Chemistry - What is an ambident substrate?

Solution 1:

There is a subsection in March’s Advanced Organic Chemistry [1, pp. 450–451] that provides a straightforward definition and a couple of examples:

10.G.viii. Ambident Substrates

Some substrates (e.g., 1,3-dichlorobutane) can be attacked at two or more positions, and these may be called ambident substrates. In the example given, there happen to be two leaving groups in the molecule. Apart from dichlorobutane, and in general, there are two kinds of substrates that are inherently ambident (unless symmetrical). One of these, the allylic type, has already been discussed (Sec. 10.E). The other is the epoxy (or the similar aziridine⁵²⁴ or episulfide) substrate.⁵²⁵ Selectivity for one or the other position is usually called regioselectivity.

Substitution of the free epoxide, which generally occurs under basic or neutral conditions, usually involves an S_N2 mechanism. Since primary substrates undergo S_N2 attack more readily than secondary, unsymmetrical epoxides are attacked in neutral or basic solution at the less highly substituted carbon, and stereospecifically, with inversion at that carbon. Under acidic conditions, it is the protonated epoxide that undergoes the reaction. Under these conditions the mechanism can be either S_N1 or S_N2. In S_N1 mechanisms, which favor tertiary carbons, attack may be expected be at the more highly substituted carbon, and this is indeed the case. However, even when protonated epoxides react by what is expected to be an S_N2 mechanism, attack is usually at the more highly substituted position.⁵²⁶ This result probably indicates significant carbocation character at the carbon (ion pairing, for example). Thus, it is often possible to change the direction of ring opening by changing the conditions from basic to acidic or vice versa. In the ring opening of 2,3-epoxy alcohols, the presence of $\ce{Ti(O\textit iPr)4}$ increases both the rate and the regioselectivity, favoring attack at C-3 rather than C-2.⁵²⁷ When an epoxide ring is fused to a cyclohexane ring, S_N2 ring opening invariably gives diaxial rather than diequatorial ring opening.⁵²⁸

Cyclic sulfates (108), prepared from 1,2-diols, react in the same manner as epoxides, but usually more rapidly:⁵²⁹

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⁵²⁴ Chechik, V.O.; Bobylev, V.A. Acta Chem. Scand. B, 1994, 48, 837.
⁵²⁵ Rao, A.S.; Paknikar, S.K.; Kirtane, J.G. Tetrahedron 1983, 39, 2323; Behrens, C.H.; Sharpless, K.B. Aldrichimica Acta 1983, 16, 67; Enikolopiyan, N.S. Pure Appl. Chem. 1976, 48, 317; Dermer, O.C.; Ham, G.E. Ethylenimine and Other Aziridines, Academic Press, NY, 1969, pp. 206–273.
⁵²⁶ Biggs, J.; Chapman, N.B.; Finch, A.F.; Wray, V. J. Chem. Soc. B 1971, 55.
⁵²⁷ Caron M.; Sharpless, K.B. J. Org. Chem. 1985, 50, 1557. See also, Chong, J.M.; Sharpless, K.B. J. Org. Chem. 1985, 50, 1560; Behrens, C.H.; Sharpless, K.B. J. Org. Chem. 1985, 50, 5696.
⁵²⁸ Murphy, D.K.; Alumbaugh, R.L.; Rickborn, B. J. Am. Chem. Soc. 1969, 91, 2649. For a method of overriding this preference, see McKittrick, B.A.; Ganem, B. J. Org. Chem. 1985, 50, 5897.
⁵²⁹ Gao, Y.; Sharpless, K.B. J. Am. Chem. Soc. 1988, 110, 7538; Kim, B.M.; Sharpless, K.B. Tetrahedron Lett. 1989, 30, 655.

Reference

1. Smith, M. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed.; Wiley: Hoboken, New Jersey, 2013. ISBN 978-0-470-46259-1.

Solution 2:

I agreed with andselisk's answer. Yet, Ambident Substrates are not limited to March’s given examples in that answer. A substrate, which can be consecutively acted either as an electrophile of a nucleophile is also called ambident substrate (Ref.1). One of the best example is acetaldehyde or propanaldehyde in aldol condensation:

In 2002, Barbas III & coworkers have reported that L-proline ($\bf{\text{cat1}}$) could catalyze the twofold condensation of propionaldehyde ($\bf{1}$), acting consecutively as a pro-nucleophile and an electrophile, to other aliphatic aldehydes providing lactols, $\bf{3}$, in a moderate yield after intramolecular hemiacetalization (Scheme B)(Ref.2).

References:

1. Céline Sperandio, Jean Rodriguez, Adrien Quintard, "Catalytic strategies towards 1,3-polyol synthesis by enantioselective cascades creating multiple alcohol functions," Org. Biomol. Chem. 2020, 18, 1025-1035 (DOI: 10.1039/C9OB02675D).
2. Naidu S. Chowdari, D. B. Ramachary, Armando Córdova, Carlos F. Barbas III, "Proline-catalyzed asymmetric assembly reactions: enzyme-like assembly of carbohydrates and polyketides from three aldehyde substrates," Tetrahedron Lett. 2002, 43(52), 9591-9595 (https://doi.org/10.1016/S0040-4039(02)02412-7).