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by: Michelle Gulgowski DVM


Marketplace > University of Kentucky > Chemistry > CHE 232 > ORGANIC CHEMISTRY II
Michelle Gulgowski DVM
GPA 3.91

John Anthony

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John Anthony
Class Notes
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This 20 page Class Notes was uploaded by Michelle Gulgowski DVM on Friday October 23, 2015. The Class Notes belongs to CHE 232 at University of Kentucky taught by John Anthony in Fall. Since its upload, it has received 37 views. For similar materials see /class/228297/che-232-university-of-kentucky in Chemistry at University of Kentucky.

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Date Created: 10/23/15
Ethers epoxides and sul des An ether is the logical and nearly terminal conclusion of a series of water alkylations quot 1k 1 t quot quotalkylatequot quotalkylatequot 5 H H ROH gt RO R gt RIG R Water Alcohol Ether Trialkyloxonium Salt YECH Ethers come in a couple of avors There is the standard dialkyl type O QO QO 0 Ether Benzyl Methyl Ether Anisole Vinyl Methyl Ether Diethyl Ether Phenyl Methyl Ether Ethyl ether all 3 in common usage And then there are the cyclic ethers the names of these can be ugly because they are often based on the molecule from which the ether was derived rather than as an accurate description of the ether 0 O O O O L7 L7 CI A P Furan Tetrahydrofuran Trimethylene Oxide Ethylene Oxide Propylene Oxide THF Oxetane Oxirane Epoxide Uses of ethers Unlike alcohols ethers in general are unreactive They are more commonly used as reaction solvents than as reactants ethers thus make great protecting groups The only real exceptions to this rule are the epoxides the three membered ring ethers We will talk more about the reactivity of these compounds later Preparation of Ethers The most common preparation of simple ethers uses the Williamson Ether Synthesis In short this preparation utilizes a deprotonated alcohol and an alkyl halide InGeneral R O39Na R39 Br gt R 0R NaBr AnExample HO OH 2NaH NaO ONa 2CH3BrgtMeO 0Me 2 H2 Notes and Restrictions The alkoxide portion of the starting material is generally produced by the action of sodium hydride NaH This hydride is the reagent of choice because the only by product is hydrogen gas a very strong driving force Because the alkoxide is very basic the alkyl halide should be primary otherwise deprotonation rather than nucleophilic attack is likely SN21 C A o Br Na gt E23 C VONa Br glt gt VOH Ylt Destruction of Ethers Now that you ve gone through all the trouble of making an ether we re going to talk about how you tear them back apart Ethers are generally cleaved by strong acids at high temperatures ie at LEAST 2M acid at 100 C HBr and HI are the reagents of choice 0 HBr 2M HOW Br H20 110 C quotHM 0 HBr 2M gt OH H20 110 C 6H 1319 Because they can form stable carbocations tertiary allylic and benzylic ethers can be cleaved under much milder conditions and form an alkene in place of the alkyl halide Epoxides Lo Because of the strain induced by the presence of a three membered ring epoxides are significantly more reactive than other ethers Thus they become useful in organic synthesis Preparation Epoxides are easily prepared from alkenes by oxidation with a peroxyacid often called a peracid This is really the only nonstereospecific epoxidation method currently in use O 3 chloroperoxybenzoic acid w ull 0quot H O 0 CI For example OH O OH O O MCPBA I O gt O I HUICOOH sulCOOH O Frenolicin RingOpening of epoxides This is where the real synthetic utility of epoxides comes into play As we discussed earlier 1 Epoxides can be ring opened to trans or anti 12 diols 2 Metallated Species RM can be added to epoxides to form primary alcohols Here we will discuss a little more about the mechanism of these reactions as well as how to predict where incoming nucleophiles will add A Acid catalyzed ring opening of epoxides With simple aqueous acids epoxides ring open to give the anti 12 diol The mechanism is relatively straightforward RCOOOH H3o OH OH I gt O gt i H gt gt or H202 quotIOH 39IIOH 11 13 39139 5 H26 4 In this case obviously the nature of the epoxide is unimportant the result is always the anti diol Epoxides can also be opened with anhydrous acids The result in this case is a halohydrin ie if you use anhydrous HCl you get a chlorohydrin With symmetrical epoxides only one product results With unsymmetrical epoxides mixtures are typically produced significantly lessening the synthetic utility of the