Alcohols, Ethers, and Epoxides (Chapter 7) PDF

Chapter 7 Alcohols, Ethers and Epoxides Introduction—Structure and Bonding Alcohols contain a hydroxy group (OH) bonded to an sp3 hybridized carbon. 1  Compounds having a hydroxy group on a sp2 hybridized carbon—enols and phenol...

Chapter 7 Alcohols, Ethers and Epoxides Introduction—Structure and Bonding Alcohols contain a hydroxy group (OH) bonded to an sp3 hybridized carbon. 1  Compounds having a hydroxy group on a sp2 hybridized carbon—enols and phenols—undergo different reactions than alcohols. Ethers have two alkyl groups bonded to an oxygen atom. 2  Epoxides are ethers having the oxygen atom in a three- membered ring. Epoxides are also called oxiranes. The C—O—C bond angle for an epoxide must be 60°, a considerable deviation from the tetrahedral bond angle of 109.5°. Thus, epoxides have angle strain, making them more reactive than other ethers. 3  The oxygen atom in alcohols, ethers and epoxides is sp3 hybridized. Alcohols and ethers have a bent shape like that in H2O. The bond angle around the O atom in an alcohol or ether is similar to the tetrahedral bond angle of 109.5°. Because the O atom is much more electronegative than carbon or hydrogen, the C—O and O—H bonds are all polar. 4 5  When an OH group is bonded to a ring, the ring is numbered beginning with the OH group. Because the functional group is at C1, the 1 is usually omitted from the name. The ring is then numbered in a clockwise or counterclockwise fashion to give the next substituent the lowest number. Figure 9.2 Examples: Naming cyclic alcohols 6  Common names are often used for simple alcohols. To assign a common name: Name all the carbon atoms of the molecule as a single alkyl group. Add the word alcohol, separating the words with a space. 7  Compounds with two hydroxy groups are called diols or glycols. Compounds with three hydroxy groups are called triols and so forth. 8 Nomenclature of Ethers Simple ethers are usually assigned common names. To do so: Name both alkyl groups bonded to the oxygen, arrange these names alphabetically, and add the word ether. For symmetrical ethers, name the alkyl group and add the prefix “di-”. 9  More complex ethers are named using the IUPAC system. One alkyl group is named as a hydrocarbon chain, and the other is named as part of a substituent bonded to that chain: Name the simpler alkyl group as an alkoxy substituent by changing the –yl ending of the alkyl group to –oxy. Name the remaining alkyl group as an alkane, with the alkoxy group as a substituent bonded to this chain. Cyclic ethers have an O atom in the ring. A common example is tetrahydrofuran (THF). 10  Nomenclature of Epoxides Epoxides can be named in three different ways—As epoxyalkanes, oxiranes, or alkene oxides. To name an epoxide as an epoxyalkane, first name the alkane chain or ring to which the O atom is attached, and use the prefix “epoxy” to name the epoxide as a substituent. Use two numbers to designate the location of the atoms to which the O’s are bonded. 11  Epoxides bonded to a chain of carbon atoms can also be named as derivatives of oxirane, the simplest epoxide having two carbons and one oxygen atom in a ring. The oxirane ring is numbered to put the O atom at position one, and the first substituent at position two. No number is used for a substituent in a monosubstituted oxirane. 12  Epoxides are also named as alkene oxides, since they are often prepared by adding an O atom to an alkene. To name an epoxide in this way: Mentally replace the epoxide oxygen with a double bond. Name the alkene. Add the word oxide. 13 Physical Properties Alcohols, ethers and epoxides exhibit dipole-dipole interactions because they have a bent structure with two polar bonds. Alcohols are capable of intermolecular hydrogen bonding. Thus, alcohols are more polar than ethers and epoxides. Steric factors affect hydrogen bonding. 14 15 Preparation of Alcohols, Ethers, and Epoxides Alcohols and ethers are both common products of nucleophilic substitution. The preparation of ethers by the method shown in the last two equations is called the Williamson ether synthesis. 