Reactions of Benzenes

Transcription

1 eactions of Benzenes lectrophilic Aromatic Substitution 1 Notation Structures and Nomenclature isubstituted benzene notation: 1,2 = orthoxylene 1,3 = metaxylene 1,4 = paraxylene IUPA: uses numbering system number round the ring to give substituents get the lowest numbers possible as usual all other things equal (and NLY when all other things are equal), then do it alphabetically 4 3 N N 2 4-omo-1,2-dinitrobenzene Some aromatic compounds have their own IUPA names: anisole styrene benzoic acid * toluene * N 2 phenol * benzaldehyde * aniline * naphthalene * you need to be able to name substituted versions of those indicated with the * symbol for test purposes carbon #1 by definition 2 N 6 2 named as substituted benzoic acid 2-bromo-6-nitrobenzoic acid carbon #1 by definition 2 N named as substituted phenol 5-ethyl-2-nitrophenol drawing structures of benzenes Accurate, good shorthand Need to use this to keep track of electrons in mechanisms Benzenes : Page 1

2 2 Miscellaneous eactions of Benzenes 2.1 eduction : Addition of ydrogen atalytic addition of 2 : forcing conditions required to add 2 to the benzene ring (breaks aromaticity) 2 less reactive aromatic 2 Pt/1000 psi Pd/ 50 psi arder to reduce benzene ring - aromatic Side hain eduction NaB 4 /t reduced to alcohol adds hydrogen π-withdrawing π-donating removes oxygen adds hydrogen the first reaction we have already seen the second reaction, a emmensen reduction, we have not seen. it reduces an aldehyde/ketone all the way to an alkane. we will return to the mechanism later in the semester, for now this is something you just "need to know", sorry! The rest of the molecule must be capable of withstanding aqueous acid. If not, there is another reaction we can use, again, see later... eduction of nitro to amine Zn(g), 2 reduced to alkane (emmenson reduction) N 2 π-withdrawing N π-donating UTIN 2 removes oxygen adds hydrogen 2 /Pd/ catalytic hydrogenation (seen already) reduces a nitro functionality into an amine, which converts a withdrawing group into a donating group - need to know!! You may see T reducing agents used to do this reduction elsewhere (examples are Fe/ or Sn/), but we only use 2/Pd/ in this course because we have seen it before and to minimize the number of reducing agents we need to learn the emmensen reduction reduces nitro groups to amines very slowly, therefore we can usually reduce an aromatic aldehyde/ketone using the emmensen reduction without also reducing a nitro group that may also be on the benzene ring 2.2 Side-hain xidation Permanganate oxidation (chromic acid reagents can also be used...) xidizes any 1, 2, allyl chain to benzoate (- 2 ), which is then converted into a carboxylic acid using 3 in a second acid workup step interestingly, 3 carbons are NT oxidized, a benzylic hydrogen is needed Benzenes : Page 2

3 xample XIATIN note LSS of second carbon atom removes hydrogen adds oxygen NT: all carbon atoms that are part of the alkyl group being oxidized are LST, except the single carbon that is attached to the benzene ring, which becomes the carbon of the carboxylic acid Mechanism - isn't completely known, except first step... Mn benzylic hydrogens are reactive due to formation of 3Mn stable intermediates -atom abstraction from the carbon attached to the ring (benzylic -), explains why 3 alkyl groups are NT oxidized, they have no such - bond 3 lectrophilic Aromatic Substitution : Many eactions, ne Mechanisms ecall owever first step in the mechanism above is slow,it doesn't "go", benzene is a relatively poor nucleophile and this step is particularly endothermic because it breaks aromaticity need a stronger electrophile to react with the poor benzene nucleophile Solution π-donating ANY alkyl group with a benzylic hydrogen is oxidized to a - 2 nucleophile (LB) AK nucleophile (LB) electrophile (LA) π-withdrawing 2 1. KMn 4 / - /boiling ANY alkyl group t-bu t-bu ITUT a 2. 3 benzylic hydrogen 2 is NT oxidized Ferric bromide (Fe 3 ) is a Lewis acid catalyst, converts 2 into a stronger electrophile exothermic reaction Δ = -30 kcal/mol electrophile (LA) not aromatic endothermic reaction X X Δ = 2 kcal/mol product not aromatic! weaker electrophile Fe 3 stronger electrophile Fe 3 LB Fe 3 Fe 3 LA "sigma-complex" faster reaction, stronger electrophile Benzenes : Page 3 exothermic reaction - Fe 3 Δ= 11 kcal/mol Product still aromatic

