Effects Thorpe-Ingold

Shorter chain dienes have an increased propensity to form stable five-, six-, and seven-membered rings. This thermodynamically controlled phenomenon is known as the Thorpe-Ingold effect.15 Since ADMET polymerization is performed over extended time periods under equilibrium conditions, it is ultimately thermodynamics rather than kinetics that determine the choice between a selected diene monomer undergoing either polycondensation or cyclization. 

This general picture is similar to that observed in the ring-closing propensity of open chain alkanes, where a gem-dimethyl group greatly improves the yield of cycles as opposed to polymers (see 87, 88). This is known as the Thorpe-Ingold effect and has been examined in depth 1451. The steric bulk of the substituents diminishes the conformational space available for the open pre-... 

The preparation of cyclobutanes via the catalytic conditions can be extremely efficient provided that the radical formed after epoxide opening is sterically shielded and cyclization promoted by the Thorpe-Ingold effect. It... 

In a similar way as described for the hydroformylation, the rhodium-catalyzed silaformylation can also be used in a domino process. The elementary step is the formation of an alkenyl-rhodium species by insertion of an alkyne into a Rh-Si bond (silylrhodation), which provides the trigger for a carbocyclization, followed by an insertion of CO. Thus, when Matsuda and coworkers [216] treated a solution of the 1,6-enyne 6/2-87 in benzene with the dimethylphenylsilane under CO pressure (36 kg cm"2) in the presence of catalytic amounts of Rh4(CO)12, the cyclopentane derivative 6/2-88 was obtained in 85 % yield. The procedure is not restricted to the formation of carbocycles rather, heterocycles can also be synthesized using 1,6-enynes as 6/2-89 and 6/2-90 with a heteroatom in the tether (Scheme 6/2.19). Interestingly, 6/2-91 did not lead to the domino product neither could 1,7-enynes be used as substrates, while the Thorpe-Ingold effect (geminal substitution) seems important in achieving good yields. 

For a review encompassing synthetic applications of the Thorpe-Ingold effect, see Jung, M. E. Piizi, G. Chem. Rev. 2005, 105, 1735-1766. 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

Five-membered carbocycles are the most easily formed [45, 107, 196, 200, 202,203]. Five-membered carbocyclic rings can be formed (with 2% MoF6 as the catalyst) even when the double bond is tetrasubstituted (Eq. 24) [200]. The stability of the catalyst toward the free OH group in this case is noteworthy. Evidently this particular t-butoxide-like alcohol does not react with this particular catalyst for steric reasons. Six-membered carbocyclic rings are also formed readily (Eq. 25) [200], as are seven-membered rings, especially if one takes advantage of a Thorpe-Ingold effect (e.g., Eq. 26) [20] or a similar conformational predisposition for the double bonds to remain near one another. 

For a discussion of the Thorpe-Ingold effect, see Eliel E, Wilen SH, (1994) Stereochemistry of organic compounds, 1st edn. Wiley Interscience, New York, p 682... 

The Thorpe-Ingold effect 208 Effects on the formation of larger rings 216 The relief of ground-state strain 217 Orbital steering 222... 

Mass-spectrometric investigation (83KGS1273) showed that the more substituted A-(3-oxoalkyl)thioureas 69 (R = R = R = Me R = H R = alkyl, Ar) exhibit a ring-chain equilibrium in the gas phase, but the less substituted derivatives 69 (R = R = H R = R = Me R = Me, Et, Bu) exist only as open-chain isomers. Clear evidence of the stabilizing effect of gem-dimethyl substitution on the cyclic form (Thorpe-Ingold effect) was presented for a gas-phase equilibrium. The mass-spectrometric data are rather similar to those obtained for this system in solution, which indicates that this equilibrium depends mainly on structural, rather than solvation, factors. 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Studies of hydrogen bonding and iodine complexation on alkyl-substituted oxetanes have shown that 2-alkyl and 2,2-dialkyl substitution enhances the electron donor ability, while 3,3-dialkyl substitution substantially diminishes it. This has been attributed to a decrease in the bond angle strain at the oxygen atom, due to a Thorpe-Ingold effect at C-3, since the effect increases with the size of the alkyl substituent at that position (71BSF4576). 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

Recently, Chirik s group reported an iron-catalyzed [2 + 2]-cycloaddition process with a,co-dienes (Scheme 9.23) [50]. The tridentate pyridine-diimine complex 31 gave excellent conversions with a short reaction time (TOF>240h-1) and a broad substrate scope is accepted by the catalyst. Esters, amides, amines and even 1,6-heptadiene can be used as substrates without requiring the Thorpe-Ingold effect. 

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