16  In theory, unsymmetrical ethers can be synthesized in two different ways; in practice, one path is usually preferred. 17  An alkoxide salt is needed to make an ether. Alkoxides can be prepared from alcohols by a BrØnsted- Lowry acid—base reaction. For example, sodium ethoxide (NaOCH2CH3) is prepared by treating ethanol with NaH. NaH is an especially good base for forming alkoxide because the by-product of the reaction, H2, is a gas that just bubbles out of the reaction mixture. 18  Organic compounds that contain both a hydroxy group and a halogen atom on adjacent carbons are called halohydrins. In halohydrins, an intramolecular version of the Williamson ether synthesis can occur to form epoxides. 19  Reactions of Alcohols Recall that, unlike alkyl halides in which the halogen atom serves as a good leaving group, the OH group in alcohols is a very poor leaving group. For an alcohol to undergo nucleophilic substitution, OH must be converted into a better leaving group. By using acid, ¯OH can be converted into H2O, a good leaving group. 20 Reactions of Alcohols—Dehydration Dehydration, like dehydrohalogenation, is a  elimination reaction in which the elements of OH and H are removed from the  and  carbon atoms respectively. Dehydration is typically carried out using H2SO4 and other strong acids, or phosphorus oxychloride (POCl3) in the presence of an amine base. 21  Typical acids used for alcohol dehydration are H2SO4 or p- toluenesulfonic acid (TsOH). O S OH O p-toluenesulfonic acid More substituted alcohols dehydrate more easily, giving rise to the following order of reactivity. 22  When an alcohol has two or three  carbons, dehydration is regioselective and follows the Zaitsev rule. The more substituted alkene is the major product when a mixture of constitutional isomers is possible. 23  Secondary and 3° alcohols react by an E1 mechanism, whereas 1° alcohols react by an E2 mechanism. 24  The E1 dehydration of 20 and 30 alcohols with acid gives clean elimination products without any by-products formed from an SN1 reaction. Clean elimination takes place because the reaction mixture contains no good nucleophile to react with the intermediate carbocation, so no competing SN1 reaction occurs. This makes the E1 dehydration of alcohols much more synthetically useful than the E1 dehydrohalogenation of alkyl halides. 25  Since 1° carbocations are highly unstable, their dehydration cannot occur by an E1 mechanism involving a carbocation intermediate. Therefore, 1° alcohols undergo dehydration following an E2 mechanism. 26  Although entropy favors product formation in dehydration (i.e., one molecule of reactant forms two molecules of product), enthalpy does not, since the  bonds broken in the reactant are stronger than the  and  bonds formed in the products. 27  According to Le Châtelier’s principle, a system at equilibrium will react to counteract any disturbance to the equilibrium. One consequence of this is that removing a product from a reaction mixture as it is formed drives the equilibrium to the right, forming more product. Thus, the alkene, which usually has a lower boiling point than the starting alcohol, can be removed by distillation as it is formed, thus driving the equilibrium to the right to favor production of more product. 28 Carbocation Rearrangements Often, when carbocations are intermediates, a less stable carbocation will be converted into a more stable carbocation by a shift of a hydrogen or an alkyl group. This is called a rearrangement. Because the migrating group in a 1,2-shift moves with two bonding electrons, the carbon it leaves behind now has only three bonds (six electrons), giving it a net positive (+) charge. 29 30  A 1,2-shift can convert a less stable carbocation into a more stable carbocation. Rearrangements are not unique to dehydration reactions. Rearrangements can occur whenever a carbocation is formed as a reactive intermediate. Consider the example below. 