4 overall SUBSTITUTIN instead of addition Lewis acid catalyst regenerated General Mechanism for lectrophilic Aromatic Substitution: LA/lectrophile..S. LB/Nucleophile "sigma-complex" The AT TMINING STP (..S.) is the reaction between the benzene and the electrophile, the benzene is the Lewis Base/Nucleophile in the..s. Many reactions, depending upon the particular electrophile All same mechanism for all reactions, in each case we just need to identify the particular electrophile, energy..s. reaction coordinate 3.1 alogenation of Benzene Substitution of a halogen for on a benzene ring via electrophilic aromatic substitution electrophile = a QUIVALNT 2 /Al 3 Al 3 Al 3 2 /Fe 3 electrophile = a QUIVALNT Fe 3 Fe 3 Lewis acid catalysts you can use almost interchangeably: Fe 3 Fe 3 Al 3 Al 3 generate the electrophile using a Lewis acid catalyst 3.2 Nitration of Benzene N 3 2 S 4 N 2 N 2 this is the electrophile needed to do the substitution where does the N 2 electrophile come from? Benzenes : Page 4

5 N - S 2 N N Nitronium ion lectrophile S 4 you may not need to know exactly how the N 2 electrophile is formed, but you should know the mechanism of the subsequent electrophilic aromatic substitution reaction 3.3 Sulfonation of Benzene S 3 2 S 4 S 3 S 3 this is the electrophile needed to do the substitution p-toluene sulfonic acid (Ts) where does the S 3 electrophile come from? S LB/BB - S LA/BA S electrophile S S S S 3 S 3 benzene sulfonic acid issolve S 3 (sulfur trioxide, gas) in concentrated 2 S 4, makes fuming sulfuric acid Lewis/ønsted acid/base reaction protonates the sulfur trioxide, this is where the electrophile comes from in this case 3.4 Alkylation and Acylation of Benzene arbon-carbon bond forming reactions, important! alkylation New - bond N 2 S 3 = N 2 = S 3 = so, all we need is an alkyl cation, i.e. a carbocation, and we have seen lots of ways to make those Benzenes : Page 5

6 For example LA/BA LB/BB t-bu LA/BA t-bu LB/BB any carbocation should react with benzene to do substitution however, the standard conditions to make carbocations are not always convenient (strong acid, silver salts, heating in polar protic solvents etc.), and a better Lewis catalytic method has been developed 1. Friedel-rafts Alkylation -X Lewis Acid X New - bond (Fe 3 or Al 3 or Fe 3 ) LB Al 3 Al 3 lectrophile LA Mechanism Al 3 xample Al 3 ( Al 3 ) But Al 3 Al 3 rearranged isopropyl cation rearrangement of carbocation intermediate, usual carbocation problems Benzenes : Page 6

7 Also Al 3 Al 3 slower faster! multiple additions occur because when 1 alkyl group adds, the new alkylated benzene becomes more reactive than benzene itself T PBLMS IT FIL-AFTS ALKYLATIN earrangements 2. Multiple Additions 3. oesn't work with benzenes that have electron withdrawing groups... withdrawing group S 3 Al 3 X no reaction withdrawing groups "pull" electrons from the ring making it less reactive as a Lewis base/nucleophile because the Friedel rafts reaction is among the slowest of the electrophilic aromatic substitution reactions, it is the most sensitive to strong withdrawing groups on the benzene ring, a Friedel rafts reaction won't go when other electrophilic aromatic substitution reactions will 2. Friedel-rafts Acylation: solves problems 1 and 2 (above), but not 3 xamples withdrawing group, deactivates towards further reaction Al 3 Al faster 3 slower electrophile Al Al 3 3 acylium ion cannot rearrange Al 3 Al 3 Zn(g) / 2 no rearrangement acylation followed by reduction is the "approved" method for alkylating benzenes in this course! Benzenes : Page 7

