Organic Synthesis and Carbon-Carbon Bond Forming Reactions. 1. To introduce basic concepts of organic synthesis:

Transcription

1 rganic Synthesis and Carbon-Carbon Bond Forming eactions 1. To introduce basic concepts of organic synthesis: etrosynthesis thinking backwards from relatively complex molecules to simpler ones the disconnection approach. Target Molecule Precursors Solomons p n.b. 2. To classify and extend the main carbon-carbon bond forming reactions (CCBF) introduced in CE1C1Y. 3. To illustrate the importance of organic synthesis with real examples. rganic Synthesis Introduction Why bother?! Ca. 7 million organic compounds known most have been made by synthesis rather than isolated from nature. easons for Synthesising rganic Compounds: a) Proof of structure of a natural compound by putting it together from simpler molecules. b) To prepare compounds that are useful to mankind e.g. pharmaceuticals, polymers, dyes etc. c) To prepare specific compounds to study reaction mechanisms or biological metabolism (e.g. labelled compounds). d) For the intellectual challenge new problems demand new solutions and can lead to the development of NEW CEMISTY, reagents etc. When faced with the challenge of preparing a specific organic compound ho do we go about it? This is the art of synthesis! e.g. ow might we attempt to make Z jasmone an important constituent of many perfumes?? α,β unsaturated ketone, alkene, 5-membered ring 1

2 In fact one synthesis uses the following as carbon sources C 2 C 2 It is not clear from this however, how the chemistry might be done! Therefore just being given the starting materials is not sufficient to help plan a synthesis. Note the importance of CCBF. We need a logical planning method. etrosynthetic Analysis (The Disconnection Approach) riginated by E.J. Corey (Nobel Prize 1990) p p p Definition of Terms Target Molecule (TM) the compound we wish to prepare e.g. methylphenyl ketone (acetophenone) etrosynthetic Analysis the process of WKING BACKWADS from the TM in order to devise a suitable synthetic route (or routes) on paper. Note: denotes disconnection of TM to its most immediate precursor. Multiple steps are required so this needs to be repeated. TM 1st Precursor 2nd Precursor Starting compounds - readily available After writing possible routes we would need to evaluate each one before deciding which to follow. 2

3 eadily Available Starting Materials (ASM) cheap, commercially available compounds. Disconnection a paper operation involving an imagined cleavage of a bond (yielding synthons ) to suggest a method and possible SM s for making the bond, ultimately leading to possible SM s for the overall synthesis. X Y X + + Y - X - + Y + X + Y Note: There must be a good chemical reaction corresponding to the reverse of the disconnections. Synthon an idealised fragment, usually a cation or anion, resulting from a disconnection. X + Y - X - Y + X Y Usually synthons don t exist as such, but help in the correct choice of reagent. In our example: Looks possible because it implies electrophilic attack on benzene ring Does not look so good (nucleophilic attack less usual) Synthetic Equivalent the actual compounds used to function as synthons. Cl AlCl 3 Friedel Crafts reagent Functional Group Interconversion (FGI) the process of writing one functional group for another to help synthetic planning and to help disconnection. Note, there must be a good reaction in the reverse (forward!) direction. 3

4 e.g. N 2? easy reduction (Sn/Cl) FGI N 2 N Easy! Nitration of benzene (N 3 / 2 S 4 ) Alternative synthesis of FGI C 3 C 3 Mg Many ways to make alcohols (e.g. via Grignard reagents) - suggests alternative synthesis to Friedel Crafts. In planning a synthetic strategy, apart from devising a means of constructing the carbon skeleton with the required functionality as above, there are other subtle factors, which we must address. X X X Control of egiochemistry Y AND NT Y Control of Stereochemistry AND NT enantiomers (Good summary p , , ) 4

