Flippin–Lodge angle
The Flippin–Lodge angle is one of two angles used by
Because chemical reactions take place in
The most prominent application and impact of the Flippin–Lodge angle has been in the area of chemistry where it was originally defined: in practical
Technical introduction
The Flippin–Lodge (FL) angle, is the latter-derived of two angles that fully define the geometry of "attack" (approach via collision) of a
(the second being the Bürgi–Dunitz angle, , see below).Nucleophiles in this
In the example of nucleophilic attack at a carbonyl, is a measure of the "offset" of the nucleophile's approach to the electrophile, toward one or the other of the two substituents attached to the carbonyl carbon.[1][2][3] The relative values of angles for pairs of reactions can be inferred and semiquantitative, based on rationalizations of the products of the reactions; alternatively, as noted in the figure, values may be formally derived from crystallographic coordinates by geometric calculations, or graphically, e.g., after projection of Nu onto the carbonyl plane and measuring the angle supplementary to LNu'-C-O (where Nu' is the projected atom). This often overlooked angle of the nucleophile's trajectory was named theThe Flippin–Lodge angle has been abbreviated variously by the symbols φ, ψ, θx, and or ;[2][3][7][8][9][a] the latter pair to closely associate the Flippin–Lodge angle with its sister angle, the Bürgi–Dunitz, which was originally abbreviated as by its discoverers/formulators (e.g., see Bürgi et al., 1974.[7]). The symbols and are used here, respectively, to refer to the Flippin-Lodge and Bürgi-Dunitz concepts and measured values.
As an experimental observable
These angles are best construed to mean the angles observed (measured) for a given system, and not an historically observed range in values (e.g., as in the range of the original Bürgi–Dunitz aminoketones), or an idealized value computed for a particular system (such as the = 0° for hydride addition to formaldehyde).[7] That is, the and angles of the hydride-formadehyde system have one pair of values, while the angles observed for other systems—combinations of nucelophile and electrophile, in combination with catalyst and other variables that define the experimental condition, including whether the reaction is in solutio or otherwise—are fully expected (and are reported) to vary, at least somewhat, from the theoretical, symmetric hydride-formaldehyde case.[2][8][a]
A stated convention for is that it is positive (>0°) when it deviates in direction:
- away from the larger substituent attached to the electrophilic center, or
- away from the more electron-rich substituent (where these two and other factors can be in a complex competition, see below);
hence, as noted, for reaction of a simple nucleophile with a symmetrically substituted carbonyl (R = R', or other symmetric planar electrophile) is expected to be 0° in vacuo or in solutio, e.g., as in the case of the computed and experimental addition of hydride (H–) to formaldehyde (H2C=O).[2]
Steric and orbital contributions to its value
In contrast to the Bürgi–Dunitz angle, ,[7] and using the case of carbonyl additions as example: the angle adopted during an approach by the nucleophile to a trigonal electrophile depends in complex fashion on:
- the relative steric size of the two substituents attached to (alpha to) the electrophilic carbonyl, which give rise to varying degrees of repulsive van der Waals's interactions (e.g., giving ≈ 7° for hydride attack on pivaldehyde (see image), where R=tertiary-butyl, and R'=H),[2]
- the electronic characteristics of substituents alpha to the carbonyl, where heteroatom-containing substituents can, through their stereoelectronicinfluence, function as overly intrusive steric groups (e.g., giving ≈ 40-50° for esters and amides with small R' groups, since R is an O- and N-substituent, respectively),[2] and
- the nature of the bonds made by more distant atoms to the atoms alpha to the carbonyl, e.g., where the energy of the σ* molecular orbital (MO) between the alpha- and beta-substituents was seen to compete with the foregoing influences,[5]
as well as on the MO shapes and occupancies of the carbonyl and attacking nucleophile.[2][3] Hence, the observed for nucleophilic attack appears to be influenced primarily by the energetics of the HOMO-LUMO overlap of the nucleophile-electrophile pair in the systems studied—see the Bürgi–Dunitz article, and the related inorganic chemistry concept of the angular overlap model (AOM)[b][11][c][d][12][13]—which leads in many cases to a convergence of values (but not all, see below); however, the required to provide optimal overlap between HOMO and LUMO reflect the complex interplay of energetic contributions described with examples above.
