Atropisomers isolation

Isobe observed that above 100°C a single atropisomer, isolated by HPLC, will scramble to yield all six isomers. Models such as [4]CC with extended Jt-systems bring us closer to the synthesis of an ultrashort CNT. One can envision, with an appropriate extension strategy, employing Isobe s synthesis to produce selectively armchair (10,10) and chiral (11,9) and (12,8) nanombes from a single precursor [44]. 

VT NMR showed that N3-[3]polynorbomane 164 existed as an equilibrium mixture of the syn-atropisomer 164a and anti-atropisomer 164b (ratio 1 1.7). NMR spectroscopy allowed distinction between the isomers on the basis of symmetry. The syn-isomer 164a exhibited two well-separated ester methyl resonances (8 3.67, 4.05) as predicted for the isomer with Cs-symmetry, whereas the anft -isomer 164b displayed a single ester methyl resonance (8 3.85) in accord with that expected for a compound with C2-symmetry. It was not possible to isolate the separate atropisomers in this system since the energy barriers governing rotation were too low. 

The introduction of microwave and far-infrared spectroscopy changed the situation somewhat. These techniques give the barriers to rotation if they are on the order of a few kilocalories per mole (10). Such values are still too low for the chemical isolation of atropisomers. 

As has been mentioned, the term atropisomerism has a broad meaning. If we discuss atropisomerism from the standpoint of vibrational spectroscopy, then almost all organic compounds would give rise to atropisomers. If we are discussing atropisomerism from the standpoint of NMR spectroscopy, then it is necessary to specify the temperature at which we measure the spectrum. The strength of the main magnetic Held (or observation frequency) is also a concern. Eliel discussed the term residual isomerism in this connection (12). Since we cannot cover all types of atropisomerism here, the present discussion will be confined to atropisomerism wherein isomers are isolated chemically. 

Even though we define the atropisomerism as above for present purposes, there remain some ambiguities. sym-Tetrabromoethane was obtained in different modifications according to the method of crystallization at low temperature (13). These were found by spectroscopy to correspond to retainers. Similar situations occur in other alkyl halides and acetates (14,15). Such cases will not be included in the discussion, mainly because crystalline atropisomers are isolated at far lower temperatures than die ambient, and their barriers to rotation have not been determined by equilibration. Also excluded is the isolation of chlorocyclohexane (16). The isolation of the equatorial and axial conformational isomers was possible only by crystallization of the former at - 150°C, although it was possible to observe equilibration between the equatorial and the axial forms at higher temperatures. 

The main purpose of this chapter is to review cases where stable retainers are isolated at room temperature or above. This means that free energies of activation of more than ca. 23 kcal/mol separate the atropisomers focused on in... 

Barriers to rotation about the C—N bond of /V,/V-dimethylformamide are known to be affected by concentration and the nature of the solvent. As expected, polar solvents tend to increase the barrier by stabilizing the polar structure (2). Therefore, it is not surprising that, whereas the barrier to rotation of N,N-dimethylformamide is about 21 kcal/mol in solution, the barrier becomes as low as 15.6 kcal/mol in the gas phase (32). In the practical question of isolating atropisomers, it is the magnitude of the barrier in solution that matters. 

As has been discussed, ordinary formamides have a barrier of about 21 kcal/ mol, which is a little less than that required for the isolation of atropisomers at room temperature. This means that, at a temperature slightly lower than ambient, it may be possible to obtain stable rotamers. This possibility was first realized by Gutowsky, Jonas, and Siddall (40). They used a uranyl nitrate complex of N-benzyl-N-methylformamide (4) crystallized from dichloromethane. When the crystals were washed with ice water to strip off the uranyl nitrate, a mixture of E and Z forms (Z/E = 1.6) was obtained. Since the equilibrium mixture gives a Z/E value of 0.8, it was possible to perform a kinetic study of equilibration... 

Siddall (48) also reported that the barriers to rotation in N-substituted N-(2-chloro-6-methylphenyl)formamides (11) were high, but not high enough for the isolation of atropisomers. The exact barriers were not reported but, if one compares them with those in compound 9, the barriers to rotation of these compounds are lowered by the substitution of the chloro group for the methyl on the aromatic ring. 

The barrier to rotation was 21.5 kcal/mol at 160°C. They extended this work in 1969 and were able to isolate the atropisomers of 4-(/V-benzyl-/V-methylaminomethy lene)-1,2-diphenyl- l,2-diazolidine-3,5-dione (32). The E isomer was isolated pure, and the Z isomer 93% pure (72). An equilibrium mixture in chloroform-d solution at 28.5°C contained 40% Z and 60% E. To distinguish the barriers to rotation about the C=C and the C—N bonds, the barriers were... 