reaction B Nucleophilic ring opening of epoxides Epoxides can also be opened by aqueous base 0 J H H RCOOOH 0 OH I gt O gt gt or H202 19 IIIOH quotIIOH It is obvious from the mechanism that any strong nucleophile not just hydroxide will be able to ring open an epoxide As we saw in before this leads to primary alcohols But what if the epoxide is substituted The really cool thing about the basic ring opening of epoxides is that the nucleophile always attacks from the less substituted side We can thus set two stereocenters in the molecule in one simple step OH OH OH L OH M CPB A In fMgBr 11 n I gt to gt quot39 quotquotquotI Ring opening of epoxides by various nucleophiles is a very powerful tool in organic chemistry You should be familiar with how this works Here is another example H2 Pd CaCO3 MCPBA JvOH 9 Et3N THF OH OH OH SR Sulfides Sulfides are the sulfur analog of ethers They are however much more reactive than ethers they can be oxidized quite easily under relatively mild conditions The oxidized sulfides the sulfoxides sulfones and mysteriously sulfates Sulfide Sulfoxide Sulfone Sulfate 0 OX 0 CH3 5 OX OX 39 H3C CH3 gt HBC gCH3 gt H3C g CH3 gt 0 g l H3 09 Oe HBC CH3 ch Hg e Smelly byPr0duct Dimethyl Sulfoxide DMSO D Lh 1 Sulf d of the Swem reaction common SOIVSHL Dlmethyl Sl fone oxic Also used for Drug Delivery 7 Alkyla ng agent can it be 39 penetrates skin EASILY made by oxidlzing the sulfone The oxygen sulfur bond is VERY polar making any sort of nucleophilic attack on Sulfur quite easy Recall the Swern reaction Reactions of Aromatic Compounds Simple alkenes tend to undergo addition reactions Br Br Br A C3H6Br2 C3H6 C3H7Br The elements of the reagent HBr or Br2 are simply added to the starting material This is called unsurprisingly and addition reaction Aromatic compounds do not react in this manner A look at a simple aromatic bromination Q Br2 FeBr OBr C6H6 C6H5Br What we have done in this case is substitute a bromine for a hydrogen Hence the term aromatic substitution Because the benzene ring is quite electron rich it almost always behaves as the nucleophile in a reaction which means that the substitution on benzene occurs by the addition of an electrophile gt electrophilic aromatic substitution There is basically one simple mechanism for all electrophilic aromatic substitutions E EH EH EH3 E gt4 gt 4 J gt U The benzene acts as a nucleophile attacking the electrophile with a pair of its JI electrons This initial step destroys the aromaticity of the molecule The resulting positive charge is delocalized over the ortho and para positions The conjugate base of the initial electrophile then assists in removing the now extraneous proton and restores aromaticity Because all electrophilic aromatic substitutions proceed in this way the only thing that matters is the preparation of a hot electrophile Why a hot electrophile As you can see the first step of the reaction involves destroying aromaticity In order to do this there must be a significant energetic driving force This driving force comes in the form of a very reactive unhappy electrophile How are such electrophiles generated Halogenation As you can imagine halogens bearing a positive charge are particularly reactive I will focus on preparing halogen electrophiles from Br Cl and I Bromine Allowing bromine to react with iron metal first generates FeBr3 which then interacts with the remaining Br2 to form a highly polarized system Br2 a 8 Fe gt FeBr3 BT31e Br Br It is this highly polarized bromine that becomes a source of Brt The reaction proceeds by the mechanism shown above to give brominated benzene Brz Br gt FeBr3 Chlorine The same chemistry shown for bromine also works with chlorine to generate Cl A mixture of benzene chlorine and ironIIIchloride yields the chlorobenzene CI E Z FeCl3 Iodine It is a little more difficult to make iodine sufficiently electrophilic For relatively activated compounds where a mild source of 1 is required copper salts are often used as a catalyst 12 2 Cu gt 2 quot1quot 2 CuI I C11ch Reaction then proceeds by the standard mechanism with IJr as the electrophile to give iodinated benzenes For more de activated systems or when more than one iodine needs to be added to the ring a harsher reagent exists I Br Br Br Br H2804 12 H5106 Why You should always ask this question What good are aromatic halides The halogens are excellent synthetic handles they can be easily converted into other functional groups For example bromobenzenes can be turned into Grignard reagents and the reacted with aldehydes