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

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

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

Template for Reactions Why stereospecific, why from same side as OH group? Interaction with metal holds the carbenoid on the top side.

Electronic Structure Electrons paired, singlet

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

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 Water Solubility 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 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 RCH2OH RCH=O PCC 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

New bond. Disconnect site. 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

hydrolysis of the nitrile group to a carboxylic acid. 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 or combine them the other way… Example, synthesize 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 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 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. Br-Mg 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

Provide a mechanism for the following conversion 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. 51

Followed by new ring closure. Leaving group leaves…. Followed by new ring closure. Done. Wow! 52

Sulfur Analogs Consider formation of acetal Sulfur Analog 53

The aldehyde hydrogen has been made acidic Why acidic? Sulfur, like phosphorus, has 3d orbitals capable of accepting electrons: violating octet rule. 54 54

Recall early steps from the Wittig reaction discussed earlier This hydrogen is acidic. Why acidic? The P is positive and can accept charge from the negative carbon into the 3d orbitals 55

Some Synthetic Applications 56

Umpolung – reversed polarity What we have done in these synthetic schemes is to reverse the polarity of the carbonyl group; change it from an electrophile into a nucleophile. electrophile nucleophilic Can you think of two other examples of Umpolung we have seen? 57

Nitrogen Nucleophiles 58

Mechanism of Schiff Base formation Attack of nucleophile on the carbonyl Followed by transfer of proton from weak acid to strong base. Protonation of –OH to establish leaving group. Leaving group departs, double bond forms. 59

Hydrazine derivatives 60

Note which nitrogen is nucleophilic Nucleophilic nitrogen Favored by resonance Less steric hinderance 61

Reductive Amination Pattern: R2C=O + H2N-R’   R2CH-NH-R’ 62

Enamines Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2. Primary amine But secondary amines react to give enamines See if you can write the mechanism for the reaction. Secondary Amine 63

Acidity of a Hydrogens a hydrogens are weakly acidic Weaker acid than alcohols but stronger than terminal alkynes. Learn this table…. 64

Keto-Enol Tautomerism (Note: we saw tautomerism before in the hydration of alkynes.) Fundamental process Mechanism in base: Negative carbon, a carbanion, basic, nucleophilic carbon. Additional resonance form, stabilizing anion, reducing basicity and nucleophilicity. Protonation to yield enol form. 65

Details… Base strength Alkoxides will not cause appreciable ionization of simple carbonyl compounds to enolate. Strong bases (KH or NaNH2) will cause complete ionization to enolate. Double activation (1,3 dicarbonyl compounds) will be much more acidic. For some 1,3 dicarbonyl compounds the enol form may be more stable than the keto form. 66

More details… Nucleophilic carbon nucleophilicity Some examples: 67

Some reactions related to acidity of a hydrogens Racemization Exchange 68

Oxidation: Aldehyde  Carboxylic Recall from the discussion of alcohols. Milder oxidizing reagents can also be used Tollens Reagent test for aldehydes 69

“Drastic Oxidation” of Ketones Obtain four different products in this case. 70

Reductions: two electron NaBH4 Or LiAlH4 71

Reductions: Four Electron Clemmenson Wolf-Kishner 72

Mechanism of Wolf-Kishner, C=O  CH2 Recall reaction of primary amine and carbonyl to give Schiff base. Here is the formation of the Schiff base. We expect this to happen. These hydrogens are weakly acidic, just as the hydrogens a to a carbonyl are acidic. Weakly acidic hydrogen removed. Resonance occurs. Same as keto/enol tautomerism. Protonation (like forming the enol) Perform an elimination reaction to form N2. 73

Haloform Reaction, overall The last step which produces the haloform, HCX3 only occurs if there is an a methyl group, a methyl directly attached to the carbonyl. a methyl If done with iodine then the formation of iodoform, HCI3, a bright yellow precipitate, is a test for an a methyl group (iodoform test). 74

Steps of Haloform Reaction The first reaction: All three H’s replaced by This must happen stepwise, like this: Pause for a sec: We have had three mechanistic discussions of how elemental halogen, X2, reacts with a hydrocarbon to yield a new C-X bond. Do you recall them? Radical Reaction: R. + X-X  R-X + X. (initiation required) Addition to double bond: C=C + X-X  + Br- (alkene acts as nucleophile, ions) Nucleophilic enolate anion: 75