2° Carbocation A rearranges to the more stable 3° carbocation by a 1,2-hydride shift, whereas carbocation B does not rearrange because it is 3° to begin with. 31  Dehydration of Alcohols Using POCl3 and Pyridine Some organic compounds decompose in the presence of strong acid, so other methods have been developed to convert alcohols to alkenes. A common method uses phosphorus oxychloride (POCl3) and pyridine (an amine base) in place of H2SO4 or TsOH. POCl3 serves much the same role as a strong acid does in acid-catalyzed dehydration. It converts a poor leaving group (¯OH) into a good leaving group. Dehydration then proceeds by an E2 mechanism. 32 33 Conversion of Alcohols to Alkyl Halides with HX Substitution reactions do not occur with alcohols unless ¯OH is converted into a good leaving group. The reaction of alcohols with HX (X = Cl, Br, I) is a general method to prepare 1°, 2°, and 3° alkyl halides. 34  More substituted alcohols usually react more rapidly with HX: This order of reactivity can be rationalized by considering the reaction mechanisms involved. The mechanism depends on the structure of the R group. 35 36 37  The reactivity of hydrogen halides increases with increasing acidity. Because Cl¯ is a poorer nucleophile than Br¯ or I¯, the reaction of 10 alcohols with HCl occurs only when an additional Lewis acid catalyst, usually ZnCl2, is added. Complexation of ZnCl2 with the O atom of the alcohol makes a very good leaving group that facilitates the SN2 reaction. 38  Knowing the mechanism allows us to predict the stereochemistry of the products when the reaction occurs at a stereogenic center. 39 Conversion of Alcohols to Alkyl Halides with SOCl 2 and PBr3 Primary and 2° alcohols can be converted to alkyl halides using SOCl2 and PBr3. SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides. PBr3 (phosphorus tribromide) converts alcohols into alkyl bromides. Both reagents convert ¯OH into a good leaving group in situ—that is, directly in the reaction mixture—as well as provide the nucleophile, either Cl¯ or Br¯, to displace the leaving group. 40  When a 1° or 2° alcohol is treated with SOCl2 and pyridine, an alkyl chloride is formed, with HCl and SO2 as byproducts. The mechanism of this reaction consists of two parts: conversion of the OH group into a better leaving group, and nucleophilic cleavage by Cl¯ via an SN2 reaction. 41 42  Treatment of a 10 or 20 alcohol with PBr3 forms an alkyl halide. The mechanism of this reaction also consists of two parts: conversion of the OH group into a better leaving group, and nucleophilic cleavage by Br¯ via an SN2 reaction. 43 44 45  Tosylate—Another Good Leaving Group Alcohols can be converted into alkyl tosylates. An alkyl tosylate is composed of two parts: the alkyl group R, derived from an alcohol; and the tosylate (short for p- toluenesulfonate), which is a good leaving group. A tosyl group, CH3C6H4SO2¯, is abbreviated Ts, so an alkyl tosylate becomes ROTs. 46  Alcohols are converted to tosylates by treatment with p- toluenesulfonyl chloride (TsCl) in the presence of pyridine. This process converts a poor leaving group (¯OH) into a good one (¯OTs). Tosylate is a good leaving group because its conjugate acid, p-toluenesulfonic acid (CH3C6H4SO3H, TsOH) is a strong acid (pKa = -7). 47  (S)-2-Butanol is converted to its tosylate with retention of configuration at the stereogenic center. Thus, the C —O bond of the alcohol is not broken when tosylate is formed. 48  Because alkyl tosylates have good leaving groups, they undergo both nucleophilic substitution and  elimination, exactly as alkyl halides do. Generally, alkyl tosylates are treated with strong nucleophiles and bases, so the mechanism of substitution is SN2, and the mechanism of elimination is E2. 49  Because substitution occurs via an SN2 mechanism, inversion of configuration results when the leaving group is bonded to a stereogenic center. We now have another two-step method to convert an alcohol to a substitution product: reaction of an alcohol with TsCl and pyridine to form a tosylate (step 1), followed by nucleophilic attack on the tosylate (step 2). 