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Ethers and Epoxides; Thiols and Sulfides; Amines Ethers Ethers and Their RelaHves • An ether has two organic groups (alkyl, aryl, or vinyl) bonded to the same oxygen atom, R–O–Rʹ′ • Diethyl ether is used industrially as a solvent • Tetrahydrofuran (THF) is a solvent that is a cyclic ether • Thiols (R–S–H) and sulfides (R–S–Rʹ′) are sulfur (for oxygen) analogues of alcohols and ethers Names and ProperHes of Ethers • Simple ethers are named by idenHfying the two organic subsHtuents and adding the word ether • If other funcHonal groups are present, the ether part is considered an alkoxy subsHtuent • R–O–R ~ tetrahedral bond angle (112° in dimethyl ether) • Oxygen is sp3-­‐hybridized • Oxygen atom gives ethers a slight dipole moment Ethers Are Common Solvents Because They React Only with Hydrogen Halides Common Names of Ethers The subsHtuents are listed in alphabeHcal order.
SystemaHc Names of Ethers Structure and Polarity • Oxygen is sp3 hybridized. • Bent molecular geometry. • C—O—C angles is 110°. • Polar C—O bonds. • Dipole moment of 1.3 D. Hydrogen Bond Acceptor • Ethers cannot hydrogen-­‐bond with other ether molecules. • Molecules that cannot hydrogen-­‐bond intermolecularly have a lower boiling point. • Ether molecules can hydrogen-­‐bond with water and alcohol molecules. SolvaHon of Ions with Ether • An ionic substance such as lithium iodide is moderately soluble in ethers because the small lithium caHon is strongly solvated by the ether’s lone pairs of electrons. • Unlike alcohols, ether cannot serve as hydrogen-­‐bond donors, so they do not solvate small anions well. Ether Complexes • Grignard reagents: ComplexaHon of an ether with a Grignard reagent stabilizes the reagent and helps keep it in soluHon. • Electrophiles: The ethers nonbonding electrons stabilize the borane (BH3). Industrial Ether Synthesis • Industrial method, not good lab synthesis. • If temperature is too high, alkene forms. C H 3C
H 2 O H + H O C H 2C
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140°C C H 3C
H 2 O C H 2C
H 3 Synthesis of Ethers • Diethyl ether prepared industrially by sulfuric acid–catalyzed dehydraHon of ethanol – also with other primary alcohols The Leaving Group of an Ether Can Be AcHvated by ProtonaHon The Williamson Ether Synthesis • ReacHon of metal alkoxides and primary alkyl halides and tosylates • Best method for the preparaHon of ethers • Alkoxides prepared by reacHon of an alcohol with a strong base such as sodium hydride, NaH Silver Oxide-­‐Catalyzed Ether FormaHon • ReacHon of alcohols with Ag2O directly with alkyl halide forms ether in one step • Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield AlkoxymercuraHon of Alkenes • React alkene with an alcohol and mercuric acetate or trifluoroacetate • DemercuraHon with NaBH4 yields an ether • Overall Markovnikov addiHon of alcohol to alkene ReacHons of Ethers: Acidic Cleavage • Ethers are generally unreacHve • Strong acid will cleave an ether at elevated temperature • HI, HBr produce an alkyl halide from less hindered component by SN2 (terHary ethers undergo SN1) The Mechanism If a relaHvely stable carbocaHon would not be formed when ROH leaves, it will be an SN2 reacHon. Ethers undergo SN1 reacHons unless they would have to form a primary carbocaHon. Ethers Cannot Be AcHvated by Other Methods An alcohol forms an intermediate that can lose a proton. An ether forms an intermediate that cannot lose a proton. ReacHons of Ethers: Claisen Rearrangement • Specific to allyl aryl ethers, ArOCH2CH=CH2 • HeaHng to 200–250°C leads to an o-­‐allylphenol • Result is alkylaHon of the phenol in an ortho posiHon Claisen Rearrangement Mechanism • Concerted pericyclic 6-­‐electron, 6-­‐membered ring transiHon state • Mechanism consistent with 14C labeling Cyclic Ethers • Cyclic ethers behave like acyclic ethers, except if ring is 3-­‐
membered • Dioxane and tetrahydrofuran are used as solvents Nomenclature of Cyclic Ethers O
O
Oxirane
O
2-Methyloxirane
O
2,2-Dimethyloxirane
O
O
Oxatane
O
