13.2 Acidity of Alcohols and Phenols A strong base is usually necessary to deprotonate an alcohol A preferred choice to create an alkoxide is to treat the alcohol with Na, K, or Li metal. Show the mechanism for such a reaction Practice with conceptual checkpoint 13.4 Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Recall from chapter 3 how ARIO is used to qualitatively assess the strength of an acid Lets apply these factors to alcohols and phenols Atom Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Lets apply these factors to alcohols and phenols Resonance Explain why phenol is 100 million times more acidic than cyclohexanol Show all relevant resonance contributors Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Given the relatively low pKa of phenols, will NaOH be a strong enough base to deprotonate a phenol? Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Lets apply these factors to alcohols and phenols Induction: unless there is an electronegative group nearby, induction won’t be very significant Orbital: in what type of orbital do the alkoxide electrons reside? How does that effect acidity? Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Solvation is also an important factor that affects acidity Water is generally used as the solvent when measuring pKa values Which of the alcohols below is stronger? ARIO can not be used to explain the difference Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Solvation explains the difference in acidity Draw partial charges on the solvent molecules to show why solvation is a stabilizing effect Practice with SkillBuilder 13.2 Copyright 2012 John Wiley & Sons, Inc.

13.2 Acidity of Alcohols and Phenols Use SCARIO and solvation to rank the following molecules in order of increasing pKa Copyright 2012 John Wiley & Sons, Inc.

13.3 Preparation of Alcohols We saw in chapter 7 that substitution reactions can yield an alcohol What reagents did we use to accomplish this transformation? We saw that the substitution can occur by SN1 or SN2 Copyright 2012 John Wiley & Sons, Inc.

13.3 Preparation of Alcohols The SN1 process generally uses a weak nucleophile (H2O), which makes the process relatively slow Why isn’t a stronger nucleophile (-OH) used under SN1 conditions? Copyright 2012 John Wiley & Sons, Inc.

13.3 Preparation of Alcohols In chapter 9, we learned how to make alcohols from alkenes Recall that acid-catalyzed hydration proceeds through a carbocation intermediate that can possibly rearrange How do you avoid rearrangements? Practice with checkpoints 13.7 and 13.8 Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction A third method to prepare alcohols is by the reduction of a carbonyl. What is a carbonyl? Reductions involve a change in oxidation state Oxidation state are a method of electron bookkeeping Recall how we used formal charge as a method of electron bookkeeping Each atom is assigned half of the electrons it is sharing with another atom What is the formal charge on carbon in methanol? Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction For oxidation states, we imagine the bonds breaking heterolytically, and the electrons go to the more electronegative atom Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Each of the carbons below have zero formal charge, but they have different oxidation states Calculate the oxidation number for each Is the conversion from formic acid  carbon dioxide an oxidation or a reduction? What about formaldehyde  methanol? Practice with SkillBuilder 13.3 Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction The reduction of a carbonyl requires a reducing agent Is the reducing agent oxidized or reduced? If you were to design a reducing agent, what element(s) would be necessary? Would an acid such as HCl be an appropriate reducing agent? WHY or WHY NOT? Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction There are three reducing agents you should know We have already seen how catalyzed hydrogenation can reduce alkenes. It can also work for carbonyls Forceful conditions (high temperature and/or high pressure) Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Reagents that can donate a hydride are generally good reducing agents Sodium borohydride Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Reagents that can donate a hydride are generally good reducing agents Lithium aluminum hydride (LAH) Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Note that LAH is significantly more reactive that NaBH4 LAH reacts violently with water. WHY? How can LAH be used with water if it reacts with water? Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Hydride delivery agents will somewhat selectively reduce carbonyl compounds Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction The reactivity of hydride delivery agents can be fine-tuned by using derivatives with varying R-groups Alkoxides Cyano Sterically hindered groups Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction LAH is strong enough to also reduce esters and carboxylic acids, whereas NaBH4 is generally not Will discuss this mechanism in chapter 21 Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction To reduce an ester, 2 hydride equivalents are needed Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction To reduce an ester, 2 hydride equivalents are needed Which steps in the mechanism are reversible? Copyright 2012 John Wiley & Sons, Inc.

13.4 Alcohol Prep via Reduction Predict the products for the following processes Practice with SkillBuilder 13.4 Copyright 2012 John Wiley & Sons, Inc.

13.5 Preparation of Diols Diols are named using the same method as alcohols, except the suffix, “diol” is used Copyright 2012 John Wiley & Sons, Inc.

13.5 Preparation of Diols If two carbonyl groups are present, and enough moles of reducing agent are added, both can be reduced Copyright 2012 John Wiley & Sons, Inc.