5 We will illustrate this approach with examples, starting with synthesis of benzene derivatives. Starting point is usually fairly obvious simple benzene derivatives or perhaps benzene itself. The Synthesis of Substituted Benzene Derivatives (Solomons p ) eactions are usually straightforward (S E Ar) and you will have met most of them before. Synthesis is simplified because the nature of the starting materials is usually clear. Thus, most reactions correspond to the following disconnection: X X S E Ar Example 1 1 st decision which bond to disconnect first! N 2 S E Ar 1 N 2 Problem! No good synthetic equivalent for N 2 + (but o/p directing effect of sub is K) N can use 2 /Fe 3 o/p directing effect of N 2 is K BUT, problem is overbromination N 2 owever, we can carry out monobromination on the N-acyl derivative of the amine: NCC 3 NCC 3 2 N 2 (some o-isomer - separate) then we can remove the protecting group ( - / 2 ) to give the required product. 5

6 So formally: N 2 FGI NCC 3 NCC 3 FGI N 2 N 2 FGI 2 C 3 CCl Sn/Cl N 3 / 2 S 4 Is there an alternative route? Try a different FGI! N 2 FGI N 2 YES N 2 o/p directing effect of is K N N 2 N 2 group is m-directing therefore not a good disconnection Example 2 FGI N synthons are K but directing effect of acyl is meta, therefore no good good synthons directing effect of K Synthesis 2 /Fe 3 C 3 CCl NaB 4 AlCl 3 (some o-isomer, separate) racemate! 6

7 Example 3 C 3 CN (C 3 C) 2 FGI N 2 Sn/Cl FGI N 2 + N 2 S 3 N 2 N N S 4, S 3 K, heat 2, boil N Guidelines for designing a synthesis 1 Use retrosynthetic analysis to work backwards from TM to the precursors and eventually to ASM. 2 Locate the functional groups in the TM for most functional groups there are good DISCNNECTINS (the reverse of real chemical reactions). 3 Examine all possible disconnections check which are chemically sound (correspond to known reactions, reagents, directing effects etc.) 4 If you can make no progress try FGI: (N 2 /N 2 ; C 3 /C; C-/C- ; C/C 2 etc.) 5 aving obtained precursors to TM, repeat the process on these intermediates. Clearly you will need a good knowledge of your basic chemistry and an appreciation of reaction mechanisms, directing effects etc. With Aromatic systems the SM s are usually fairly obvious. Usually benzene or a benzene derivative such as toluene, phenol etc. bond to be disconnected is almost always the bond joining the aromatic ring to the rest of the molecule. Also FGI s often correspond to some simple types of reaction e.g. reduction (N 2 to N 2 ), oxidation (C 3 to C), diazonium chemistry (N 2 N 2 + Ar-X). 7

8 In aromatic chemistry CCBF revolve around: 1) Friedel Crafts type reactions Cl Ar Ar C 2) Displacements on aromatic diazonium salts Ar N 2 CN CuCN Ar C N (3) Not forgetting Grignard reagents + carbonyls) With aliphatic acyclic and cyclic systems the process is not always as straightforward need to consider a greater array of CCBF s and FGI s. etrosynthesis In An Aliphatic Molecule A Guide To Alternative Disconnections. etrosynthetic analysis 1 Path A B synthetic equiv.? (can't think of one) K Mg (+ + ) Synthesis Mg Mg 2 8

9 etrosynthetic analysis 2 Path A B synthetic equiv.? (can't think of one) Mg Synthesis Mg Mg 2 9

10 etrosynthetic analysis 3 Path A B synthetic equiv.? (can't think of one) (+ + ) Mg Synthesis Mg Mg 2 10

11 etrosynthetic analysis 4 FGI Path A B C 3 C 2 Et not great, but see later Synthesis C 3 base NaB 4 11

12 etrosynthetic analysis 5 FGI LiCu(C 2 C 2 ) 2 Synthesis LiCu C 2 C 2 C 2 C 2 CuI LiC 2 C 2 NaB 4 Li + C 2 C 2 We shall discuss possible synthesis later, but we will concentrate on CCBF in aliphatic systems. eview and extend CCBF from 1C1Y, in particular: Aldol and Claisen condensations Alkylation of β-keto esters (CC 2 C 2 ) Grignard reactions And illustrate their use in synthesis. 12

