Functional Group Interconversions Lecture 4 2.1 rganic Synthesis A. Armstrong 20032004 3.4 eduction of aromatic systems We can reduce aromatic systems to cyclohexanes under very forcing hydrogenolytic conditions, though this isn't a generally useful process. More interesting is the partial reduction of arenes to skipped 1,4cyclohexadienes by dissolving metal reduction the Birch reduction. When the starting benzene ring is substituted, the Birch reduction displays useful regioselectivity. Thus, electron withdrawing groups end up deconjugated from the alkenes (since they stabilise the anionic intermediates) while electron donating groups end up on the alkenes they avoid being adjacent to negative charge. Birch reduction Partial reduction of an aromatic ring to a nonconjugated, 1,4diene Li or Na liquid N 3 (often t Bu) EWG = C 2, CN, etc. EWG EWG EWG (relatively fast reaction) EDG = alkyl, Me, N 2, etc. EDG EDG EDG (relatively slow reaction) It is sometimes possible to trap the intermediate anions with electrophiles. For example, if the amount of added alcohol is limited to 1 equivalent, then the enolate formed by reduction of benzoate esters can be trapped with alkyl halides: C 2 Et 1. e 2. t Bu 3. e C 2 Et add E (e.g. haloalkane) Et 2 C E 1
e.g. 2.1 rganic Synthesis A. Armstrong 20032004 Me C 2 Na, liq. N 3 Me C 2 C 3 7 Br Me C 2 3 via enol ether hydrolysis; decarboxylation of βketoacid; migration of alkene into conjugation with carbonyl 3.5 eduction of α,βunsaturated carbonyl compounds There are three possible outcomes to this: total reduction to the saturated alcohol; partial reduction to the unsaturated ketone; and partial reduction to the allylic alcohol: 1 A 2 1 B 1 2 C 2 1 2 utcome A total reduction can be accomplished by using LiAl 4 at elevated temperatures: 1 2 LiAl 4 1 Al 2 heat intramolecular attack on alkene 1 Al 2 1 2 3 (work up) 2
2.1 rganic Synthesis A. Armstrong 20032004 utcome B reduction of the alkene can often be done by using 2 and a catalyst (e.g. Pd/C). Alternatively, we can use Na in liquid N 3, which allows the useful possibility of trapping the intermediate enolate with electrophiles. This process allows regiospecific enolate formation from the enone. Na 3 Na liq. N 3 E For outcome C reduction of the carbonyl group only one of the most reliable methods involves the use of NaB 4 along with CeCl 3 in Me (known as the Luche reduction). (Mechanistically, the CeCl 3 is believed to accelerate the reaction between NaB 4 and Me to give alkoxyborohydrides (see Lecture 1), as well as increasing the ability of the Me to undergo hydrogen bonding to the carbonyl group in the enone). NaB 4 Me with no CeCl 3 : 59:41 with CeCl 3 : 99:1 3
2.1 rganic Synthesis A. Armstrong 20032004 Section 4: eductive cleavage of CX bonds 4.1 ydride displacements LiAl 4, NaCNB 3 and LiEt 3 B (sold as Super hydride!) can all displace halides, tosylates and mesylates from primary and secondary alkyl positions. Since the reactions are S N 2 in nature, this is a useful way of making stereospecifically deuterated compounds through the corresponding deutero reducing agents. This is of much use in biosynthetic studies. e.g. Br LiEt 3 BD (D = deuterium = 2 ) D Epoxides are a special class of CX species: there are two possible sites of attack and we can tailor our reaction conditions to gain access to either. Thus, nucleophilic conditions give rise to attack at the less hindered carbon, while the use of a Lewis acid promotes attack at the best cationstabilising centre (usually more substituted) on account of the polarised transition state. (Again, inversion of stereochemistry is seen at the centre being attacked by ). LiAl 4 NaB 3 CN BF 3 Et 2 (Lewis acid) 4.2 adical reactions Don't need to worry about these at the moment (await 3rd year!) but they are very useful, and not just for CX reductions. Much of the work was pioneered by the Nobel Laureate Sir Derek Barton, who spent most of his career at Imperial College. 4.3 ydrogenolysis Cleavage of benzylic ethers and amines by hydrogenolysis gives rise to useful protecting groups for synthesis (see later in the course!) Bn = Ph or 2, Pd/C NBn = N Ph Next time (Monday 15 th Dec at 9am): xidation of C bonds, alcohols AA 11.12.03 4
EFEENCE SECTIN! 2.1 rganic Synthesis A. Armstrong 20032004 Functional Group eactivity with Various educing Agents eaction eagent NaB 4 /Et LiAl 4 LiAl( t Bu) 3 B 3 TF (ibu) 2 Al (DIBAL) Catalytic hydrogenation C C 2 C' C()' CCl C * CCl C 2 Lactone Diol Epoxide Alcohol C' C 2 ' C C 2 CN'" C 2 N'" CN'" C C N C 2 N 2 N 2 N 2 C=C C 2 C 2 = gives reaction shown = does not give reaction shown = gives other reaction = borderline case * = if one equivalent used 5
2.1 rganic Synthesis A. Armstrong 20032004 Ease of reduction of various functional groups by lithium aluminium hydride* Substrate Product Ease of reaction C C' CCl lactone epoxide C' C C CN' C N C 2 C' C diol alcohol C 2 C 2 C 2 C 2 N' C 2 N 2 Easiest N 2 N 2 C C ' Most difficult Inert * lithium aluminium hydride is VEY reactive, so discrimination between functional groups in the same reaction may be difficult see notes for use of modified hydride reagents Ease of reduction of various functional groups by borane Substrate Product Ease of reaction C C C ' C 2 C 2 C 2 ' Easiest C' C' C N C 2 N 2 epoxide alcohol C' C 2 Most difficult CCl Inert 6
2.1 rganic Synthesis A. Armstrong 20032004 Ease of reduction of various functional groups by catalytic hydrogenation Substrate Product Ease of reaction CCl C Easiest N 2 N 2 C ' C C ' ' C 2 C 2 C 2 C' ArC 2 C N C' CN' C' ArC 3 C 2 N 2 C 2 C 2 N' Most difficult C Inert 7