8 3. Friedel-rafts for "1 carbon" (Gatterman-Koch eaction) / Al 3 Al 3 the Friedel rafts reagent you would ANT to use in this case, formyl chloride, unfortunately does not exist, since it is unstable and spontaneously dissociates into carbon monoxide () and hydrogen chloride () Therefore you have to make it "in situ", i.e. by mixing and, a small of formyl chloride will form, as shown below, which can then react with aluminum trichloride to produce a small amount of the formyl cation that will then undergo electrophilic aromatic substitution with benzene formyl chloride unstable Al 3 Al 3 Formyl cation () u is also often included as a catalyst in addition to Al3, but we omit it here for simplicity to minimize reagent memorization, but be aware that you may see u elsewhere xample - to add a methyl group to benzene, first add the corresponding formyl group to form an aldehyde, then reduce / Zn/g 3 Al 3 / 2 4 eactions of isubstituted Benzenes ITING and ATIVATING effects of substituents ecall electron donating and withdrawing groups on pi-systems increasing electron withdrawing ability increasing electron donating ability N = N F 3 δ 3 S 2 N 3 N δ δ 2 N δ F Ar 2 δ δ N N 2 N 2 the halogens are electron withdrawing when attached to a π-system even though they have non-bonding electrons due to electronegativity Summary of electron donating and withdrawing effects on electrophilic aromatic substitution increasingly faster rates with increasingly stronger (activating) electron donating groups -groups are ortho- and para-directing Benzenes : Page 8

9 increasingly slower rates with increasingly stronger (deactivating) electron withdrawing groups -groups are meta-directing X X the "exceptions" somewhat slower rates with halogens (X), weakly deactivating X- are ortho- and para-directing 4.1 onating Groups : Activating and rtho- and Para-irecting 2 N donating Me N 3 2 S 4 N 40% 3% 2 57% N 2 hy is this?? the methyl group is a weak donating (-) group N 2 N 2 N 2 N 2 N 2 "3 " "2 " "2 " N 2 N 2 N 2 N 2 "2 " "2 " "2 " N 2 N 2 N 2 N 2 N 2 "2 " "3 " "2 " N 2 the methyl donor group stabilizes the charge for ortho and para attack, but not meta attack ere is a partial reaction energy diagram for the first step in the mechanism comparing benzene and toluene relative energy N 2 on benzene N 2 N 2 versus N 2 N 2 2 N meta position on toluene ortho position on toluene reaction coordinate Benzenes : Page 9

10 The donating group makes attack at both the meta and ortho/para positions faster than for simple benzene (the a smaller for both reactions with the methyl substituent), but attack at ortho/para is faster than for meta eaction does not occur at the meta position because reaction there is slow, it is NT, it is just not as fast as reaction at the ortho- and para-positions lectron onating groups are o- and p- directing lectron onating groups are activating (make reaction go faster) The stronger the electron donating group, the faster the reaction 4.2 ithdrawing Groups : eactivating and Meta-irecting N 2 N 2 N 2 N 2 N 2 N 3 2 S 4 the sigma complex is LAST destabilized for meta-addition ortho addition N 2 6% 93% N N N 2 2 N 2 N 2 1% electron withdrawing group destabilizes the sigma-complex meta addition N 2 N electron withdrawing group does not ITLY destabilize the sigma-complex N 2 N 2 para addition N 2 N electron withdrawing group destabilizes the sigma-complex N 2 N 2 N 2 N 2 ortho position on nitrobenzene N 2 2 N N 2 meta position on nitrobenzene versus N 2 N 2 on benzene eaction does not occur at the meta position because reaction there is fast, it is NT, it is just not as slow as reaction at the ortho- and para-positions electron ithdrawing groups are m- directing electron ithdrawing groups are deactivating (make reaction go slower) the stronger the electron withdrawing group, the slower the reaction Benzenes : Page 10

