ethers - SUMMARY General Information Synthesis of Ethers 0...

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Unformatted text preview: SUMMARY General Information Synthesis of Ethers 0 Williamson Ether Synthesis 0 From Alkenes via Alkoxymercuration-Demercuration Reactions of Ethers 0 Preparation of Alkyl Halides and Alcohols via Acidic Cleavage Synthesis of Epoxides 0 From Alkenes ' From Vicinal Halohydrins Reactions of Epoxr'des 0 Epoxide Ring-Opening Reactions via Acid or Base Catalysis 0 Epoxide Ring~0pening Reactions {Synthesis of Extended Alcohols via Grignard Reagents) Synthesis of Sulfides 0 From Thiolate Anions Ethers 1 Ethers 2 Ethers 3 Ethers 4 Bikers 5 Bikers 6 Ethers 7 Ethers 8 Bikers 9 Ethers GENERAL INFORMATION Ethers 1 Ethers (R—O—R’) Introduction: Ethers are derivatives of water in which, in place of two hydrogens, two organic groups are bound to a cen- tral oxygen (R—O—R'). Many ethers [e.g., diethyl ether and tetrahydrofuran (THF)] are used as solvents in the chemical industry. Sulfides are another class of compounds similar to ethers, except that the central oxygen is replaced by a sulfur atom (R—S—R'}. Physical Properties: ' Because of the electronegativity of the central oxygen, ethers have dipole moments and intermolecular dipole—dipole interactions. This feature causes ethers to have a higher boiling point than alkanes of the same molecular weight. 0 Most ethers are liquid at room temperature. Chemical Properties: 0 The central oxygen is sp3 hybridized, and the bond angle in R—O—R' is ~112°. Not surprisingly, these para— meters are close to those of the geometry of H20. - They do not form hydrogen bonds with themselves; however, they do have dipole moments that enhance the ether’s intermolecular forces. They do form hydrogen bonds with water and alcohols. O They are mainly inert compounds and are reactive only in hot andfor concentrated acid; they are primarily used as solvents to carry out other reactions. The only exceptions are cyclic ethers with three-membered rings, known as epoxides. Here ring strain makes for higher reactivity. Nomenclature: 0 The larger organic group attached to the oxygen is used as the “stem,” while the other group takes the alkoxy form (e.g., CH3CH2—O—CH3 a methoxyethane; common name: ethyl methyl ether). 0 For epoxides, the root word “oxirane” is used, and numbering begins on the oxygen of the ring. (30 / \ cuacn — CH2 ® <3) Z-Methyloxirane - For sulfides, the alkoxy term of ethers is replaced with the alkylthio form (e.g., CH3CH2—S—CH3 a methylthioethane; common name: ethyl methyl sulfide). Spectroscopy: H NMR: Hydrogens on carbons adjacent to the central oxygen appear at 8 = 3.5—4.5 ppm (shifted from the typical alkane hydrogen resonance of 5 : 0—2). C NMR: Characteristic peak at 5 = 70 ppm for oxygen-bearing carbon. IR.- The C—O bond absorbs at 1050—1150em‘1 but is not specific for ethers and so is not very useful. SYNTHESIS OF ETHERS Ethers 2 WILLIAMSON ETHER SYNTHESIS N H @- (CH3):COH Ly (CH3)3CO'Na* + H2 (CHa)aCO Na" + CHz-Br —> (CH3)3COCH3 + NaBr 2-Methyl-2—propanol 1,1-Dimelhylethoxide reButoxide Bromomethane Z-Methoxy72rinethylpropane Keys: 1. This classic synthesis is a very good method of preparing ethers with at least one 1” alkyl group. 2. It is an 5N2 reaction between an alkoxide (RO‘: R = 1°, 2°, 3°, aryl) and at 1° alkyl halide. 3. The alkoxide is formed using a strong base [e.g., sodium hydride (NaH)] to remove an H+ from an alco- hol . 