ketones etc 8 Bng OMe co Ho 0 COOH ltlt HO NITRATION We can also make a highly electrophilic form of N02 H30 4 H quotgt I quot0 O gt ON O gt I N I H b o Which can then react with aromatic compounds via the standard mechanism to give nitrated aromatics ClAQ a Why There are a couple of good reasons to nitrate things The first is in the manufacture of explosives highly nitrated organic molecules are frequently used as explosives trinitrotolueneTNT nitroglycerine etc The second reason is that nitro groups are generally easy to reduce to amines And since it is nearly impossible to make an amine electrophilic in order to add it to an aromatic ring under electrophilic aromatic substitution conditions aromatic nitro compounds are about the only precursors to aromatic amines 1 SnC12 H N02 gt NH2 2 HO Sulfonation Just as with nitration it is easy to make a solution of highly electrophilic 03 This solution can be used to sulfonate aromatic compounds O I o 0 8 A H H lose proton gt 08 gt SOsH OH I 9 HO Why First of all the reaction is REVERSIBLE Cook it up in hot AQUEOUS acid and the S03 group falls right off again Second aromatic sulfonic acids were used as the first antibiotics the so called sulfa drugs sulfanilamide etc They can also be used in making detergents oh what fun FriedelCrafts Reactions This reaction comes in two avors alkylation and acylation Alkylation first The basic premise of this reaction is the electrophilic addition of alkyl groups to an aromatic ring The general scheme R Cl AlCl3 gt R AlCl439 w 2 QR Ralkyl A simple example CI A G A1C13gt lt There are a number of drawbacks to this reaction 1 Does not work at all on aromatic rings with de activating groups nitro any carbonyl cyano attached 2 Because alkyl groups are activating over alkylation is a significant problem 3 Because a carbocationic intermediate is involved rearrangements tend to take place For example 5 a 1 0 Major product AlCl 6 A be 3 he 2 74 MESS However 01 Friedel amp Crafts came up with another reaction without so many drawbacks The Friedel Crafts acylation generally proceeds without complication 2 O OAR AlCl at z 902 For example Om O AlCl3 Note the only significant restriction is that we still can t have any de activating groups on the ring Over acylation cannot be a problem because an acyl group is de activating only one can add There is also no problem with rearrangements A very efficient Substituent Effects Most of what I ve talked about so far has involved the addition of a compound to an unsubstituted benzene ring What about additions to a substituted ring I will summarize Activatingde activating groups Because the benzene ring s electrons are acting as the nucleophile in all of the above reactions rings substituted with strong electron donating groups particularly JI electron donating are considered activated they will often even react without a catalyst Some examples of activating groups are OH OR NH2 NR2 Alkyl The oxygen and nitrogen based activating groups increase reactivity by a resonance effect QA A A A U 9 A 2 OR OH NH2 NR2 As you can see the very nature of the activation requires ortho para direction Alkyl groups work somewhat differently They are not as strong at activating the ring and their main function is stabilizing the positive charge formed after the attack on the electrophile R R fStable tertiary carbocation WH 399 E H E H R 2 alkyl Note well All activating groups direct ortho para ElJ The Halogens The halogens are in a class by themselves and behave in an unusual manner They are VERY electron withdrawing and thus DE ACTIVATE the ring towards electrophilic substitution However their multiple lone pairs are able to stabilize the cation formed after electrophilic addition and thus direct ortho para l3r Br e39B39r r e E H E H MetaDirecting De activators Strongly electron withdrawing groups de activate the ring towards electrophilic substitution Examples of such groups are Ester COOR Acid COOH Aldehyde CHO Nitro N02 Ketone or acyl COR Cyano CN Acid Halide COCl However with a strong enough electrophile the rings often will react However in order to avoid putting the charge that develops after attacking an electrophile on the carbon attached to the electron withdrawing group the incoming electrophile must attach to the meta carbons see below Note that the charge cannot be delocalized onto the carbon containing the acyl group also note the charge delocalizes over all of the ortho and para positions a ama Other considerations Sterics Sterics Sterics This is particularly a problem with bulky