50  Step 1, formation of the tosylate, proceeds with retention of configuration at a stereogenic center. Step 2 is an SN2 reaction, so it proceeds with inversion of configuration because the nucleophile attacks from the backside. Overall there is a net inversion of configuration at a stereogenic center. Example: 51  Figure 9.8 Summary: Nucleophilic substitution and β elimination reactions of alcohols 52 Reaction of Ethers with Strong Acid In order for ethers to undergo substitution or elimination reactions, their poor leaving group must first be converted into a good leaving group by reaction with strong acids such as HBr and HI. HBr and HI are strong acids that are also sources of good nucleophiles (Br¯ and I¯ respectively). When ethers react with HBr or HI, both C—O bonds are cleaved and two alkyl halides are formed as products. 53  The mechanism of ether cleavage is SN1 or SN2, depending on the identity of R. When 2° or 3° alkyl groups are bonded to the ether oxygen, the C —O bond is cleaved by an SN1 mechanism involving a carbocation. With methyl or 1° R groups, the C—O bond is cleaved by an SN2 mechanism. Example: In the reaction of (CH3)3COCH3 with HI, the 3° alkyl group undergoes nucleophilic substitution by an SN1 mechanism, resulting in the cleavage of one C—O bond. The methyl group undergoes nucleophilic substitution by an SN2 mechanism, resulting in the cleavage of the second C—O bond. 54 55 Reactions of Epoxides Recall that epoxides do not contain a good leaving group. Epoxides do contain a strained three-membered ring with two polar bonds. Nucleophilic attack opens the strained three-membered ring, making it a favorable process even with a poor leaving group. 56  The reaction occurs readily with strong nucleophiles and with acids like HZ, where Z is a nucleophilic atom. 57  Virtually all strong nucleophiles open an epoxide ring by a two- step reaction sequence: In step 1, the nucleophile attacks an electron-deficient carbon, thus cleaving the C—O bond and relieving the strain of the three- membered ring. In step 2 the alkoxide is protonated with water to generate a neutral product with two functional groups on adjacent atoms. Common nucleophiles that open the epoxide ring include ¯OH, ¯OR, ¯CN, ¯SR and NH3. With these strong nucleophiles, the 58 reaction occurs by an SN2 mechanism. Consider the following real examples: 59 Let’s now consider the stereochemical consequences of the reaction of 1,2-epoxycyclohexane with ¯OCH3. Nucleophilic attack of ¯OCH3 occurs from the backside at either C—O bond, because both ends are similarly substituted. Since attack at either side occurs with equal probability, an equal amount of the two enantiomers (i.e., a racemic mixture) is formed. 60 Optically inactive starting materials give optically inactive products! 61  Acids HZ that contain a nucleophile Z also open epoxide rings by a two-step sequence. HCl, HBr and HI, as well as H2O and ROH in the presence of acid, all open an epoxide ring in this manner. 62  Figure 9.9 Opening of an unsymmetrical epoxide ring with HCI 63  Ring opening of an epoxide with either a strong nucleophile or an acid HZ is regioselective because one constitutional isomer is the major or exclusive product. Note that the site selectivity of these two reactions is exactly opposite. 64  Alcohols and Phenols Alcohols contain an OH group connected to a a saturated C (sp 3) They are important solvents and synthesis intermediates Phenols contain an OH group connected to a carbon in a benzene ring Methanol, CH3OH, called methyl alcohol, is a common solvent, a fuel additive, produced in large quantities Ethanol, CH3CH2OH, called ethyl alcohol, is a solvent, fuel, beverage Phenol, C6H5OH (“phenyl alcohol”) has diverse uses - it gives its name to the general class of compounds OH groups bonded to vinylic, sp2-hybridized carbons are called enols 65  Why this Chapter? To begin to study oxygen-containing functional groups These groups lie at the heart of biological chemistry 66 17.1 Naming Alcohols and Phenols General classifications of alcohols based on substitution on C to which OH is attached Methyl (C has 3 H’s), Primary (1°) (C has two H’s, one R), secondary (2°) (C has one H, two R’s), tertiary (3°) (C has no H, 3 R’s), 67  IUPAC Rules for Naming Alcohols Select the longest carbon chain containing the hydroxyl group, and derive the parent name by replacing the -e ending of the corresponding alkane with -ol Number the chain from the end nearer the hydroxyl group Number