13.5 Preparation of Diols Recall the methods we discussed in chapter 9 to convert an alkene into a diol Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions Grignard reagents are often used in the synthesis of alcohols To form a Grignard, an alkyl halide is treated with Mg metal How does the oxidation state of the carbon change upon forming the Grignard? Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions The electronegativity difference between C (2.5) and Mg (1.3) is great enough that the bond has significant ionic character The carbon atom is not able to effectively stabilize the negative charge it carries Will it act as an acid, base, electrophile, nucleophile, etc.? Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions If the Grignard reagent reacts with a carbonyl compound, an alcohol can result Note the similarities between the Grignard and LAH mechanisms Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions Because the Grignard is both a strong base and a strong nucleophile, care must be taken to protect it from exposure to water If water can’t be used as the solvent, what solvent is appropriate? What techniques are used to keep atmospheric moisture out of the reaction? Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions Grignard examples With an ester substrate, excess Grignard reagent is required. WHY? Propose a mechanism List some functional groups that are NOT compatible with the Grignard Practice with SkillBuilder 13.5 Copyright 2012 John Wiley & Sons, Inc.

13.6 Grignard Reactions Design a synthesis for the following molecules starting from an alkyl halide and a carbonyl, each having 5 carbons or less Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols Consider the reaction below. WHY won’t it work? The alcohol can act as an acid, especially in the presence of reactive reagents like the Grignard reagent The alcohol can be protected to prevent it from reacting Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols A three-step process is required to achieve the desired overall synthesis Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols One such protecting group is trimethylsilyl (TMS) The TMS protection step requires the presence of a base. Propose a mechanism Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols Evidence suggests that substitution at the Si atom occurs by an SN2 mechanism Because Si is much larger than C, it is more open to backside attack Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols The TMS group can later be removed with H3O+ or F- TBAF is often used to supply fluoride ions Copyright 2012 John Wiley & Sons, Inc.

13.7 Protection of Alcohols Practice with conceptual checkpoint 13.18 Copyright 2012 John Wiley & Sons, Inc.

Study Guide for Sections 13.2-13.7 DAY 5, Terms to know: Sections 13.2-13.7 induction, solvation, carbonyl, oxidation, reduction, oxidation state, heterolytic, reducing agent, hydride, LAH, carboxylic acid, ester, oxidizing agent, peracid, diol, syn addition, anti addition, Grignard reagent, protecting group, TBAF DAY 5, Specific outcomes and skills that may be tested on exam 1: Sections 13.2-13.7 Be able to use both SCARIO for qualitative analysis of acidity and pKa for quantitative analysis of acidity Given relevant pKa values, be able to determine whether a specific base will be able to deprotonate a specific alcohol or phenol Be able to determine oxidation numbers for atoms involved in organic compounds Be able to choose appropriate reagents for the reduction of a specific carbonyl group to produce an alcohol Given a specific carbonyl and specific reducing reagents, be able to predict the products of the reaction and draw a complete mechanism Be able to choose appropriate reagents for the addition across a C=C to produce either a syn or anti 1,2 diol Given a specific alkene and specific reagents, be able to predict the products of an addition reaction giving an alcohol or a diol and draw a complete mechanism Be able to choose appropriate reagents for a Grignard reaction to produce a specific alcohol Given a specific carbonyl and specific Grignard reagent, be able to predict the products of the reaction and draw a complete mechanism Be able to give an appropriate solvent for a Grignard reaction and describe techniques that can be used to prevent moisture from reaching the reaction Be able to describe what a protecting group is and give an example when one might be useful in a synthesis Be able to predict the characteristics of peaks in IR, NMR, and MS data obtained for alcohols Be able to give a reasonable structure for a compound given some combination of IR, NMR, and MS data

Extra Practice Problems for Sections 13.2-13.7 Complete these problems outside of class until you are confident you have learned the SKILLS in this section outlined on the study guide and we will review some of them next class period. 13.4a 13.5 13.6 13.7 13.8 13.9 13.10 13.12 13.13 13.14 13.15 13.16 13.17 13.18a 13.33 13.34 13.53 13.54 13.55 13.56

Prep for Day 6 Must Watch videos: Other helpful videos: https://www.youtube.com/watch?v=KPh60w6McPI (alcohol substitution reactions, Khan) https://www.youtube.com/watch?v=YLblFkbYWqc (reaction with PBr3, The Organic Chemistry Tutor) https://www.youtube.com/watch?v=j-rBgs_p-bg (oxidation of alcohols, Khan) https://www.youtube.com/watch?v=0w96SqrvVjw (biological redox, Khan) Other helpful videos: http://ocw.uci.edu/lectures/chem_51b_lec_15_organic_chemistry_reduction_and_oxidization_part_3.html (alcohols, UC-Irvine) start at 20 minute mark Read Sections 13.8-13.13