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  1. Carbenes, :CH2 Preparation of simple carbenes 1. carbene 2. Mechanism of the a elimination.

  2. Reactions of Carbenes, :CH2 (not for synthesis) Addition to double bond. liquid Insertion into C-H bond Formation of ylide (later)

  3. Simmons Smith Reaction (for synthesis, addition to alkenes to yield cyclopropanes) CH2I2 + Zn(Cu)  ICH2ZnI Carbenoid, properties similar to carbenes.

  4. Electronic Structure Electrons paired, singlet

  5. Triplet and Singlet Methylene Dominant form in solution Gas phase Rotation can occur around this bond.

  6. Aldehydes and Ketones Chapter 16

  7. Structure Aldehydes Ketone Carbonyl group sp2 2-pentanone pentanal

  8. Examples of Naming

  9. Resonance result

  10. Extension of resonance

  11. Boiling points For compounds of comparable molecular weight… Alkanes, ethers < aldehydes, ketones < alcohols < carboxylic acids Dipole-dipole Hydrogen Bonding Dispersion Forces Water Solubility Ketones and Aldehydes, like ethers, can function as hydrogen bond acceptors and smaller compounds have significant water solubility.

  12. Recall Preparation from Alcohols PCC RCH2OH RCH=O Can also be done using KMnO4 in base with heat or bleach in acid solution (HOCl). Be sure you can balance this kind of reaction. Use PCC to limit oxidation of primary alcohol to the aldehyde. Secondary are oxidized to ketone. Primary alcohol Secondary PCC R2CHOH R2C=O

  13. Preparations, con’d Reaction of acid chloride and Gilman But where do we get these??

  14. Note that we have two possible disconnects available

  15. Example: Prepare 2-butanone from ethyl alcohol Requirement to start with ethanol suggests a disconnect into two carbon fragments. Done!

  16. Aldehydes from carboxylic acids Reduction And from alcohols, as before: Oxidation

  17. A Common Sequence Observe these parts at this moment.

  18. Reactions Addition of a nucleophile: Nucleophilic Addition Good nucleophile, usually basic + Attack of nucleophile occurs on both sides of carbonyl group. Produces both configurations. + Overall: H – Nu was added to carbonyl group double bond. Notice that the CO bond order was reduced from 2 to 1. The addition reduced the bond order. We will use this idea later.

  19. Reaction can also be done in acid environment. Nucleophiles not expected to be as strong (why?) but the oxygen may become protonated making the carbonyl a better electrophile (why?). Very electronegative, protonated oxygen. Pulls the pi electrons into itself strongly. Problem: If there is too much acid present the nucleophile may become protonated, deactivating it

  20. Addition of Grignard (Trumpets Please) Recall the formation of a Grignard and its addition to an oxirane Carbonyls may be added to in same way… If a new chiral center is created both configurations will be produced.

  21. Common Reactions of Grignards ROHRXRH(D) Both of these reactions extend carbon chain & keep -OH functionality at end of chain. Can extend further. Examine reaction with ester further. ROH + R’CH2OHRX + R’CO2HR2C(OH)R’ ROH + R’R”CHOH RX + R’R”CO RR’C (OH)R” ROHRXRCO2H ROH + R’CH2OHRX + R’CHORCH(OH)R’

  22. Grignard Reacting with an Ester.Look for two kinds of reactions. Substitution Any alcohol will do here. But where does an ester come from? Acid chloride Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2. Addition

  23. Synthetic Planning… Use of epoxides and carbonyls offer different disconnect sites. Pattern HO-C-C-R epoxide Nucleophile New bond. Disconnect site. New bond. Disconnect site Pattern HO-C-R carbonyl Want this to be the nucleophile (Grignard).

  24. Patterns to recognize: carbonyl vs oxirane We can create the following fragments of target molecules by using an organometallic (carbon nucleophile) The difference is the extra CH2 when using an oxirane.

  25. Synthetic Planning… Three different disconnects possible Give synthetic routes to If none of the Rs are H then these three synthetic routes may be available.

  26. Example: Synthesize from ethanol Done • Preliminary Analysis • Hmmm, even number of carbons, at least that is good; ethanol is a two carbon molecule. • Now the problem is to divide it up into smaller fragments. • Ether linkage is easily constructed. Williamson. • Two butyl groups attached to the central 2 carbon fragment. Grignard + ester.

  27. Bisulfite Addition Addition product. Practical importance: liquid carbonyl compounds can be difficult to purify. The bisulfite addition products will be crystalline and may be recrystallized.

  28. Addition of Organolithium Compounds to Carbonyls Generally the reactions are the same as for Grignards but the lithium compounds are more reactive (and more difficult to handle). bromocyclohexane Decreased reactivity of electrophile due to steric hindrance to attack. So we used the alkyl lithium instead of a Grignard.

  29. Nucleophiles derived from terminal alkynes Can do all the reactions of an alkyne and an alcohol. But remember that we have two acidic groups: the more acidic OH and the less acidic terminal alkyne. We discussed this problem earlier. For example, once formed, the new alkynyl alcohol can be hydrated in two ways, Markovnikov and anti Markovnikov. Note that the regioselectivity used here is only effective if this alkyne is terminal. Otherwise get a mixture. Carefully observe the structure of the products, the relationship of the OH and the carbonyl.

  30. Addition of hydrogen cyanide basic Think of what the mechanism should be…. pH issue. Slightly basic media so that HCN has partially ionized to cyanide ion, the actual nucleophile. Followed by protonation of the alkoxide ion (perhaps by unionized HCN).

