Steric effects

Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape (conformation) and reactivity of ions and molecules. Steric effects complement electronic effects, which dictate the shape and reactivity of molecules. Steric repulsive forces between overlapping electron clouds result in structured groupings of molecules stabilized by the way that opposites attract and like charges repel. Steric hindrance Steric hindrance is a consequence of steric effects. Steric hindrance is the slowing of chemical reactions due to steric bulk. It is usually manifested in intermolecular reactions, whereas discussion of steric effects often focus on intramolecular interactions. Steric hindrance is often exploited to control selectivity, such as slowing unwanted side-reactions. Steric hindrance between adjacent groups can also affect tor

New Synthetic Applications of Water Acetate Pd/TPPTS Catalyst Generated in situ. Evidence for true Pd(0) Valent Species Intermediate

Christian Amatore

Studies on the sp-sp intermolecular coupling reactions with the palladium water-soluble catalyst prepared in situ from palladium(II) acetate and sulfonated triphenylphosphine P(C6H4-m-SO3Na)(3) (TPPTS) in a homogeneous acetonitrile-water system, without Cu(I) promotor, afford diynes with moderate yields (45-65%). Under the same conditions, the sp(2)-sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indolic and furanic products in good yields (60-99%). Under these aqueous conditions, an efficient and short synthesis of eutypine illustrated the synthetic potentiality of the coupling. Furthermore, through a series of kinetic and P-31 NMR experiments, we have demonstrated that a mixture of Pd(OAc)(2) and TPPTS affords spontaneously a palladium(0) complex, through formation of bivalent complex Pd(OAc)(2)-(TPPTS)(2). A detailed mechanism of the reaction has been investigated thoroughly and the pertinent rate constants measured. The resulting palladium(0) complex reacts with phenyl iodide via an oxidative addition. This complex is considerably less reactive than the corresponding complex generated from PPh(3), probably due to steric effects.

1995

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

Assunta Ginanneschi

The use of organometallic reagents for functionalization of arenes and heterocycles has recently been renewed by our group. The use of bulky trialkylsilyl groups allows one to shield an acidic position by steric hindrance and the introduction of a chlorine atom permits the activation of the nearby site. The organometallic methods were applied to fluorinated indoles, taking into account the growing attention toward halogen as a key factor for improving drug activity. Only few commercial fluoroindoles are inexpensive. Therefore it was necessary to find a method allowing an efficient preparation of the staring material. Many methods have been developed to synthesize halogenated indoles. The more common ways implies electrophilic cyclization. Once obtained the starting material, all four fluoroindoles were subjected to exhaustive functionalization by organometallic reagents, using either bromine/metal permutation or direct metalation in conjunction with chlorine or triisopropylsilyl residues as protecting groups. Once protected position 2 by steric shielding, the metalation occurs at the position next to the fluorine. In the case of 4 and 7-fluoroindoles there is no ambiguity, but for the 4 and 6 isomers we were obliged to play with bases in order to achieve a good regioselectivity. The use of chlorine was necessary to reach the meta position to the fluorine. Only a few derivatives of fluoroindoles are known in literature. However one could expect such compounds to be versatile building blocks for the synthesis of biologically active compound, due to the presence of fluorine or trifluoromethyl group, helping to fine-tune the lipophilicity of a molecule or to protect against metabolic oxidation. This thesis work aimed to fill the gaps in this field by elaborating methods to efficiently and easily prepare functionalized derivatives of fluoroindoles and in particular all twelve possible regioisomeric fluoroindole carboxylic acids.

EPFL2005

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

Assunta Ginanneschi

EPFL2005

New Synthetic Applications of Water Acetate Pd/TPPTS Catalyst Generated in situ. Evidence for true Pd(0) Valent Species Intermediate

Reactivity measurements and their interpretation in systems with large spatial effects

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

Reactivity measurements and their interpretation in systems with large spatial effects

New Synthetic Applications of Water Acetate Pd/TPPTS Catalyst Generated in situ. Evidence for true Pd(0) Valent Species Intermediate