Barriers to rotation of nitrosamines in which the amino part is embedded in a cyclic system seem generally to be smaller. However, Harris and associates (82) reported that the barrier of /V-nitroso-2,2,5,5-tetramethylpyrrolidine (43) was over 22.6 kcal/mol. This must be higher than the barrier required for isolation of rotamers at room temperature, and is even higher than that in /V-nitroso-2,2,6,6-tetramethylpiperidine (44). Harris and Pryce-Jones attribute the high barrier of 43 relative to 44 to the more stable ground state of the former. If the pyrrolidine derivative is properly substituted, the atropisomers are expected to be isolable at room temperature. 

Evidently, very special circumstances will be required to make the E conformation of esters so stable that atropisomers can be isolated at ambient temperatures. 

Nakamura and Oki (96) isolated the rotamers of 9-(2-bromomethyl-6-meth-ylphenyl)fluorene (56), and found that the Arrhenius activation energy for rotation was 27.1 kcal/mol for the sp — ap process, log A being 10.8. For the reverse process, the values were 27.1 kcal/mol and 11.4, respectively. This is direct proof that the energy barrier obtained by the dynamic NMR technique is useful for diagnosing the possibility of isolating atropisomers, since the barrier... 

Such barriers are high enough for the isolation of atropisomers if the benzene ring is properly substituted. Miller and Curtin (112) brominated 71 and were able to isolate 86% pure ap isomer of the dibromo compound (73). The barrier... 

There are two other systems known that show barriers to rotation of more than 23 kcal/mol, although no isolation of atropisomers has been reported in these systems. It is a surprise to note that the barrier to rotation in 9-mesitylxanthene (81) is low (12S), after knowing that the barriers to rotation in 9-mesitylfluorenes are very high. This phenomenon is a result of the structure of these compounds. Compound 81 is unstable in the equatorial conformation because the central 6-membered ring assumes the boat form (126). The mesityl group then takes the axial position (82), where steric hindrance to rotation is not high. 

Treatment of either the sc or the ap atropisomer of the diester (97) with potassium hydroxide effected the hydrolysis of only one of the ester groups for steric reasons, to afford monocarboxylic acid sc-98 and ap-98, respectively. The sc isomer was converted into a nienthyl ester (99) for resolution into optical isomers. Thus the three rotameric forms of the monocarboxylic acid ( + sc, -sc, ap) were isolated (142). 

After finding that rotation of the rm-butyl group in dimethyl 9-rm-butyl-9,10-dihydro-9,10-ethenoanthracene-ll,12-dicarboxylate (95) was locked on the laboratory time scale, Oki and Suda introduced an isopropyl group in place of the rm-butyl group and found that the barrier was so much lowered ( , = 15.4 kcal/mol) that the attempt to isolate atropisomers had to be abandoned (140). Since then, triptycene systems have been found to give higher barriers to rotation than the ethenoanthracene system. Thus it became attractive to examine die barriers to rotation about a rec-alkyl-to-triptycyl bond. 

It is then expected that, if one introduces yet another peri substituent, the barrier may become high enough for the isolation of atropisomers. Thus Yamamoto and Oki (167) prepared 8,13-dichloro-l,4-dimethyl-9-(3,5-dimethyl-benzyl)triptycene (118) and succeeded in isolating the ap and sc atropisomers. 

The barrier to rotation was 24.8 kcal/mol at 48°C, and the population ratio was 2.0 in chloroform-, which is the statistical value. The size of the peri substituent has an important effect on the barrier to rotation about the CH2—C(9) bond, because if a 1,4-dimethoxybenzeno bridge is introduced in place of the 1,4-dimethylbenzeno, the coalescence of the AB quartet due to the benzylic CH2 protons is observed at 167°C corresponding to a free energy of activation of 22 kcal/mol, which is too low for isolation of the atropisomers at room temperature. 

As early as 1967, after their success in isolating atropisomers of haloacetamide derivatives (12), Chupp and Olin (49) examined the separate reactivities of these atropisomers in Menschutkin reactions with pyridine (Scheme 7). They found... 

Stable, isolable atropisomers 170 and 171 of the C-20 unsubstituted carbo-methoxycleavamines 172 and 173 (Scheme 46). On heating to 40°C (for 171) or 100°C (for 170), these compounds could be converted to their respective lower energy conformational isomers 172 and 173 121). 

The naphthyl group at C(2) in N-benzoylindoline (109) allows isolation of (82H2015) two diastereomeric atropisomers, owing to slow rotation around the exocyclic C(2)—C bond. 

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