13 Classification of CCBF in aliphatic chemistry There are several ways of doing this. We shall consider the following: a) Carbanion Alkylation C X C i) Alkylation of enolate ions + X p ii) Alkylation of acetylide or cyanide C C + ' X ' p N C ' X + CN p 804 iii) rganometallic alkylation Mg X + p 483 Note iv) Direct alkylation of carbanions is possible in some cases 2 CuLi + ' X ' p Where ' = methyl or 1 o alkyl halide (Not a typical substitution mechanism!) b) Carbonyl Addition And Carbonyl Substitution eactions i) Aldol and related reactions (Add n ) 2 p ii) Claisen condensation and related reactions (Sub n ) 2 p

14 iii) rganometallic reactions (Add n ) + Mg p iv) Acetylide/cyanide addition + p N CN p v) Wittig reaction (Add n ) + CP 3 P 3 p P 3 c) Conjugate Addition eactions - Michael (1,4 Addition) + C(C 2 Et) 2 C 2 Et C 2 Et p Mg 2 CuLi better d) eaction f Alkenes, Alkynes And Aromatics p 777 i) Pericyclic reactions: Cycloadditions Diels Alder 14

15 Electrocyclic reactions (MJC) Sigmatropic reactions Cope earrangement ii) Friedel Crafts and related reactions C iii) Addition of carbenes to alkenes 2C: Simmons Smith (carbenoid) In the main we will be looking at ionic reactions. C C C C In CCBF the carbonyl group is very important δ- δ+ as an electrophile as a nucleophile Also in CCBF, organometallic compounds are important. e.g. δ - δ + Mg - Grignard eagents, Lithium alkyls Li etc 2 CuLi - rganocuprates 15

16 Carbonyl Chemistry for Forming C-C Bonds Carbonyl compounds having an α-hydrogen act as weak (protic) acids and react with a base to yield enolate anions. enolate anion base + base- Compare pka acetone = 19.3 ethane = 60 (approx) Ka = [ + ][C 3 CC 2 - ] [C 3 CC 3 ] pka = logka Presence of neighbouring carbonyl group increases the acidity of a ketone over an alkane by a factor of 10 40! The use of such enolate anions from carbonyl compounds is fundamental to organic synthesis and you will already have met them as intermediates in the aldol reaction and claisen condensation. When we have two carbonyl groups adjacent to a methylene group, the acidity of the α- is greatly increased. Because of the acidity of their methylene (C 2 ) hydrogens, malonic esters, ethylacetoacetate and β-dicarbonyl compounds etc are often called active hydrogen compounds. 16

17 Active Methylene Compounds 3 C C C 2 C Et ethylacetoacetate (ethyl 3-oxobutanoate) Et C C 2 C Et diethyl malonate (diethyl propandioate) 3 C C C 2 C C 3 acetyl acetone (2,4-pentandione) C 2 Me 2-methoxycarbonylcyclohexanone 1,3-cyclohexanedione pka 3 C C C 2 3 C C C 2 Et C C 2 C C 3 C Et C Et 9 (2 x ketones) 11 (1 x ketone, 1 x ester) 13 (2 x ester) 3 C C C 3 19 C 3 C Et 25 Compare: C 5 C 3 C C C 25 C 3 C

18 Such compounds are often used in synthesis because: 1) They are readily made and cheap 2) The anion can be generated quantitatively 3) Self condensation does not occur with 1 mole of base is deprotonated 4) The site of deprotonation is unambiguous 5) The enolate ions formed on deprotonation can be alkylated and acylated offering useful products. Example: Et NaEt (pka Et = 16) Et pka 20 pka 11 Et Et eactions of Active Methylene Compounds Et 1) Carbanion Alkylation Most important use is for preparation of ketones (from β-keto esters CC 2 C 2 Et) and of acids from malonic esters (C 2 (C 2 ) 2 ). Et 1) NaEt 2) Et Et heat decarboxylation Et 18

19 Note: is the synthetic equivalent to Et C 2 Et group is used to activate α-carbon atom So etrosynthesis Et synthetic equivs Why not just use? Seems K but problems 1 1) In unsymmetrical case, which α-position reacts? 2) Product may alkylate 3) may prefer to react with starting ketone or product 2 The use of activating group stabilises the required enolate so that conversion is complete with Et Et reaction with SM cannot therefore occur The alkyl halide is added in a separate step-no base remains to form anion of product Note. The activating group is easily removed 19