ortho para directors the ortho positions are blocked forcing addition to the para positions Br Fe 2 gt HNO 0 0 35 NO ORTHO N02 r Multi functional compounds What if the ring has several substituents Your text has a rather detailed description of what to do so here I ll just supplement that data 1 If the effects of two substituents point to reactivity at one particular carbon you re in luck That s where the electrophile will go providing the sterics are not horrible 2 The strongest directing group almost always prevails e g OH over alkyl NR2 over Br 3 The order of precedence is a Strong op directors OR NR2 b Alkyl groups and halogen c All meta directors 4 And of course keep a close eye on the steric environment Nucleophilic Aromatic Substitution Your text has a good description of this phenomenon Sec 168 This sort of reaction is not very common but it would be a good idea to be familiar with the mechanism Benzyne Benzyne was discovered when some crazed scientists mixed chlorobenzene and sodium hydroxide at high temperature and pressure The resulting phenol was found to have arisen from an eliminationre addition reaction H 7 91 H20 GOH HQ gt gt Because benzyne is such a useful intermediate a method has been discovered which allows it to be prepared by much milder means It starts with anthranilic acid diazotizes the amine which then decomposes to benzyne carbon dioxide and nitrogen The benzyne can then be used in many ways OH 0 OH 0 gN NH2 HNO 7 N mild base H SO 2 4 quotdiazotizationquot ROH gt Diels Alder Slow Decomposition DID Biphenylene Reactions on the Aromatic Side Chain Alkyl groups attached to a benzene ring are surprisingly reactive The hydrogens on a carbon atom attached to the benzene ring are called benzilic Notice a similarity to allylic systems Benzilic Hydrogens H H J H V Allylic hydrogens Benzilic hydrogens show a reactivity similar to allylic hydrogens They can be brominated with NBS for example N Br g NBS Br gt PhCO20 CC14 Aromatic compounds with benzilic hydrogens are also susceptible to oxidative degradation Potassium permanganate KMnO4 decomposes these to the benzoic acid caution you loose the WHOLE side chain on this one CH3 COOH a KMno4 g HO HO O KMno4 Note if there are NO benzilic hydrogens last example the benzilic position is not oxidized in this case only the alcohol on the side chain gets oxidized Hydrogenation With a sufficiently active catalyst it is possible to hydrogenate the aromatic system to a completely saturated system Because aromatic chemistry is so rich amp diverse this is one method to prepare highly substituted cyclohexanes COOH COOH Rh C H2 HOOC COOH EtOH HOOC COOH gtgt Kemp s Triacid OOH molecular recognition It is also extremely easy to hydrogenate a side chain As a simple example take ethyl cinnamate OEt OEt o H Pd C 0 Ethyl Acetate 100 Along with hydrogenation we can also do a different kind of reduction a de oxygenation This reaction ONLY works on Aryl Ketones R H and is a PERFECT way to turn a Friedel Crafts Acylation into an Alkylation o R R RJLCI 0 H2 Pd D gt gt A1c13 R 7 H Aromatic airlines Preparation There is basically one method commonly used to prepare aromatic amines and you have already seen it The reduction of aromatic nitro compounds leads to the aromatic amine under quite mild conditions While there are a number of methods that can be used the one I would remember is SnC12 HCl followed by NaOH in water 02 NHg HNO3 1 SnCl2 HCl gt st04 2 NaOH H20 So an amino group is powerfully activating can this cause problems Of course It is frequently necessary to tone down the reactivity of an aromatic amine in order to get only monosubstitution or for Friedel Crafts reactions to work at all The absolute best way to do this is to turn the amine into an amide usually by allowing it to react with acetic anhydride pyridine The lone pair on nitrogen becomes a bit more strongly delocalized out the amide end thus leaving the ring a bit less activated After the reaction is finished the amide can be cleaved to give back the amine with NaOH water note an amide is a bulky group therefore additions usually go para first NH2 CI 4 No reaction actually a foul mess AlCl3 O o NH2 0 o HNJK i HNJK NHZ LOJK NaOH gt gt gt Pyridine A103 Hz0 The next cool reaction you can do with aromatic amines it the Sandmeyer This reaction is probably the neatest thing about aromatic compounds in general The Sandmeyer proceeds in two stages First reaction with sodium nitrite to give the diam compound Basically you re now looking at a benzene ring with nitrogen gas