11 4.3 alogens are IFFNT! They are eactivating BUT rtho- and Para-irecting! lectron donation versus withdrawing isn't black versus white, it isn't really binary like that There is a continuum, from very strong withdrawing, to weaker withdrawing to not withdrawing or donating at all (), to weakly donating to strongly donating. So we shouldn't be surprised that there are substituents that are very close to the middle, like, for reasons that cancel TIS is the ALGNS, they are VY LS T T MIL increasing electron withdrawing ability N The halogens are LTNGATIV, therefore withdrawing via the INUTIV FFT, BUT, the ALGNS also have non-bonding electrons that could, in principle, be donated T ALGNS TUS AV MIX BAVI AS SUBSTITUTNTS The ALGNS are electron-withdrawing, and therefore ATIVATING owever, ALGNS are also T- and PAA-directing since they can stabilize the intermediate cation (sigma complex) by SNAN NATIN of a pair of NN-BNING LTNS for reaction in the ortho- and para-positions, but not in the meta- position xample F 3 3 S 2 N 3 N 2 N F neither increasing electron donating ability Ar 2 halogens are LS T MIL of the NTINUUM N N 2 N 2 S 3 S 3 S 3 e should not be surprised that there is a substituent type that is in the middle, this is the halogens! 4.4 Predicting Products for Multiply-Substituted Benzenes hen there is more than one substituent, consider the following... 1) The most electron donating group determines the directing effects (electronic) -group N 2 3 in reactions with an electrophile -group reacts faster by a factor of 10 4!!! 2) But we also need to consider steric effects! S S 3 2 S 4 N N 2 2 N S 2 3 two products formed Benzenes : Page 11

12 3 3 not formed for electronic reasons 3 S N 2 not formed for steric reasons S 3 N 2 The -3 group ITS the reactivity because it is ATIVATING reaction occurs at the ortho- and para-positions with respect to the -3 group, except that N of the orthopositions is "blocked" due to steric hindrance xamples 3 N Fe 3 N 2 3 N 2 not formed The -3 group ITS the reactivity because it is ATIVATING reaction occurs at the ortho- position with respect to the -3 group, the para-position in this case is BLK, we can't substitute the -N2 substituent The two ortho-positions in this case are equivalent (by symmetry), reaction at either gives the same product # #2 Al 3 Not formed (steric) # eaction at positions #1 is equivalent, gives the same products, reaction at position #2 does not occur for steric reasons #1 3 3 S 3 3 #2 3 S S 4 3 #2 #1 both formed 3 S Positions #1 and positions #2 are equivalent, reaction at each #1 gives the same product same for #2 lectrophilic aromatic substitution reactions AN give more than one product, we need to be aware of this S Me Me STILL get Friedel rafts acylation 3 S S 3 S The -Me is the STNGST NATING group, IT ITS the reactivity because it is M ATIVATING than the weakly donating -Me substituent eaction occurs at one para- position with respect to the -Me group, the two ortho-positions are BLK, we can't substitute the -S3 or the -3 substituents BUT AIT! ow can we have a Friedel rafts reaction on a ring that has a strong - substituent, the -S3, doesn't that break our "rule? This is a problem with rules! Note that we also have 2 donating (activating) Benzenes : Page 12 Al 3

13 substituents that offset the deactivating effect of the withdrawing -S3. And so, we have to use some common sense and adapt the "rule" that there is no Friedel rafts reactions with strongly withdrawing substituents accordingly when there are also strong donating substituents 5 Synthesis of Substituted Benzenes xamples 2 Fe 3 o,p-directing N 3 2 S 4 N 2 m-directing N 2 N 2 N 2 N 3 2 S 4 2 Fe 3 note the different products from the two last reaction sequences, the MATTS 1. KMN 4, eat Al 3 2 makes MTAdisubstitued benzene 2 2 Al 3 separate the orth-isomer from the para-isomer 1. KMN 4, eat 2. 3 makes Tdisubstitued benzene again, isomeric products from different reaction sequences where necessary, "separate the isomers" to complete a benzene synthesis sequence N 2 N 2 N 3 2 S 4 Al3 -group deactivates towards F- Acylation No eaction ALL: Friedel rafts acylation (above) cannot be performed on the benzene that has a strong electron withdrawing substituent Benzenes : Page 13

14 ompare: Al 3 Zn/g / 2 N 3 2 S 4 N 2 Zn/g / 2 N 2 N 3 2 S 4 N 2 N 2 xample Synthesis Problem #1 Synthesize the trisubstituted benzene derivative on the right from benzene work backwards using retrosynthetic approach, ask which substituent you are able to "add" backwards separate the isomers S 3 S 3 2 S 4 2 /Fe 3 Al 3 S 3 2 S 4 S 3 Zn/g / S 3 S groups, not obvious which "wins" At each step (backwards), ask "which of the substituents can be generated, decide which reaction to do on that basis ventually you don't have to actually write out all of the possible reactions, you can analyze the possibilities in your head It would be difficult to predict that Friedel-rafts acylation should be the first step in the synthesis problem above, these problems are definitely best solved backwards Benzenes : Page 14

