Organic Chemistry Notes by Jim Maxka [email protected] CH 18: Ethers and Epoxides
Topics: Naming ethers and understanding ethers’ inertness Preparing ethers via Williamson ether synthesis: SN2 vs E2 Reaction of ethers in strong acidic solution Epoxides’ Synthesis and reactivity Acid ring opening to give both steric and electronic products: Both SN1 and SN2 Base ring opening to give steric products: SN2
Connections:
ROH - O RO+ R1 Br R R1 Substitution-R > R1
OR1
CH2
R RCH3
O ROH+ R1 X R R1 Substitution-R > R1
O CH2
R R OH OH anti-addition O O Nu OH R R R R acidic conditions Nu = OH, OR, X Nu
Product depends on Substitution OH R
OH S 2 OH S 2 N O N O Nu OH R R R R basic conditions Nu = OH, OR, X, R (from Grignard) and H (from LAH)
CH18-1 Organic Chemistry Notes by Jim Maxka [email protected] Ethers and Epoxides Naming ethers: Common: Take the substituent names of each side of the O and add ether Name: CH3CH2OCH2CH3 (CH3)2CHOCH2Ph (CH3)3COCH3
IUPAC: Take the shortest chain and make it a substituent with O (alkoxy)alkane. Name the above.
Epoxides are cyclic ethers base on a 3-membered ring. Since epoxides are made from alkenes, we usually call them by the alkene name followed by “oxide”. The IUPAC name is epoxy denoting the positions. (e.g. 1,2-epoxy-)
O O O O
Physical properties: Why does ethanol boil at 780 while diethyl ether boils near room temperature?
Why is ethanol completely soluble in water and boils as a 95:5 mixture with water, a while diethyl ether is used as an extraction solvent with water? b
When mixed with water, ether separates by more than 97% (there is a tiny solubility – Do you know why? What technique must we use to deal with the solubility of ether in water after the extraction?)
When ether is mixed with water does it go to the top or bottom? How can you tell?
Assume similar volume for the unit of an organic (CH2) vs OH2. Which one would be most dense?
CH H O 2a 2 a a a a a
Synthesis of ethers: Ethers are made from alkenes like alcohols or from SN2 reaction between an alkoxide (alcohol anion) and an alkyl halide or tosylate. From alkenes and alcohols Predict the product of the reaction of ethanol + propene (1) acid Hg(OAc)2 // (2) NaBH4
Williamson Ether Synthesis SN2 reaction of alkoxide with alkyl halide Let’s consider the synthesis of MTBE, a gas additive to oxygenate the fuel. CH3 O H3C CH3 H3C
(1) Creating the Nucleophile = alkoxide anion Hydroxide is never used because the reaction ROH + NaOH does not lead cleanly to alkoxide. Why?
CH18-2 Organic Chemistry Notes by Jim Maxka [email protected] There are two methods for creating the alkoxide ion cleanly: One is NaH. Given pka(H2)=38, predict the direction and magnitude of the reaction of methanol + NaH Æ
But the best way is to react the alcohol with metallic Na. The general reaction works like this: (note this is an acid/base and a redox reaction): Given pKa(H2) = 38. + - 2ROH + 2 Na(s) Æ 2 Na 2 RO + H2(g)
Any unsymmetical ether can be made from the alkoxide from one side and the alkyl halide from the other side or the reverse. Usually, there is a correct way and a wrong way. First let’s try this approach: methanol Æ methoxide + tert-butyl bromide Æ ? Draw out the reaction scheme: CH3 Na - H C O H C Br H3C OH 3 3
CH3
This strategy does not work to make MTBE. Why?
The reaction mechanism here is . The main organic product is? H CH2 - H3C O H3C Br
CH3 If we reverse the nucleophile and the alkyl bromide, would this be a better way to make TBME? Na - S 2 (H C) COH C Br N (H3C)3COH 3 3 3
Summary Substitution Pattern Reactive Type Least Substituted Electrophile = R-Br Most Substituted Nucleophile = R-OH + Na Æ RO-- Reactions of ethers: Ethers can be cleaved by strong acids. Why must the acid be so strong? Write the arrows for the cleavage of THF (tetrahydrofuran) with HI? H
+ H O 2 4 O - 1 4 I O + HI I 1 3 2 3
H 2 4 NaOH O I 1 3 What is the driving force of the lower reaction? Because of the inertness of ethers, ethers are used as reaction and extraction solvents.