stuck onto it Who could ask for a better leaving group Next you add your favorite nucleophile as a copper salt for example if you wanted to add bromide you d dump in some CuBr If you wanted to add cyanide dump in CuCN etc Warm that puppy up for a few minutes and voila Instant substitution First a simpler example 391 NH 6 Br NaN02 CuBr aq HCl There are a couple of fairly cool modifications that you can do here First if you add hypophosphorous acid H3P02 to a diazonium salt the aromatic ring just gets protonated This is usually the best way to make 135 trihalobenzenes remember halogens are op directing Ill NHZ NH2 He 1 1 I2 I NaNo2 1 1131302 gt1 I aqHCl 1 I 1 This is one of the best and most common ways to abuse an aromatic amine you just use it for its activating and directing effects then you throw it away Another modification can be used to make phenols If you just add water to the diazonium salt you add an OH group to the ring 39I39xle OH H20 gt Cyanide is also pretty easy to add N N Iquot NHZ No 393 I I NaNOZ I I I I H SO gt CuCN 24gt HOOC COOH aq39 HCI NaCN HOOC COOH HOOC COOH I I I Phenols and Quinones Aromatic alcohols are not quite as reactive as aromatic amines The lone pair is not nearly so hyperactive However aromatic alcohols called phenols are very easy to deprotonate no surprise here the resulting negative charge is delocalized over the ring leading to an anion that is mildly basic and very nucleophilic The acidity of the phenolic proton is also highly dependent on the other substituents on the aromatic ring Electron withdrawing groups stabilize the anion and thus make the phenol more acidic for example trinitrophenol is VERY acidic Electron donating groups have the opposite effect Preparation The best way to make phenols is to use the cool reaction you learned with aromatic amines the Sandmeyer This reaction is usually done last in a sequence so first substitute the aromatic amine as you want then make the diam compound and heat it up with water N NHZ we OH NaN02 H20 gt gt aq HCl Reactivity Reactions of phenols can get a bit tricky The main problem is that they react both as highly activated aromatic rings and as alcohols Thus with an acid chloride you can form an ester Or with methyl bromide and a base you can form an ether 0 O OJJCH3 OH OCH 3 H3CJJC K2CO3 gt G E CH3Br The aromatic ring is also highly activated as you might expect Thus with a sufficiently good electrophile the ring is easily substituted However since the lone pairs on oxygen are not as hyperactive as those on nitrogen it is usually easy to control the degree of substitution OH OH OH OH Br Br Br2 HBr lt 2 CC14 r r 1 Br2 H20 2 NaHSO4 OH Br Br I Carbon dioxide is also sufficiently electrophilic to react with phenols and this is a great way to prepare phenolic acids Under normal conditions the ortho isomer is formed However if the product is heated under basic conditions it isomerizes to the para isomer 0 H O O H EOZCOE o 240 C 2 150 C proton transfer 0 gig o o o6 o 5 gt o o O Some alkyl cations are also susceptible to addition to phenol Frequently these react without the need of any metal catalysts eg aluminum OH gt OH st04 H 35 The aluminum catalyzed Friedel Crafts reaction WILL NOT WORK WITH PHENOL However if you simply protect the alcohol as an ether Friedel Crafts reactions work QUITE well G K2C03 O O O gt gt CH3B1 Alc13 OH O Oxidation of Phenols Phenols undergo a rather unusual oxidation to compounds called quinones OH O K8032NO gt 2 The oxidation of a phenol monohydroxybenzene to a quinone requires rather harsh conditions Fremy s salt However ortho and para dihydroxybenzenes oxidize to quinones VERY easily They are also easily reduced back to the dihydroxybenzene Na CrO OH 2 2 Lgt 0 K80 NO OH ILgtH20 0 HO O SnC12 NaBHa H The Claisen Rearrangement Okay time to look at electrocyclic stuff again Allyl phenyl ethers rearrange in a rather unique way OH 0 W 1 NaH gt 2 BrCHZCHCHZ An Allyl Phenyl Ether O O OH a H 2 This rearrangement involves a 6 membered ring intermediate and pushes 6 electrons in a circle The initial result is a cyclic ketone which rapidly tautaumerizes to regain aromaticity This is generally a good method for the preparation of phenols with allyl groups substituted on the ring This rearrangement is kinda cool but what happens if both positions ortho to the hydroxy group are blocked The allyl group then migrates again to the para position m o 0 OH A 5 3l H 3 Be sure you understand the stereo and regiochemistry of this reaction


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