position 4) of α,β-unsaturated carbonyl compounds (enones). Additionally, enolates and enamines are used in specific conjugate addition reactions such as the Michael reaction and Stork enamine synthesis, respectively, to form 1,5-dicarbonyl compounds.
What is a Michael reaction in organic chemistry?
A Michael reaction is a type of conjugate addition where an enolate ion acts as the nucleophile and adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This reaction results in the formation of a 1,5-dicarbonyl compound. The Michael reaction is significant in organic synthesis because the 1,5-dicarbonyl products can undergo further reactions, such as cyclization, to form six-membered rings. This reaction is a key method for forming carbon-carbon bonds and constructing complex molecular architectures.
What is Stork enamine synthesis?
Stork enamine synthesis is a method in organic chemistry where an enamine acts as a nucleophile in a conjugate addition reaction. The enamine attacks the β-carbon of an α,β-unsaturated carbonyl compound (enone), resulting in the formation of a 1,5-dicarbonyl compound. This reaction is similar to the Michael reaction but uses an enamine instead of an enolate. The 1,5-dicarbonyl products formed can further cyclize to form six-membered rings, making Stork enamine synthesis a valuable tool for constructing complex molecules in organic synthesis.
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