CH18-3 Organic Chemistry Notes by Jim Maxka [email protected] Synthesis of epoxides Epoxides are generally made from the reaction of alkenes with a peroxy acid. A normal carboxylic acid has the form R-COOH. A peroxy acid has an extra oxygen: RCO3H The most common acid used is called MCPBA for meta-chloroperbenzoic acid. Draw it.
Why do you think MCPBA is meta? Why Cl? How would you make MCPBA from benzene?
The general reaction goes like this. propene + MCPBA Æ propylene oxide or 1,2-epoxypropane. Is this reaction oxidation? Does it make a chiral product? MCPBA O
H3C H3C CH2 What is the stereochemistry of the epoxide?
O H C CH O 3 3 CH 3 OOH H3C CH R H3C 3 O
What is the stereochemistry from trans-2-butene + MCPBA Æ
Draw the reaction of cis-2-butene + MCPBA Æ O
OOH
H3C CH3 R
What is the stereochemistry?
Reactions of epoxides – because epoxides have strain, they are much more reactive than regular ethers. Epoxides can be ring opened by either acid or basic conditions.
CH18-4 Organic Chemistry Notes by Jim Maxka [email protected] Acidic conditions: Weak nucleophiles. Acids can protonate the oxygen in the epoxide ring making it a better leaving group and the carbons in the epoxide more . Below is the ring opening of cyclohexene oxide with aqueous acid. Note only the attachment of water on Cb is shown. Water can also attach to Ca.
OH H OH2 OH H H2O b a b a a b + H OH O H + H O + + H O MCPBA H H 3 H
H2O O b H OH H O 2 H OH a + a b O a b + H2O O H H OH H H H + H3O What is the product of the water, coming onto Ca?
What is the relationship between the water reaction at Ca vs Cb?
What mechanism is this most like from before?
What is the role of the H+ here? How could you make the cis diol?
When another nucleophile like Cl- is used, the reaction of 10/20 epoxide: 1,2-epoxybutane with HCl gives a mixture of products.
+ a HCl OH O a b Cl- b H C H3C 3
Can you see the pluses and minuses of the either product? 1-chloro (b) is promoted by . 2-chloro (a) is promoted by . When the epoxide is on a tertiary C, then the most substituted carbon is substituted with the weak nucleophile. Consider the reaction of 1-methyl-1,2-epoxycyclohexane with HBr. Why does it go one way and not both? CH3 CH 3 - combine ions HBr Br + O OH
most stable Carbo cation
CH18-5 Organic Chemistry Notes by Jim Maxka [email protected]
Basic conditions. Strong Nucleophiles. Basic conditions are just SN2 reactions. The regiochemistry is always on the least substituted. Question about the reactions above: Can there be a strong nucleophile under acidic conditions? What kind of solvent is usually used in SN2?
Another method for forming 1,2-diols is with NaOH and an epoxide.
- - H2O MCPBA OH- O H + H O OH H H OH b + a b a b H2O a b a b a O H OH OH H H OH OH H 2 moles OH- Consider the reaction of 1,2-epoxybutane with ethoxide:
EtO- a O
H C b only b why? 3
Another common reaction is the reaction of Grignards: + EtMgBr = Et:- MgBr a O b only b why? H3C
Another reaction with a strong nucleophile is the reaction with LAH (H:-) LAH = H:- a O b only b why? H3C
All of the basic reactions must be acidified on workup to give an alcohol. Practice: What strong nucleophile and epoxide were used to make these alcohols? OH
CH3
OH
OH
O CH3
CH18-6 Organic Chemistry Notes by Jim Maxka [email protected] Reactions with epoxides DNA damage by aromatics (BaP)
http://www.sienahts.edu/~swathen/organic/pah.html
Key Synthetic Step in synthesis of phenylephrine - O OH O
HO HO HO
H N + 2 CH HN H2N 3 CH3 CH3 Br HO HO HO
CH2
O O
HO3S HO3S
This procedure is rather pained, but all the steps are based on reactions you have studied. Why would this procedure never really be used?
CH18-7