Origin and current scope of concept
Bürgi–Dunitz angle theory was initially developed based on "frozen" interactions in crystals,[2][3]: 124ff [7] while most chemistry takes place via collisions of molecules tumbling in solution; remarkably, the theories of the , with the complexity they reflect, evolved not from crystallographic work, but from studying reaction outcomes in such practical reactions as addition of enolates to aldehydes (e.g., in study of diastereoselection in particular aldol reactions).[1][3] In applying both angles of the nucleophile trajectory to real chemical reactions, the HOMO-LUMO centered view of the Bürgi-Dunitz angle, , is modified to include further complex, electrophile-specific attractive and repulsive
Finally, in constrained environments (e.g., in
Applications
The Flippin-Lodge and Bürgi-Dunitz angles were central, practically, to the development of a clearer understanding of asymmetric induction during nucleophilic attack at hindered carbonyl centers in synthetic organic chemistry. It was in this area that was first defined by Heathcock, and has been primarily used.[1][3] Larger substituents around the electrophilic center, such as tert-butyls, lead to higher stereoselectivities in asymmetric induction than smaller substituents like methyls. The trajectory of the nucleophile approaching a center flanked by two large substituents is more limited, i.e. the Flippin–Lodge angle is smaller. For example, in Mukaiyama aldol addition, the bulkier phenyl tert-butyl ketone has a higher selectivity for the syn isomer than the smaller phenyl methyl ketone. Likewise, if bulky a nucleophile, such as a t-butylmethylsilyl enolate, is used, the selectivity is higher than for a small nucleophile like a lithium enolate.[6]
Given a reaction system of a given nucleophile with a carbonyl having the two substituents R and R', where substituent R' is
A surpassing area of application has been in studies of various
See also
Notes
- ^ a b c d While Radisky & Koshland, op. cit., explicitly mention the rootedness of their protein crystallography analysis in the work of Bürgi and Dunitz (citing three of their reports), and while they clearly report an azimuthal angle in their data (their θx), they do not cite the relevant earlier work of Heathcock, Flippin and Lodge (1983-1990), the connection to which, in the context of their Bürgi-Dunitz acknowledgments, and the text and review material of Fleming (2010) and Gawley & Aubé (1996), is viewed as obvious to WP editors.
- ^ While the AOM is almost uniformly applied to inorganic cases, per IUPAC definition it applies to main group elements as well, see Minkin, op. cit., and this extension is explicitly covered in the text and other writings of the late Prof. Jeremy Burdett, et. op. cit.
- ^ [Quoting:] Angular Overlap Model (AOM)—A method of description of transition metal-ligand interactions and main-group element stereochemistry, whose basic assumption is in that the strength of a bond formed using atomic orbitals on two atoms is related to the magnitude of overlap of the two orbitals. The interactions between the central-atom and ligand orbitals are usually divided into the σ-, π- and δ-types and parametric equations of the type[:] εstab,σ = F2εσ – (F2)2ƒσ [and] εdestab,σ = – [F2εσ – (F2)2ƒσ] are used, where F is angle-dependent contribution to the overlap integral Sab between the two interacting orbitals, whereas parameters εσ and ƒσ are proportional to S2 and S4 respectively and depend on the identity of atoms A and B as well the A–B distance. Similar equations are derived for the π- and δ-type interactions. Neither orbital mixing nor nuclear repulsions are accounted for by the model. Its advantage is in that for simple systems a molecular orbital diagram is easily constructed on the basis of two-orbital interactions and clearly reveals trends in orbital energies on distortion ([citing] 5 [Burdett (1980), Molecular Shapes,], 6 [Richardson (1993)]).