15 xample Synthesis Problem #2 N 2 N 3 2 S 4 N 2 separate the isomers N 2 S 3 Al 3 N 2 Zn(g) / 2 S 3 S 3 S 3 2 S 4 Al 3 2 N 2 2 /Pd/ N 2 N 2 N 2 Zn(g) Al 3 separate the isomers / 2 f course, there may be more than one possible solution to these problems, as above In reality even these reactions have complications that we don't really have the time to get into here, specifically, once the amine is formed the Freidel crafts reaction becomes very slow again even though the amine is very activating, because the amine will also undergo a Lewis acid base reaction with the Al3, making it less donating, organic can be complicated sometimes! 6 Nucleophilic Aromatic Substitution Substitute using a nucleophile (not electrophile) Substitutes for a halogen (not hydrogen) Two Mechanisms: 1) Addition-elimination 2) limination-addition, we consider Addition/limination only LTPILI Aromatic Substitution: basic principle electrophile proton leaves electrons "left behind" the substituted atoms "leaves" in the form of a proton, formally the electrons in the - bond are "left behind" and are needed to complete the bonding with the electron deficient electrophile NULPILI Aromatic Substitution: basic principle when a nucleophile substitutes, can't substitute for a hydrogen, since the electrons must also "leave" (the nucleophile brings its own electrons, hydride anion (-) is a very poor leaving group, need a better leaving group that can "take" the electrons, need a conventional leaving group such as halide X X Nu Nu addition Nu nucleophile elimination :X halide anion leaves takes electrons the X- can be a good leaving group, BUT, there are no SN1 or SN2 reactions at an sp2 hybridized carbon atom one way round this is the addition/elimination mechanism Benzenes : Page 15

16 X Nu addition X Nu X Nu X Nu elimination Nu X leaving group hen a NULPIL is the reactant, then substitution occurs for a halogen, not hydrogen, as occurs when an electrophile is the reactant nly works with = strong withdrawing group in ortho- or para- position nly works with strong nucleophile xamples strong nucleophile strong Na 3 2 N 2 N 3 3, eat strong N 2 N 2 strong moderate nucleophile N 3 N eat N 2 N 2 N 2 N 2 N 2 Benzenes : Page 16

17 7 Summary of Aromatic eactions o NT start studying by trying to memorize the reactions here! ork as many problems as you can, with this list of reactions in front of you if necessary, so that you can get through as many problems as you can without getting stuck on the reagents/conditions, and so that you can learn and practice solving reaction problems. Use this list AFT you have worked all of the problems, and just before an exam. By then you will have learned a lot of the reagents/conditions just by using them and you will only have to memorize what you haven't learned yet. Then do the following: over the entire page of reagents/conditions with a long vertical strip of paper, see if you can write down the reagents/conditions for each reaction, check to see which you get correct, if MPLTLY correct, circle Y, if incorrect or even slightly incorrect, circle N. In this way you keep track of what you know and what you don't know. Keep coming back to this list and so the same thing only for those reactions you circled N, until all are circled Y. Knowing the reagents/conditions on this page is INSUFFIINT to do well on an exam since you will ALS need to recognize how to use and solve reaction problems in different contexts, this page NLY helps you to learn the reagents/conditions that you have not YT learned by working problems. Zn (g) / 2 (emmenson reduction) t t-bu Me 1. KMn 4 / /boil t-bu N N /Pd/ 2 Fe 3 2 Al 3 S 3 S 3 2 S 4 N 2 N 3 2 S 4 /Al 3 (Friedel-rafts alkylation) do not use in synthesis /Al 3 (Friedel-rafts acylation) //Al 3 (u) (Gatterman Koch reaction) u should be included, we omit it for simplicity 2 N Na 3 / 3 3 N 2 (nucleophilic aromatic substitution) 2 N N 2 Benzenes : Page 17