O
O
2-Methyloxetane
O
Tetrahydrofuran
O
O
Tetrahydro-2H-pyran
(2S, 3S)-2,3-Diethyloxirane
3-Methyltetrahydro-2H-pyran
1,4-Dioxane
2,2-Dimethyltetrahydrofuran
O
O
2,5-Dimethyl-1,4-dioxane
Epoxides (Oxiranes) • Three membered ring ether is called an oxirane (root “ir” from “tri” for 3-­‐membered; prefix “ox” for oxygen; “ane” for saturated) • Also called epoxides • Ethylene oxide (oxirane; 1,2-­‐epoxyethane) is industrially important as an intermediate • Prepared by reacHon of ethylene with oxygen at 300 °C and silver oxide catalyst PreparaHon of Epoxides Using a Peroxyacid • Treat an alkene with a peroxyacid Epoxides from Halohydrins • AddiHon of HO-­‐X to an alkene gives a halohydrin • Treatment of a halohydrin with base gives an epoxide • Intramolecular Williamson ether synthesis Epoxides are More ReacHve Than Ethers Because of Ring Strain ReacHons of Epoxides: Ring-­‐Opening • Water adds to epoxides with dilute acid at room temperature • Product is a 1,2-­‐diol (on adjacent C ’s: vicinal) • Mechanism: acid protonates oxygen and water adds to opposite side (trans addiHon) Halohydrins from Epoxides • Anhydrous HF, HBr, HCl, or HI combines with an epoxide • Gives trans product Regiochemistry of Acid-­‐Catalyzed Opening of Epoxides  Nucleophile preferably adds to less hindered site if primary and secondary C ’s  Also at terHary because of carbocaHon character Under Neutral or Basic CondiHons the Nucleophile Alacks the Less SubsHtuted Carbon Base-­‐Catalyzed Epoxide Opening • Strain of the three-­‐membered ring is relieved on ring-­‐opening • Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-­‐diols 1,2-­‐Diols Adding Water to an Alkene Without a CarbocaHon Rearrangement The regioselecHvity is the same as the acid-­‐catalyzed addiHon of water because the hydride ion adds to the sp2 carbon bonded to the most hydrogens. AddiHon of Grignards to Ethylene Oxide • Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain • Acyclic and other larger ring ethers do not react Crown Ethers • Large rings consisHng of repeaHng (-­‐OCH2CH2-­‐) or similar units • Named as x-­‐crown-­‐y – x is the total number of atoms in the ring – y is the number of oxygen atoms – 18-­‐crown-­‐6 ether: 18-­‐membered ring containing 6 oxygen atoms • Central cavity is electronegaHve and alracts caHons Thiols and Sulfides • Thiols (RSH), are sulfur analogues of alcohols – Named with the suffix -­‐thiol – SH group is called “mercapto group” (“capturer of mercury”) Thiols: FormaHon and ReacHon • From alkyl halides by displacement with a sulfur nucleophile such as –SH – The alkylthiol product can undergo further reacHon with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol Sulfides • Sulfides (RSRʹ′), are sulfur analogues of ethers – Named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy Sulfides (Thioethers) • R—S—Rʹ′, analog of ether. • Name sulfides like ethers, replacing “sulfide” for “ether” in common name, or “alkylthio” for “alkoxy” in IUPAC system. S C H 3 methyl phenyl sulfide or methylthiobenzene Using Thiourea to Form Alkylthiols • Thiols can undergo further reacHon with the alkyl halide to give dialkyl sulfides • For a pure alkylthiol use thiourea (NH2(C=S)NH2) as the nucleophile • This gives an intermediate alkylisothiourea salt, which is hydrolyzed cleanly to the alkyl thiourea Thiols and Thiolates • Thiolates are easily synthesized by the Williamson ether synthesis, using dithiolate as the nucleophile. OxidaHon of Thiols to Disulfides • ReacHon of an alkyl thiol (RSH) with bromine or iodine gives a disulfide (RSSR) • The thiol is oxidized in the process and the halogen is reduced Sulfides • Thiolates (RS-­‐) are formed by the reacHon of a thiol with a base • Thiolates react with primary or secondary alkyl halide to give sulfides (RSR’) • Thiolates are excellent nucleophiles and react with many electrophiles Sulfides as Nucleophiles • Sulfur compounds are more nucleophilic than their oxygen-­‐