20 Acids C 2 Et C 2 Et 1) NaEt 2) C 2 Et C 2 Et 1) K 2) + / C +C 2 1) NaEt 2) ' ' C 2 Et C 2 Et 1) K 2) + / ' C +C 2 Note: with 2 equivalents of NaEt and a dihalide (e.g. (C 2 ) 4 ) - can get cycloalkane carboxylic acids. e.g. C So etrosynthesis: C 2 C 2 + C 2 C 2 C 2 Et C 2 Et - Practice with C C 2 Note: FGI s can be carried out on intermediates/products. Note especially: C 2 5 (LiAl 4 ) 2 1 C 2 Et C 2 Et FGI 2 1 C 2 C 2 1,3 diol elps in the synthesis of 1,3 diols. 20

21 Enolate Anions as Ambident Nucleophiles e.g. reacts as alkoxide 3 C C C 2 3 C C 2 reacts as carbanion Site of alkylation depends, in part, on substrate Alkyl halides C-alkylation (C 3 ) 3 SiCl -alkylation Si 3 C C (C 3 ) 3 SiCl 3 C C 3 CC 2 C 2 C 2 silyl enol ether (strong Si- bond formed 2. eaction of Active Methylene Compounds with Carbonyl Compounds (Knoevenagel Condensation) C 2 Et C 2 Et C 2 Et C 2 Et C C(C 2 Et) 2 (i) (ii) (iii) heat - 2 C 2 Et C 2 Et C CC 2 Usually uses weak base/weak acid as catalyst, ( 2 N/Ac). Any combination of stabilising groups can be used (CN, C 2 Et etc). 21

22 3. Michael eaction with Active Methylene Compounds (Conjugate Addition eaction) Carbanions derived from active methylene compounds react with α,β-unsaturated compounds by 1,4-(conjugate) addition known as Michael addition. 3 C C 2 Et C 2 Et 3 C C 2 Et C 2 Et 3 C C 2 (i) (ii) (iii) heat 3 C C 2 Et C 2 Et In retrosynthesis terms 3 C C 2 3 C 3 C C 2 Et C 2 Et Question ow would you prepare C 2? C 2 C 2 Et C 2 Et 22

23 4. Dianions in Synthesis We have discussed the regioselective reactions of this active methylene carbon (C- 2) in ethylacetoacetate. Can regiospecifically trap C-4 via the dianion. Et Et pka 20 pka 11 pka 30 least acidic forms most reactive anion Need two equivalents of base and second one needs to be strong (pka>20) Me 1)Na, 2) BuLi or 2 x LiN i Pr 2 (LDA) lithium diisoprpylamide Me LiN 1) X (1 equiv) 2) Me 23

24 Carbonyl Addition and Carbonyl Substitution Aldol and Claisen eactions. Usually self-condensations, these reactions combine nucleophilic attack and α- substitution as the first step. The Aldol Condensation of Aldehydes and Ketones 3 C C 2 C C 3 C C 3 C C C 2 C 2 C C 2 General for aldehydes and ketones with α- NB eversible Product favoured with C 2 C SM favoured with 2 CC 3 C 3-hydroxybutanal aldol C C 2 C - 2 more vigorous conditions (heat) eason for dehydration 1) Acidity of α- 2) Stability of conjugated product 3 C C C C C 3 C CC 2-butenal Note the Aldol condensation can also be performed with acid catalysis in which dehydration usually follows (enol form is involved mechanism p 773). NB dehydration drives the reaction when the equilibrium is unfavourable. 3 C C C 3 98% 3 C C C 2 C 3 2% C C 3 C good yield C 3 In retrosynthesis terms FGI ecognise aldol or aldol product 24

25 Unsymmetrical ketone? egioselectivity is a problem! strong base kinetic enolate proton removed from least hindered site - 2 thermodynamically preferred enol ence different products from acid and basic conditions Claisen Condensation of Esters 3 C Et 2 C Et not complete deprotonation Et pka = 16 C 3 C 2 Et pka = 25 2 C Et 3 C Et 3 C C 2 Et C 2 Et 2 C Et 2 C C 2 C 2 Et Et 3 C C C 2 Et pka 11, drives reaction Note: the only difference between the Aldol and Claisen reaction is the fate of the tetrahedral intermediate Claisen expels alkoxide, Aldol alkoxide is protonated. 25