  31. Follow-up reactions on the cyanohydrins… We saw this hydrogenation before.

  32. Let’s see what we can do with the mechanism of the hydrolysis of the nitrile group to a carboxylic acid. Overall The action is at the nitrile group, CN --> CO2H. But how does a nitrile group behave? What could be happening? We are breaking the CN bond; bond order goes from 3 to 0. Probably stepwise. Chemically speaking: the nitrogen of the nitrile is basic (lone pair) and can be protonated. This makes it a better electrophile (cf. carbonyl). Multiple bond can undergo addition (cf. carbonyl) reducing bond order. Goal: Break the C to N bonding and create C-O bonds. Considerations: neither the electrophile (RCN) nor the nucleophile (water) is very reactive. Since we are in acid protonate the CN group to make it a better electrophile. Then attack it with the water nucleophile to add water. This results in reduction of C-N bond order and creation of C to O bonds .

  33. Again, we are in acid environment. Let’s protonate something…. Protonate the multiple bonded N atom to make better electrophile and attack with the nucleophile, water. What have done so far? Reduced the CN bond order from 3 to 2 and added one O to the C. Moving in the right direction! Want to reduce the CN bond order to zero and introduce more O on the C. Keep going! To induce the water to attack again (adds another O) need to increase the reactivity of the electrophile. Protonate again!! On the O.

  34. Initial equilibrium with acid Now want to get rid of the NH2. We have all the O’s we need. We know what we have to do. Have to get the N protonated to make it a good leaving group. Done.

  35. Wittig Reaction Substitution Elimination Example, synthesize or combine them the other way…

  36. Wittig Reaction Mechanism Acidic hydrogen Nucleophilic substitution Nucleophilic center Phosphonium ylide betaine

  37. Friedel Crafts Acylation And then all the reactions of ketones…

  38. Formation of Hydrates, carbonyls and water. Carbonyl side of equilibrium is usually favored.

  39. Hemiacetals and Acetals, carbonyls and alcohols Addition reaction. (Unstable in Acid; Unstable in base) (Unstable in Acid; Stable in base) Substitution reaction

  40. Formation of Hemiacetals, catalyzed by either acid or base. Let’s do it in Base first. But first let’s take stock. We have an addition reaction. Just mixing a carbonyl and an alcohol do not cause a reaction. One of them must be made a better reactant. Carbonyl can be made into a better electrophile by protonating in acid. Alcohol can become a better nucleophile in base by ionization. Use Base to set-up good necleophile. Poor nucleophile Good nucleophile An addition of the alcohol to the carbonyl has taken place. Same mechanism as discussed earlier. hemiacetal

  41. Alternatively, hemiacetal formation in Acid Protonation of carbonyl (making the oxygen more electronegative) Attack of the (poor) nucleophile on (good) electrophile. Deprotonation Overall, we have added the alcohol to the carbonyl.

  42. Hemiacetal to Acetal, Acid Only Protonate the hemiacetal, setting up leaving group. Departure of leaving group. Attack of nucleophile Substitution reaction, cf SN1. Deprotonation

  43. Equilibria Generally, the hemiacetals and acetals are only a minor component of an equilibrium mixture. In order to favor formation of acetals the carbonyl compound and alcohol is reacted with acid in the absence of water. Dry HCl) The acetals or hemiacetals maybe converted back to the carbonyl compound by treatment with water and acid. An exception is when a cyclic hemiacetal can be formed (5 or 6 membered rings).

  44. Hemiacetal of D-Glucose The alcohol The carbonyl Try following the stereochemistry here for yourself The hemiacetal can form with two different configurations at the carbon of the carbonyl group. The carbon is called the anomeric carbon and the two configurations are called the two anomers. The two anomers are interconverted via the open chain form.

  45. Stabilities of the Anomers… Here note the alternating up-down relationships. More stable b form, with the OH of the anomeric carbon is equatorial Less stable a form. Here see the cis relationship of these two OH groups, one must be axial.

  46. Acetals as Protecting Groups Br-Mg E Synthetic Problem, do a retrosynthetic analysis Target molecule N Form this bond by reacting a nucleophile with an electrophile. Choose Nucleophile and Electrophile centers. Grignard would react with this carbonyl. The nucleophile could take the form of an organolithium or a Grignard reagent. The electrophile would be a carbonyl. Do you see the problem with the approach??

  47. Use Protecting Group for the carbonyl… Acetals are stable (unreactive) in neutral and basic solutions. Create acetal as protecting group. protect Now create Grignard and then react Grignard with the aldehyde to create desired bond. react Remove protecting group. deprotect Same overall steps as when we used silyl ethers: protect, react, deprotect.

  48. Tetrahydropyranyl ethers (acetals) as protecting groups for alcohols. Recall that the key step in forming the acetal was creating the carbocation as shown… There are other ways to create carbocations…… Recall that we can create carbocations in several ways: 1. As shown above by a group leaving. 2. By addition of H+ to a C=C double bond as shown next. This resonance stabilized carbocation then reacts with an alcohol molecule to yield the acetal. An acid This cation can now react with an alcohol to yield an acetal. The alcohol becomes part of an acetal and is protected.

  49. Sample Problem Provide a mechanism for the following conversion First examination: have acid present and will probably protonate Forming an acetal. Keep those mechanistic steps in mind. Ok, what to protonate? Several oxygens and the double bond. Protonation of an alcohol can set-up a better leaving group. Protonation of a carbonyl can create a better electrophile. We do not have a carbonyl but can get a similar species as before.

  50. Strongly electrophilic center, now can do addition to the C=O The protonation of the C=C Now do addition, join the molecules Product Now must open 5 membered ring here. Need to set-up leaving group.