4. Do not use 2° or 3° alkyl halides because the bulky alkyl group hinders the direct alkoxide attack and forces an E2 side reaction with the generation of undesired alkenes (see Alkyl Halides 10 for a review). Note: If a symmetric ether is desired, another alternative is to use hot sulfuric acid (H2504) to combine two alcohol molecules. Two different alcohols are rarely used because complex mixtures are usually produced. 2 R—OH + H2804 —> R—O—R + H20 Mechanism: 1. An acid‘base reaction between the alcohol and strong base [e.g., sodium hydride (NaH)] produces an alkoxide ion. 2. A one-step 5N2 reaction occurs in which the nucleophilic alkoxide attacks an alkyl halide and displaces the halide ion, yielding the desired ether (see Alkyl Halide: 6 for more details on 5N2). @G) as H—OH + NaH —> Hfi: Na + H2 Alcohol Alkoxifi ion ® R—O—R' Nax (— R‘rx 'u Ether Alkyl halide (X = 1, Br, or Cl) SYNTHESIS OF ETHERS Ethers 3 FROM ALKENES VIA ALKOXYMERCURATI ON—DEMERCURATI ON H c H DCH3 3 \ / H g(OgCCF3}2 (11301-1 NaBH4 I /c=c\ ——> —> —> cua—c—cua H H I H Propene Z-Methoxypropane (alkene) {isopropyl methyl ether) Keys: 1. The reaction can be divided into two stages: (1) alkoxymercuration, where an alkene reacts with an alcohol and the reagent mercuric trifluoroacetate [Hg(OOCCF3)2], and (2) demercuration, where sodium borohy- dride (NaBH4) is used to form the desired ether. 2. The regiochemistry of this reaction follows Markovnikov’s rule (i.e., the oxygen of the alcohol attaches to the most substituted carbon, while the hydrogen attaches to the less substituted carbon of the alkene). 3. The reaction mechanism is very similar to synthesis of alcohols via hydroxyrnercuration (see Alcohols 2). Note: The reaction works well with 1° and 2° alcohols, and it can also use 3° alcohols as long as the alkenes are not multisubstituted. Reason: the reaction between 3° alcohols and multisubstituted alkenes faces severe steric hindrance. Therefore, ditertiary ethers (R3C—O-CR3) can never be formed with this reaction. C|:H3 H\ /CH3 No Reaction CH3 \ /CH3 CH3+070H + /c=c\ +p CH37C—O—C\—CH3 g“: A H CH3 CH3 CH3 3” Alcohol Multi substituted Ditertiary ether” alkene Mechanism: I. Alkoxymercuration 1. Electrophilic attack on Hg(02CCF3)2 by an alkene to yield a mercurinium ion. 2. Nucleophilic attack by an alcohol on the more substituted carbon of the mercurinium ion (Markovnikov addition). 3. Abstraction of a proton from the newly substituted alcohol by the previously freed trifluoroacetate moiety of the mercuric reagent. H. Demercuration 4. Reaction with NaBH4 to replace mercury with hydrogen, thereby forming the ether product. OgCCF; | n HQ®H9 \ / {1) \ / \ / .. C = C —-—> C A“ C + H'— OH pt / \ Fl/ \ -- g; \ Chzcca V Alkene Hg\0 CCF Mercurinium Alcohol 2 3 ion 9 R'O Hg - oacha H — OR' Hg — 02CCF3 | | (g) | | H-t-t- <— “‘t—t‘ NaB®4 H 9:0266F3 R “"r e “‘f‘ t - H . ether REACTIONS OF ETHERS Ethers 4 PREPARATION OF ALKYL HALIDES AND ALCOHOLS VIA ACIDIC CLEAVAGE Cg: CH:i EXCESS CH3 I H]. H20 I HI, H30 I Hsc—p—OCHcha —fi—> omen2 71 + CHa—(iJ—OH T4» CH3CHZ —1 + culieil heal H H heal longer H Ethyl isopropyl ether Iodoethane Isopropyl alcohol 2-Iodopropane (ether) (alkyl halide) (alcohol) Keys: 1. This reaction proceeds through an 8N2 mechanism and yields two useful products, an alcohol and an alkyl halide. 2. Primary and secondary alkyl ethers can be used in this reaction (see Notes for reactions involving 3° alkyl ethers). 