compound analogues – 3p valence electrons (on S) are less Hghtly held than 2p electrons (on O) • Sulfides react with primary alkyl halides (SN2) to give trialkylsulfonium salts (R3S+) OxidaHon of Sulfides • Sulfides are easily oxidized with H2O2 to the sulfoxide (R2SO) • OxidaHon of a sulfoxide with a peroxyacid yields a sulfone (R2SO2) • Dimethyl sulfoxide (DMSO) is onen used as a polar aproHc solvent Sulfide ReacHons • Sulfides are easily oxidized to sulfoxides and sulfones. C H 3 S C H 3 H 2O
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C H 3C
O O H C H 3 S C H 3 H 2O
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C H 3C
O O H C H 3 S C H 3 O • Sulfides react with unhindered alkyl halides to give sulfonium salts. C H 3 S C H 3 + C H 3 I The image part with
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C H 3 + S C H 3 I C H 3 _ Sulfides as Reducing Agents • Because sulfides are easily oxidized, they are onen used as mild reducing agents. RelaHve ReacHviHes ProtonaHng an Amine Does Not Form a Compound with a Good Leaving Group Amines cannot undergo subsHtuHon and eliminaHon reacHons. Amines are Common Organic Bases ClassificaHon of Amines The classificaHon depends on how many groups are bonded to N. • Primary amine = one group bonded to N • Secondary amine • TerHary amine = two groups bonded N = three groups bonded N Common Names SystemaHc Names of Amines • The suffix “amine” denotes the amine funcHonal group. • The “e” at the end of the alkane name is replaced by “amine.” Common Names of Heterocyclic Amines • If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic • Each ring system has its own parent name SystemaHc Names of Amines • A subsHtuent on the chain is indicated by a number. • A subsHtuent on the nitrogen is indicated by an “N.” Quaternary Ammonium Salts When there are four groups bonded to the N, the groups are stated in alphabeHcal order followed by “ammonium” and then the name of the anion. Hydrogen Bonds in Amines Hydrogen bonds are stronger in primary amines than in secondary amines because primary amines have stronger dipole–dipole interacHons. TerHary amines cannot form hydrogen bonds with each other. Chirality Is Possible (But Not Observed) • An amine with three different subsHtuents on nitrogen is chiral (in principle but not in pracHce) : the lone pair of electrons is the fourth subsHtuent • Most amines that have 3 different subsHtuents on N cannot be resolved because the molecules interconvert by pyramidal inversion Amines Form H-­‐Bonds • Amines with fewer than five carbons are water-­‐soluble • Primary and secondary amines form hydrogen bonds, increasing their boiling points Basicity of Amines • The lone pair of electrons on nitrogen makes amines basic and nucleophilic • They react with acids to form acid–base salts and they react with electrophiles Amides • Amides (RCONH2) in general are not proton acceptors except in very strong acid • The C=O group is strongly electron-­‐withdrawing, making the N a very weak base • AddiHon of a proton occurs on O but this destroys the double bond character of C=O as a requirement of stabilizaHon by N= Basicity of Arylamines • The N lone-­‐pair electrons in arylamines are delocalized by interacHon with the aromaHc ring π electron system and are less able to accept H+ than are alkylamines Amines are Common Nucleophiles Synthesis of Amines • Arylamines are prepared from nitraHon of an aromaHc compound and reducHon of the nitro group • ReducHon by catalyHc hydrogenaHon over plaHnum is suitable if no other groups can be reduced • Iron, zinc, Hn, and Hn(II) chloride are effecHve in acidic soluHon SN2 ReacHons of Alkyl Halides • Ammonia and other amines are good nucleophiles Uncontrolled MulHple AlkylaHon • Primary, secondary, and terHary amines all have similar reacHvity, the iniHally formed monoalkylated substance undergoes further reacHon to yield a mixture of products SelecHve PreparaHon of Primary Amines: The Azide Synthesis • Azide ion, N3-­‐ displaces a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RN3 • Alkyl azides are not nucleophilic (but they are explosive) • ReducHon gives the primary amine Gabriel