substituents according to position on chain, listing the substituents in alphabetical order 68  Naming Phenols Use “phenol” (the French name for benzene) as the parent hydrocarbon name, not benzene Name substituents on aromatic ring by their position from OH 69  17.2 Properties of Alcohols and Phenols The structure around O of the alcohol or phenol is similar to that in water, sp hybridized 3 Alcohols and phenols have much higher boiling points than similar alkanes and alkyl halides A positively polarized OH hydrogen atom from one molecule is attracted to a lone pair of electrons on a negatively polarized oxygen atom of another molecule This produces a force that holds the two molecules together These intermolecular attractions are present in solution but not in the gas phase, thus elevating the boiling point of the solution 70  Properties of Alcohols and Phenols: Acidity and Basicity Weakly basic and weakly acidic Alcohols are weak Brønsted bases Protonated by strong acids to yield oxonium ions, ROH + 2 71  Alcohols and Phenols are Weak Brønsted Acids Can transfer a proton to water to a very small extent Produces H3O+ and an alkoxide ion, RO, or a phenoxide ion, ArO 72  Acidity Measurements The acidity constant, K , measures the extent to which a a Brønsted acid transfers a proton to water [A] [H3O+] Ka = ————— and pKa = log Ka [HA] Relative acidities are more conveniently presented on a logarithmic scale, pKa, which is directly proportional to the free energy of the equilibrium Differences in pK correspond to differences in free energy a Table 17.1 presents a range of acids and their pK values a 73 pKa Values for Typical OH Compounds 74  Relative Acidities of Alcohols Simple alcohols are about as acidic as water Alkyl groups make an alcohol a weaker acid The more easily the alkoxide ion is solvated by water the more its formation is energetically favored Steric effects are important 75  Inductive Effects Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide) 76  Generating Alkoxides from Alcohols Alcohols are weak acids – requires a strong base to form an alkoxide such as NaH, sodium amide NaNH2, and Grignard reagents (RMgX) Alkoxides are bases used as reagents in organic chemistry 77  Phenol Acidity Phenols (pK ~10) are much more acidic than alcohols a (pKa ~ 16) due to resonance stabilization of the phenoxide ion Phenols react with NaOH solutions (but alcohols do not), forming salts that are soluble in dilute aqueous solution A phenolic component can be separated from an organic solution by extraction into basic aqueous solution and is isolated after acid is added to the solution 78  Nitro-Phenols Phenols with nitro groups at the ortho and para positions are much stronger acids 79  17.3 Preparation of Alcohols: A Review Alcohols are derived from many types of compounds The alcohol hydroxyl can be converted to many other functional groups This makes alcohols useful in synthesis 80  Review: Preparation of Alcohols by Regiospecific Hydration of Alkenes Hydroboration/oxidation: syn, non-Markovnikov hydration Oxymercuration/reduction: Markovnikov hydration 81  1,2-Diols Review: Cis-1,2-diols from hydroxylation of an alkene with OsO4 followed by reduction with NaHSO3 Trans-1,2-diols from acid-catalyzed hydrolysis of epoxides 82  17.4 Alcohols from Reduction of Carbonyl Compounds Reduction of a carbonyl compound in general gives an alcohol Note that organic reduction reactions add the equivalent of H2 to a molecule 83 Reduction of Aldehydes and Ketones Aldehydes gives primary alcohols Ketones gives secondary alcohols 84  Reduction Reagent: Sodium 4 Borohydride NaBH is not sensitive to moisture and it does not reduce other common functional groups Lithium aluminum hydride (LiAlH ) is more powerful, 4 less specific, and very reactive with water Both add the equivalent of “H-” 85  Mechanism of Reduction The reagent adds the equivalent of hydride to the carbon of C=O and polarizes the group as well 86  Reduction of Carboxylic Acids and Esters Carboxylic acids and esters are reduced to give primary alcohols LiAlH4 is used because NaBH4 is not effective 87  17.5 Alcohols from Reaction of Carbonyl Compounds with Grignard