3. Since ethers are mostly inert compounds, this reaction works only in the presence of a strong acid (specifi— cally HI, HBr, and H2804, but not HCl or HF). Note: The halide ions of these acids (i.e., I:_ and Br?) serve as nucleophiles in this reaction and always attack the less substituted alkyl group of the ether (see Mechanism). Therefore, this reaction always gives consistent products. Notes: 1. If excess hydrogen halide is used, both 1° and 2° alkyl groups are eventually converted to alkyl halides because the alcohol initially produced reacts further with free HX to produce more alkyl halide (see Mechanism). 2. When 3“ ethers are used instead, this reaction proceeds through an 5N1 or E1 mechanism instead of an 5N2 mechanism. Benzylic or allylic ethers proceed by 5N2 or 5N1 depending on reaction conditions. Reason: These ethers can form stable intermediate carbocations and are therefore suited for SNL’El (see Alley] Halides 7 and 9 for details on SleEl reactions} CH5 en: | H1304 I Hac — ti: — o — CHZCHa —> Hat: — c = CH; + CH,CH20H en3 r-Butyl ethyl ether 2-Methylpropene Ethanol (3° ether) Mechanism: 1. The oxygen of the ether is protonated by the acid. 2. The nucleophilic halide ion (X:—} attacks the carbon of the protonated ether in an 5N2 reaction; one alco- hol and one alkyl halide are formed. (Note that the halide ion always attacks the less substituted carbon of the protonated ether). 3. With an excess of hydrogen halide (PIX), the alcohol is further protonated and reacts with halide ion to give another alkyl halide. H I .. n (D I_ l _ :9 Ether Hydrogen Protonated halide ether 7. a—x + H20 {@— '7%H, «i Fr—in + n—x C U eEJ-Hw 2nd Alkyl excess Alcohol Alkyl halide halide Hydrogen halide SYNTHESIS OF EPOXIDES Ethers 5 FROM ALKENES o fol 0 Hac\ /“ ll . room temp H3c\ / \ /" ll C=C + R’C’O—QH ‘v—b CiC + RMC—OH / \ / \ H H H H Propene Aperoxycarboxylic acid 2-Methyloxirane Acarboxylic acid (alkene) (e.g., MMPP) (epoxide) Keys: 1. This reaction involves a one—step syn addition of an Oxygen atom to the double bond of the alkene, form— ing the three-membered epoxide ring. 2. In most cases, peroxycarboxylic acids (RCO3H) are used as oxidizing agents in the reaction. 3. The oxygen transferred from the peroxycarboxylic acid is that of its hydroxyl (—OH) group. Note: One of the most commonly used peroxycarboxylic acids in these reactions is magnesium monoperoxyphtha- late (MMPP). Although “peroxy acids” are generally not very stable compounds, MMPP tends to be more stable and relatively safe. Mechanism: 1. The peroxycarboxylic acid is aligned in a conformation to facilitate formation of an intramolecular hydro- gen bond between the carbonyl oxygen and hydroxyl proton. A transition state compound is formed (note that all formed or broken bonds are shown by dotted lines}. 2. The hydroxyl oxygen is transferred to the alkene, and the hydroxyl proton goes to the carbonyl oxygen all in one step (no intermediate leading to the epoxide and a carboxylic acid is formed). o o ---- --H Il/“H \c/ a) / 5 \ / /C\f\ —> H—c §_‘__.—-Cl R 0— f0 \‘0, Joint l? / \ C\ / . . Peroxycarboxylic Alkene Transmon state acid compound 3 ‘ /°H \ / \ / <2 R— C + C — C \0 / \ Carboxylic acid Epoxide SYNTHESIS OF EPOXIDES Ethers 6 FROM VICINAL HALOHYDRINS HO \CH3 0 \c \s‘ NaOH 6/ \c \\ ~C‘IH -—> \\ — r, + NaBr + H20 w“) \ r120 H\“‘ i ‘ Won, H Br H H 2ABronloelepropanol 2-Melh loxirane y (halohydnn) (epoxide) EYE—I 1. Halohydrins (compounds with one alcohol and one halide group—an example of which is shown above) react in the presence of base to form epoxides. 