Synthesis of Primary Amines • A phthalimide alkylaHon for preparing a primary amine from an alkyl halide • The N-­‐H in imides (–CONHCO–) can be removed by KOH followed by alkylaHon and hydrolysis ReducHve AminaHon of Aldehydes and Ketones • Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent ReducHve AminaHon Is VersaHle • Ammonia, primary amines, and secondary amines yield primary, secondary, and terHary amines, respecHvely Mechanism of ReducHve AminaHon Reducing Step • Sodium cyanoborohydride, NaBH3CN, reduces C=N but not C=O • Stable in water Hofmann and CurHus Rearrangements • Carboxylic acid derivaHves can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the CurHus rearrangement Hofmann Rearrangement • RCONH2 reacts with Br2 and base • Gives high yields of arylamines and alkylamines CurHus Rearrangement • HeaHng an acyl azide prepared from an acid chloride • MigraHon of –R from C=O to the neighboring nitrogen with simultaneous loss of a leaving group ReacHons of Amines • AlkylaHon and acylaHon have already been presented Hofmann EliminaHon • Converts amines into alkenes • NH2-­‐ is very a poor leaving group so it is converted to an alkylammonium ion, which is a good leaving group Silver Oxide Is Used for the EliminaHon Step • Exchanges hydroxide ion for iodide ion in the quaternary ammonium salt, thus providing the base necessary to cause eliminaHon OrientaHon in Hofmann EliminaHon • We would expect that the more highly subsHtuted alkene product predominates in the E2 reacHon of an alkyl halide (Zaitsev's rule) • However, the less highly subsHtuted alkene predominates in the Hofmann eliminaHon due to the large size of the trialkylamine leaving group • The base must abstract a hydrogen from the most sterically accessible, least hindered posiHon Steric Effects Control the OrientaHon It Must Be a Quaternary Hydroxide Aqueous silver oxide converts a quaternary ammonium halide to a quaternary ammonium hydroxide. ReacHons of Arylamines • Amino subsHtuents are strongly acHvaHng, ortho-­‐ and para-­‐
direcHng groups in electrophilic aromaHc subsHtuHon reacHons • ReacHons are controlled by conversion to amide Arylamines Are Not Useful for Friedel-­‐Crans ReacHons • The amino group forms a Lewis acid–base complex with the AlCl3 catalyst, prevenHng further reacHon • Therefore we use the corresponding amide Diazonium Salts: The Sandmeyer ReacHon • Primary arylamines react with HNO2, yielding stable arenediazonium salts Uses of Arenediazonium Salts • The N2 group can be replaced by a nucleophile PreparaHon of Aryl Halides • ReacHon of an arenediazonium salt with CuCl or CuBr gives aryl halides (Sandmeyer ReacHon) • Aryl iodides form from reacHon with NaI without a copper(I) salt Aryl Nitriles and Carboxylic Acids • An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH FormaHon of Phenols (ArOH) • From reacHon of the arenediazonium salt with copper(I) oxide in an aqueous soluHon of copper(II) nitrate ReducHon to a Hydrocarbon • By treatment of a diazonium salt with hypophosphorous acid, H3PO2 Diazonium Coupling ReacHons • Arenediazonium salts undergo a coupling reacHon with acHvated aromaHc rings, such as phenols and arylamines, to yield brightly colored azo compounds, Ar–N=N–Arʹ′ How Diazonium Coupling Occurs • The electrophilic diazonium ion reacts with the electron-­‐rich ring of a phenol or arylamine • Usually occurs at the para posiHon but goes ortho if para is blocked Azo Dyes • Azo-­‐coupled products have extended π conjugaHon that lead to low energy electronic transiHons that occur in visible light (dyes) Heterocyclic Amines • A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually C along with N, O, or S Pyrole and Imidazole • Pyrole is an amine and a conjugated diene, however its chemical properHes are not consistent with either of these structural features Chemistry of Pyrole • Electrophilic subsHtuHon reacHons occur at C2 because it is posiHon next to the N • A more stable intermediate caHon having 3 resonance forms • At C3, only 2 resonance forms Polycyclic Heterocycles