Reagents Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuran to generate Grignard reagents, RMgX Grignard reagents react with carbonyl compounds to yield alcohols 88  Reactions of Grignard Reagents with Carbonyl Compounds 89  Reactions of Esters and Grignard Reagents Yields tertiary alcohols in which two of the substituents carbon come from the Grignard reagent Grignard reagents do not add to carboxylic acids – they undergo an acid-base reaction, generating the hydrocarbon of the Grignard reagent 90  Grignard Reagents and Other Functional Groups in the Same Molecule Can't be prepared if there are reactive functional groups in the same molecule, including proton donors 91  Mechanism of the Addition of a Grignard Reagent Grignard reagents act as nucleophilic carbon anions (carbanions, : R) in adding to a carbonyl group The intermediate alkoxide is then protonated to produce the alcohol 92  17.6 Reactions of Alcohols Conversion of alcohols into alkyl halides: - 3˚ alcohols react with HCl or HBr by SN1 through carbocation intermediate - 1˚ and 2˚ alcohols converted into halides by treatment with SOCl 2 or PBr3 via SN2 mechanism 93 94 Conversion of Alcohols into Tosylates Reaction with p-toluenesulfonyl chloride (tosyl chloride, p-TosCl) in pyridine yields alkyl tosylates, ROTos Formation of the tosylate does not involve the C–O bond so configuration at a chirality center is maintained Alkyl tosylates react like alkyl halides 95  Stereochemical Uses of Tosylates The SN2 reaction of an alcohol via a tosylate, produces inversion at the chirality center The SN2 reaction of an alcohol via an alkyl halide proceeds with two inversions, giving product with same arrangement as starting alcohol 96  Dehydration of Alcohols to Yield Alkenes The general reaction: forming an alkene from an alcohol through loss of O-H and H (hence dehydration) of the neighboring C–H to give  bond Specific reagents are needed 97  Acid- Catalyzed Dehydration Tertiary alcohols are readily dehydrated with acid Secondary alcohols require severe conditions (75% H SO , 2 4 100°C) - sensitive molecules don't survive Primary alcohols require very harsh conditions – impractical Reactivity is the result of the nature of the carbocation intermediate 98  Dehydration with POCl3 Phosphorus oxychloride in the amine solvent pyridine can lead to dehydration of secondary and tertiary alcohols at low temperatures An E2 via an intermediate ester of POCl2 (see Figure 17.7) 99  Conversion of Alcohols into Esters 100  17.7 Oxidation of Alcohols Can be accomplished by inorganic reagents, such as KMnO4, CrO3, and Na2Cr2O7 or by more selective, expensive reagents 101  Oxidation of Primary Alcohols To aldehyde: pyridinium chlorochromate (PCC, C5H6NCrO3Cl) in dichloromethane Other reagents produce carboxylic acids 102  Oxidation of Secondary Alcohols Effective with inexpensive reagents such as Na Cr O in 2 2 7 acetic acid PCC is used for sensitive alcohols at lower temperatures 103  Mechanism of Chromic Acid Oxidation Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone The mechanism was determined by observing the effects of isotopes on rates 104  17.8 Protection of Alcohols Hydroxyl groups can easily transfer their proton to a basic reagent This can prevent desired reactions Converting the hydroxyl to a (removable) functional group without an acidic proton protects the alcohol 105  Methods to Protect Alcohols Reaction with chlorotrimethylsilane in the presence of base yields an unreactive trimethylsilyl (TMS) ether The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol 106  Protection-Deprotection An example of TMS-alcohol protection in a synthesis 107  17.9 Phenols and Their Uses Industrial process from readily available cumene Forms cumene hydroperoxide with oxygen at high temperature Converted into phenol and acetone by acid 108  17.10 Reactions of Phenols The hydroxyl group is a strongly activating, making phenols substrates for electrophilic halogenation, nitration, sulfonation, and Friedel–Crafts reactions Reaction of a phenol with strong oxidizing agents yields a quinone Fremy's salt [(KSO ) NO] works under mild conditions 3 2 through a radical mechanism 109