26 Mixed Aldol and Mixed Claisen Condensations These are not very useful generally as there are four potential products. owever, they can be useful if one component has no α-. Mixed Aldol C Et Claisen Schmidt condensation Mixed Claisen Condensations nly successful when one of the ester components has no α- e.g. C 2 Et CEt. 1) Et Et Et 2) Et Can also carry out mixed Claisen between ester and ketone 1) Et Et 2) favoured because removal of proton from here drives equilibrium Synthesis of dimedone C 2 Et 2 x aldol C 2 Et Michael C 2 Et C 2 Et (i) (ii) C 2 Et (iii) heat 26

27 C-C Bond Formation to Make ings Intramolecular Aldol eactions and Claisen Condensations When certain dicarbonyl compounds are treated with base intramolecular Aldol reactions can occur. Similarly diesters can undergo intramolecular Claisen Condensations (this reactions is known as the Dieckmann cyclisation). Aldol Na - 2 Et 5 and 6 membered rings preferred The intramolecular Aldol condensation forms the basis of a very useful method for making rings The obinson Annulation eaction: Et Michael Et intramolecular C 2 Et aldol 27

28 Intramolecular Claisen Condensations The Dieckmann Cyclisation eaction works best with 1,6 or 1,7 diesters to give 5 or 6 membered rings. 1 Me 6 Me NaMe Me Me Me Me 1 Me C 2 Me cyclic β-ketoesters 7 can be functionalised and decarboxylated egioselective Formation of Enolate Ions (p786) W eak base LiN i Pr 2 Li Protic solvent DME (MeC 2 C 2 ME aprotic) Thermodynamically favoured (More stable due to more substituted double bond) Kinetically Favoured Sterically hindered base rapidly removes proton from less substituted α position (where there are more of them also) Alkylation is regiospecific: Li C 3 I but ClSiMe 3 SiMe 3 This kinetic enolate, trapped as the TMS ether can be regenerated with F (Si-F very strong) SiMe 3 F C ther Useful CCBF s 28

29 The Wittig eaction (p 734) ' + '' X P 3 ''' Base ' ''' '' + P 3 Very useful method for alkene synthesis as the position of the double bond is known. The first step is formation of a osphorus Ylide (a neutral compound with C - and P + ). 3 P: C 2 C 2 Et 3 P CC 2 Et. Base 3 P CC 2 Et Does not contribute much 3 P CC 2 Et C 3 C CC 2 Et P 3 C 2 Et Acetylene anion as a synthon for C 3 C= C' + ' gs ' Dithiane Anions Acyl anion equivalents which exhibit Umpolung (reversed polarity p 907). Two S atoms attached to the same carbon atom of a 1,3-dithiane cause the atoms to be more acidic (pka 32) than normal alkyl C-. 29

30 1,3-dithianes are easily prepared from aldehydes, they are thioacetals. C + S S + BuLi S S S S 1) 'C 'X ' 2) g 2+ / 2 0 1,2 -di g 2+ / 2 0 S S ' ' adical Dimerisation eactions Leading To 1,2-di Pattern 1. Pinacol Formation etrosynthesis C C C C Synthesis Mg/ether electron transfer C Mg C C Mg C 2 e- C C 30

31 2. Acyloin Condensation Similar to ester dimerisation, used traditionally to make large rings. (C 2 ) n C 2 Et 2 x Na (C 2 ) n Et (C 2 ) n Et C 2 Et Et Et 2 x Na (C 2 ) n (C 2 ) n (C 2 ) n 2 (C 2 ) n 2-hydroxy ketone (acyloin) Now improved by addition of Me 3 SiCl which traps the intermediate dianion. C 2 Et Na Me 3 SiCl SiMe 3 SiMe

32 So to finish -cis jasmone (Can J. Chem. 1978, Vol 56, p2301) C 2 Me K/TF C 2 C Et Pd/BaS 4 (Lindlar cat) C 2 Me 2 z-alkene C 2 Me 1) Na 2) BuLi C 2 Me (SiMe 3 ) gs 4, 2 C 2 Me 1) C 2 C SiMe 3 2) 2 C 2 Me then heat SiMe 3 intamolecular aldol