2. The reaction is basically an intramolecular 8N2 displacement reaction and can be thought of as an intramolecular form of Williamson ether synthesis (i.e., the oxygen of the halohydrin attacks and expels its own halide) (see Ethers 2 for the Williamson ether synthesis). Note: Preparation of vicinal halohydrins {see Aikenes 5 for more details): X H "(r/’4; \\\“\H X2 \ \x‘Q czc ‘w—p. \\\\C*C-IR + Hx a! \R H20 "“1 \ ' OH x; : Clg, Br; H A lkene lmnseHalohydrin o_ Treatment of an alkene with halogen (C12 or Brz) and water creates a “halo alcohol,’.’, called a halohydrin, with one hydroxyl and one halide group on the opposing alkene carbons. 1. A strong base abstracts a proton from the alcohol of the halohydrin to form an alkoxide ion. This is a sim- ple acid-base reaction. 2. A one-step internal SNZ reaction follows: Intramolecular backside displacement of the halide by the nega- tively charged oxygen atom results in departure of the halide ion and formation of the epoxide product. 9.. n: CQHf—E H; (:0: x9 R" o / Na fim I g / \ “an RMFT/c _c "In; .1) I Hm p T _c '71!” ® (c —C\\ R k H m . x \R' x) \H' H R Halohydrin Alkoxide Epnxide ion X=Br.C1,I REACTIONS OF EPOXIDES Ethers 7 EPOXIDE RING~OPENING REACTIONS VIA ACID OR BASE CATALYSIS (acid H. H H+ catalyzed) 3“ “\C *C‘d— H H c“‘ H2. 3 l 0.1” Hac 0 H \CL CH2 I .2-Propanediol c/ (base Hlfi \H ‘ Nfl.H catalyzed) _\ e“ 2-Melhylox1rane “\x C * C\--l H (epoxide) H20 H30“ l \ H OH 1.2-Propanediol Keys: 1 2. . Epoxides are very reactive compounds because of their ring strain. Therefore, they undergo ring-opening reactions under either mild acid or base conditions. Base-catalyzed reactions a. The reaction follows an 8N2 mechanism (see Alkyl Hal'ides 6), with the attacking nucleophile and the released epoxidc Oxygen trans to one another. b. With asymmetric epoxides, the base attacks the less substituted, less sterically hindered carbon. . Acid-catalyzed reactions :1. The reaction generally follows an SN] mechanism (see Alley! Halides 7) and proceeds through a carboca— tion intermediate. b. With asymmetric epoxides, the nucleophile attacks the more substituted carbon because more substituted carbons form more stable carbocations. '0 . In the above example, H20 is the nucleophile in the acid-catalyzed case, while, HO_ serves that role in the base-catalyzed reaction; both reactions yield a 1,2-diol (also known as a glycol). However, other nucle— ophiles can also be used in this reaction, giving different products (see Notes). Notes: Preparation of trans-halohydrins 1. In this ring-opening reaction, halide ions are the nucleophiles (as opposed to the H20 used above}. 2.. The mechanism is the same as that of the acid-catalyzed ring-opening reaction. Fl 0 x \H \ / \ HX \ S C—CHZ —> “NC 70 --H , Ether n‘ 1 \ F' 8. HO Epoxide Irrms- Halohydn' I‘l Mechanism: I. Acid-catalyzed reactions T 1. The epoxide oxygen is protonated by acid, H [cad n ff) H (‘DH ‘ ‘ ' ‘ - H’ \@ leading to formatlon of a carbocation'lnterme \cicflz : \c_CH2 C_CHZ diate (note that the more highly substltuted H/ < (13 R/ H/ carbon forms the carbocation because of its Epoxide " ,2 inherently higher stability). "2°" k 2. H20 acts as a nucleophile and adds onto the “I OH H OH carbocation. ’2 r5. \ E R --’c—c/ <—~\:u--— C*CH 3. The newly attached water loses a proton, and / "I‘ll/H H25. 