ATTACHMENT OF A LINKER TO ACLACINOMYCIN A
BASIC (B) ACIDIC (A)
K * _ EH^ = R—/;© 'ok BIMOLLCULAR (2) T ACYL C^XYGEN- FISSION (AC) O R l U r ^ COMMON
X .
R-/:e ai I X r ' o k \ OK O H ; Aac-2 COMMON R. OH U N IM O I.K aJI.A R ( 1 ) ,0 R_/ BacI NOT OBSERVED! OH / / SLOW ® R—C, ® -. R—C^O O R ROHA a c I ARYL CARBOXYLATES IN STRONG ACID
BIMOLECULAR ( : ) ALRYI, O X Y G E N , n s s i o N lA L) p o / / s u m - / / R— c --- ► R— X + R'OH
Bal^ (SN 2) METHYL ESTERS O F STRONG ACIDS
/ ? ' suwv O H , Aa l: n o t O B SE R V E D ' R - c f UNIMOLECULAR ( 11 O / p // s u i w / // R ® ° u O \ , HjO ^ OH R'OH
B a i. I (S N 1 ) TERTIARY ESTERS OF STRONG ACIDS
'^K
V R®
A ai, I TERTIARY ESTERS IN IONISING MEDIA
fig 45 The m echanism s for acidic and basic hydrolysis o f esters
2.2 Equilibrium displacem ent chem istry
For all (trans)esterifications and ester hydrolyses the reactions are reversible,
and there exists an equilibrium position expressed in term s o f the equilibrium
constant, K (fig 46). For a reaction to be practically viable it is essential that the equilibrium position lies in favour o f the products, i.e. K is m axim ised
RCOOR' + R'OH ^ '• RCOOR" + R’OH K=[RCOOR"][ROH]/[RCOOR'][R"OH]
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From the definition of K it can be seen that, to increase the value of K, the most reactive R"OH must be used. This can be estimated from equilibrium studies which have shown that:" "
1. Thermodynamically, methanol has the strongest replacing power. 2. The replacing power of R” OH decreases as its chain length increases. 3. Chain branching reduces the reactivity o f R ” OH.
An alternative method to promote the forward reaction, in accordance with Le Chatelier’s Principle, is to remove either the ester or R'OH as they are being formed. Methods which have been employed to facilitate this have included the use of molecular sieves, although this may reduce the level of base if alkoxide is used or it may affect counter ion exchange with the base and reduce its effectiveness." "
Also the alcohol can be removed by azeotropic distillation, either with the product, or with an entraining material such as a hydrocarbon, cyclohexane, benzene or a xylene. Finally the reactions may be carried out in a perflurocarbon medium. These are extremely dense solvents and are imiscible with the organic alcohol produced."
2.3 Electrophilic and nucleophilic chemistry^
In covering all the mechanisms available it is advisable to mention a special case for unhindered esters- generally methyl and ethyl esters. With the increase in organoelement chemistry over recent decades, more reagents are available which display high nucleophilicity and yet low basicity. Upon reaction with an unhindered carboxylic ester, a mechanism is encountered, similar to B al2, which involves
nucleophilic attack upon the alkyl group itself in an Sn2 type reaction (fig 47).^
fig 47 Nucleophilic attack on a methyl ester by a soft nucleophile
For such a mechanism to occur, it is essential that there is low steric hindrance about the alkyl group and, as a result, the pathway is only seen when
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highly nucleophilic, low basicity, reagents are reacted with methyl and ethyl esters. This is of great synthetic use as it means that the reaction is highly selective and is of much use when the substrate is sensitive to more traditional hydrolytic conditions. Reagents commonly used for this type of decarbalkoxylation include the anion of trimethyl silane, the phenyl selenide anion and the phenyl sulphide anion.
Methods such as this also enable the mechanisms to discussed in terms of Hard/Soft - Acid/Base T h e o r y . T h e ester functionality has two sites which can be potentially be attacked by a nucleophile. It is, therefore, possible to choose a nucleophile, on the ground o f its hardness which can differentiate between the two sites.
When looking at a carboxylic acid the carbinol centre is deemed to be a soft electrophilic site (and, hence, attacked by soft nucleophiles) and the carbonyl centre is somewhat harder (and, hence, more readily attacked by hard nucleophiles) as shown in fig 48. H A R D N U C LE O PH IL IC C E N T R E S SO FT E LEC TR O PH ILIC C E N T R E H A R D ELEC TR O PH ILIC C EN T R E
fig 48 Hard and soft sites for a typical carboxylic ester
Many reagents exist which combine both hard acid centres and soft nucleophile centres. These are systems which when considered individually would not be able to hydrolyse an ester, but when coupled provide very reactive systems. A typical system o f this type is TMS-iodide which cleaves esters in essentially neutral conditions either neat or in CDCI3 or CCI4. The silicon forms a strong bond with the oxygen of the carbonyl group and the soft I nucleophile is delivered to the soft
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electrophilic site in such a manner that isolated C=C, ketones and thioethers are not affected, but ethers are cleaved (fig 49).’*’