Mechanism of Haloform Reaction-1 Using the last of the three possibilities One H has been replaced by halogen. Repeat twice again to yield Where are we? The halogens have been introduced. First reaction completed. But now we need a substitution reaction. We have to replace the CBr3 group with OH. 76

Mechanism of Haloform - 2 This is a substitution step; OH- replaces the CX3 and then ionizes to become the carboxylate anion. Here’s how: Attack of hydroxide nucleophile. Formation of tetrahedral intermediate. Anticipate the attack… Reform the carbonyl double bond. CX3- is ejected. The halogens stabilize the negative carbon. Neutralization. 77

Cannizaro Reaction Overall: Restriction: no a hydrogens in the aldehydes. a hydrogens No a hydrogens Why the restriction? The a hydrogens are acidic leading to ionization. 78

Mechanism What can happen? Reactants are the aldehyde and concentrated hydroxide. Hydroxide ion can act both as Base, but remember we have no acidic hydrogens (no a hydrogens). Nucleophile, attacking carbonyl group. Attack of nucleophilic HO- Acid-base Re-establish C=O and eject H- which is immediately received by second RCHO 79

Experimental Evidence These are the hydrogens introduced by the reaction. They originate in the aldeyde and do not come from the aqueous hydroxide solution. 80

Kinetic vs Thermodynamic Contol of a Reaction Examine Addition of HBr to 1,3 butadiene 81

But which is the dominant product? Mechanism of reaction. Allylic resonance But which is the dominant product? 82

Nature of the product mixture depends on the temperature. Product mixture at -80 deg 80% 20% Product mixture at + 40 deg 20% 80% Goal of discussion: how can temperature control the product mixture? 83

When two or more products may be formed in a reaction A  X or A  B Thermodynamic Control: Most stable product dominates Kinetic Control: Product formed fastest dominates Thermodynamic control assumes the establishing of equilibrium conditions and the most stable product dominates. Kinetic Control assumes that equilibrium is not established. Once product is made it no longer changes. Equilibrium is more rapidly established at high temperature. Thermodynamic control should prevail at high temperature where equilibrium is established. Kinetic Control may prevail at low temperature where reverse reactions are very slow. 84

Nature of the product mixture depends on the temperature. Product mixture at -80 deg 80% 20% Product mixture at + 40 deg 20% 80% More stable product Thermodynamic Control Kinetic Control Product formed most quickly, lowest Ea 85

Formation of the allylic carbocation. Can react to yield 1,2 product or 1,4 product. 86

Most of the carbocation reacts to give the 1,2 product because of the smaller Ea leading to the 1,2 product. This is true at all temperatures. At low temperatures the reverse reactions do not occur and the product mixture is determined by the rates of forward reactions. No equilibrium. 87

Most of the carbocation reacts to give the 1,2 product because of the smaller Ea leading to the 1,2 product. This is true at all temperatures. At higher temperatures the reverse reactions occur leading from the 1,2 or 1,4 product to the carbocation. Note that the 1,2 product is more easily converted back to the carbocation than is the 1,4. Now the 1,4 product is dominant. 88

Diels Alder Reaction/Symmetry Controlled Reactions Quick Review of formation of chemical bond. Electron donor Electron acceptor Note the overlap of the hybrid (donor) and the s orbital which allows bond formation. For this arrangement there is no overlap. No donation of electrons; no bond formation.

Diels Alder Reaction of butadiene and ethylene to yield cyclohexene. We will analyze in terms of the pi electrons of the two systems interacting. The pi electrons from the highest occupied pi orbital of one molecule will donate into an lowest energy pi empty of the other. Works in both directions: A donates into B, B donates into A. B HOMO donates into A LUMO Note the overlap leading to bond formation LUMO acceptor LUMO acceptor A HOMO donates into B LUMO HOMO donor HOMO donor Note the overlap leading to bond formation B A

Try it in another reaction: ethylene + ethylene  cyclobutane LUMO LUMO Equal bonding and antibonding interaction, no overlap, no bond formation, no reaction HOMO HOMO

Reaction Problem 92

Synthesis problem 93

Mechanism Problem Give the mechanism for the following reaction. Show all important resonance structures. Use curved arrow notation. 94