4 2 the 1,2-diol is formed. H0 H \af—F-I—HgH 1,2-diol II. Base-catalyzed reactions 1. Because of steric hindrance from R figs/fl H0\ \H ' / \ - 8‘ H15. 8‘ the more substituted carbon, the c_CH2 .DH : “\‘c 6‘” _\. “\‘Ciéflfl + Hoe base attacks the least substituted R. q a) n“ I n“ 1 carbon in SNZ fashion, forming FI' 0" H' 0” an alkoxidc' Epoxide 1.2-dio] 2. The alkoxide abstracts a proton from water, and the 1,2-diol is formed. REACTIONS OF EPOXIDES Ethers 8 EPOXIDE RING-OPENWG REACTIONS (SYNTHESIS OF EXTENDED ALCOHOLS VIA GRIGNARD REAGENT S) .b'. / \ H+ CchHzMQBr + HZC — CH2 T CHQCHQCHZCHZ — OH Ethylmagnesium bromide Ethylene oxide [oxirane] liButanol (grignard reagent) (epoxide) (alcohol) Keys: 1. This reaction is a simple, efficient way to produce an alcohol with two more carbon atoms than the R group of the Grignard reagent. 2. This reaction is analogous to the base~catalyzed ring~opening reactions described in Etbe‘rs 7. a. Instead of the hydroxyl (’OH) group, an organometallic compound known as a Grignard reagent acts as the nucleophile. b. Attack occurs at the less substituted, less sterically hindered carbon of the ether, but neither carbon of the epoxide can be disubstituted (otherwise a rearranged product may be formed). Note: Preparation of Grignard reagents {see Alley! Halides 4 for details}: M FIX —g> R — ng Ether Alkyl halide Grignard reagent Beware: Grignard reagents cannot be formed if the reacting alkyl halide also contain; functional groups such as ketones, alcohols, carboxylic acids, or amines. Mechanism: 1. The carbon attached to the magnesium bromide part of the Grignard reagent acts as a carbanion (a power- ful nucleophile} and attacks (via 5N2 fashion) the less substituted, less sterically hindered epoxide carbon. 2. Acid added to the reaction mixture protonates the newly freed epoxide oxygen, forming the alcohol. Note that the carbon chain of the R group of the Grignard reagent has been extended by two carbons (a useful trick in organic synthesis). F... "0"? WEE-fl Ho H \ / \ H | l + I | C—CHz —®—> FI”—C—C—H refit—P micicifl n/ flame; l | ® I | ’ 9 R H H‘ H Epoxide Grignard Alcohol reagent SYNTHESIS OF SULFIDES Ethers 9 FROM THIOLATE ANIONS N OH CflchZSH —a——> CHacHQS’Nr + H20 Ethane thiol Sodium ethane thiolate "(—3 EB THF CH3CH2§= Na + CHJCH2CH2— Br fl—> CH30H2 Le S 7 CH2CH20H3 1- Br Sodium Propyl bromide Ethyl propyl sulfide cthanelhiolale {alkyl halide) (ethyl thiopropane) (ihiolaie anion} Keys: . The reaction follows an 5N2 mechanism and is very similar to Williamson ether synthesis (see Ether-s 2). . The thiolate anion (RS?) acts as the nucleophile here (analogous to an alkoxide anion). . The thiolate anion can be formed by first using NaOH to remove an H+ from a thiol {RS—H). . Unlike Williamson ether synthesis, both 1° and 2° (but not 3") alkyl halides can be used for this reaction. Note: Both symmetric and asymmetric sulfides can be prepared by appropriate combination of thiolates and alkyl halides. AmNt—t Mechanism: 1. The hydroxide ion {‘OH) abstracts a proton from the thiol to generate a thiolate anion. 2. A one—step 8N2 reaction foilows: Nucleophiiie thiolate anion attacks alkyl halide and displaces the halide ion, thereby producing the sulfide. , H—SH in» Regen? + H'Q i» R—S—mR' + Max 8 \___,J Thiol =DH Thiolale anion Alkyl halide Dialkyl sulfide X = Br. C1, or I ...
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ethers - SUMMARY General Information Synthesis of Ethers 0...

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