Amines strain effects

An interesting and useful property of enamines of 2-alkylcyclohexanones is the fact that there is a substantial preference for the less substituted isomer to be formed. This tendency is especially pronounced for enamines derived from cyclic secondaiy amines such as pyrrolidine. This preference can be traced to a strain effect called A or allylic strain (see Section 3.3). In order to accommodate conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This creates a steric repulsion when the enamine bears a p substituent and leads to a... 

While all strain effects in monoamines are basicity weakening, it is possible to find cases in di- and polyamines where strain is relieved upon protonation, leading to increased basicity. This phenomenon is observed in 1,4-diaminobutane derivatives where an almost linear N... H—(N+) hydrogen bond in the mono-protonated derivatives leads to a stable, seven-membered ring structure. Thus, for example, the measured PA of l,6-diazabicyclo[4.4.4]tetradecane (73) is 228.3 kcalmol-1, about 11 kcalmol-1 higher than its monoamine analog 75, despite the similar, inwardly pyramidalized, nitrogen conformation of both neutral amines. 

However, in more complicated amines, this straight correlation is violated. The bicyclic tertiary amine l-azabicyclo[4.4.4]tetradecane (22) and the acyclic tertiary amine n-Bu3N have nearly the same first IP (7.84 and 7.90 eV, respectively), but the proton affinity of the bicyclic amine is 20 kcal mol 1 lower than that of the acyclic52. On the other hand, for other bridge-head tertiary amines like l-azabicyclo[2.2.2]octane (quinuclidine, 20) and l-azabicyclo[3.3.3]undecane (manxine, 21) the expected relation between proton affinities and IP values is observed. The extraordinary properties of l-azabicyclo[4.4.4]tetradecane (22) are caused by its unusual conformation the nitrogen lone-pair is directed inward into the bicycle where protonation is not possible. In the protonated form, the strained out-conformation is adopted. This makes it the least basic known tertiary amine with purely saturated alkyl substituents. Its pKa, measured in ethanol/water, is only +0.693. Strain effects on amine basicities have been reviewed by Alder88. 

Alder, R.W. (1989) Strain effects on amine basicities. Chemical Reviews, 89, 1215-1223. 

Staab, H.A. and Saupe, T. (1988) Proton sponges and the geometry of hydrogen bonds aromatic nitrogen bases with exceptional basicities. Angewandte Chemie - International Edition, 27,865-879 Alder, R.W. (1989) Strain effects on amine basicities. Chemical Reviews, 89,1215-1223. 

Brown s investigation of the addition compounds of trimethyl borane, diborane, and boron trifluoride with amines has provided a quantitative estimation for steric strain effects in chemical reactions. He also investigated the role of steric effects in solvolytic, displacement, and in elimination reactions. His results demonstrate that steric effects can assist, as well as hinder, the rate of a chemical reaction. 

The protonation of amines causes a shielding of carbons adjacent to the nitrogen except for branched systems, where some deshielding is often seen. The effect of protonation can be about -2 ppm at an a-carbon, -3 ppm at a P-carbon and up to -1 ppm at a y-carbon. For example, the shifts of ethylamine are 36.9 ppm (CH2) and 19.0 (CH3) and these are shifted by -0.2 and -5.0 ppm, respectively, on protonation. Again, ring strain effects in cyclic amines are mirrored by large shift effects. 

On the theoretical side, study of the dissociation of addition compounds of amines with trimethylborane, boron trifluoride, and borane provide a new quantitative approach to steric strains. These studies quickly removed doubts as to the importance of steric effects in chemical behavior. 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

A considerable amount of the strain in l,8-bis(dimethylamino)naphtha-lene is relieved by protonation and the N—H N bond length (260 pm) in the protonated amine shows that the molecule is able to adopt a conformation [55] with an intramolecular hydrogen bond (Truter and Vickery, 1972). The infra-red spectrum of protonated l,8-bis(dimethylamino)naphthalene and the chemical shift (5 19.5) of the acidic proton in the nmr spectrum confirm the presence of an intramolecular hydrogen bond (Alder et al., 1968). The magnitude of the isotope effect on the chemical shift (Altman et al., 1978) and the appearance of two Nls peaks in the photoelectron spectrum... 

We now mm to derivatives of biphenyl. Our archives show a 12.8 6.3 kJmol-1 difference in the enthalpies of formation of the 2- and 4-amine as solids35. Is this difference due to strain in the former species One probe of the strain energy is to consider the enthalpies of reaction 12 for R = 2- and d-PhCgFU. 2 f°r the 2-isomer equals 1.5 2.6 kJ mol-1. We do not know what it is for the 4-isomer because we lack all phase-change enthalpy data for this species. Intuitively, this difference quantity should be 0 because no stabilizing or destabilizing effects are expected for this isomer. We thus conclude that 2-aminobiphenyl is essentially strain-free. 

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