- ^ The co-authors (members of the IUPAC Working Party) for the foregoing report, in addition to the author given, were S. Alvarez, Y. Apeloig, A. Balaban, M. Basilevsky, F. Bernardi, J. Bertran, G. Calzaferri, J. Chandrasekhar, M. Chanon, J. Dannenberg, R. Gleiter, K. Houk, Z. Maksic, R. Minyaev, E. Osawa, A. Pross, P. v. R. Schleyer, S. Shalk, H.-U. Siehl, R. Sustmann, J. Tomasi, D. Wales, I. Williams and G. Zhidomirov. IUPAC Project Year 1993, Project Code 320/16/93.
References
- ^ a b c d e f g h C.H. Heathcock (1990) Understanding and controlling diastereofacial selectivity in carbon-carbon bond-forming reactions, Aldrichimica Acta 23(4):94-111, esp. p. 101, see "Archived copy" (PDF). Archived from the original (PDF) on 2014-01-06. Retrieved 2014-01-06.
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: CS1 maint: archived copy as title (link), accessed 9 June 2014. - ^ ISBN 0-470-74658-0, [1], accessed 5 January 2014.
- ^ ISBN 0-08-041875-9.
- ^ ISBN 978-3-527-61608-4. Retrieved 1 March 2016.
- ^ a b c d e E.P. Lodge & C.H. Heathcock (1987) Steric effects, as well as sigma*-orbital energies, are important in diastereoface differentiation in Additions to chiral aldehydes, J. Am. Chem. Soc., 109:3353-3361.
- ^ a b L.A. Flippin & C.H. Heathcock (1983) Acyclic stereoselection. 16. High diastereofacial selectivity in Lewis acid mediated additions of enolsilanes to chiral aldehydes, J. Am. Chem. Soc. 105:1667-1668.
- ^ .
- ^ PMID 12142461.
- ^ Koskinen (2012), pp. 3-7f.
- ^ Pubchem. "Trimethylacetaldehyde". nih.gov. Retrieved 2 March 2016.
- S2CID 6475517. (print); 1365-3075 (online). Retrieved 1 March 2016.
- .
- ISBN 978-0-471-97130-6. Retrieved 29 February 2016.; Burdett, J.K. (1980). Molecular Shapes: Theoretical Models of Inorganic Stereochemistry. New York, NY, USA: Wiley Interscience.[page needed]; Burdett, J.K. (1978). "A new look at structure and bonding in transition metal complexes". Adv. Inorg. Chem. print review. 21: 113ff.
- ^ S.H. Light, G. Minasov, M.-E. Duban & W.F. Anderson (2014), Adherence to Bürgi-Dunitz stereochemical principles requires significant structural rearrangements in Schiff-base formation: insights from transaldolase complexes, Acta Crystallogr. D 70(Pt 2):544-52, DOI: 10.1107/S1399004713030666, see [2], accessed 10 June 2014.
- PMID 11749441. Retrieved 5 December 2015.
- ^ Evans, D.A., et al. (2006) "Carbonyl and Azomethine Electrophiles [Lectures 21, 22]," Chemistry 206, Advanced Organic Chemistry, packet pp. 91-99, 106-110, and 116, Cambridge, MA, USA: Harvard University Chemistry Department, [3], accessed 5 December 2015.
- ^ S.B.J. Kan, K.K.-H. Ng & I. Paterson (2013) The Impact of the Mukaiyama Aldol Reaction in Total Synthesis, Angew. Chemie Int. Ed. 52(35), 9097-9108, see [4], accessed 30 November 2014.
- ^ D.A. Evrard & B.L. Harrison (1999) Ann. Rep. Med. Chem. 34, 1.[page needed]
- ^ J.-J. Li, D.S. Johnson, D.R. Sliskovic & B.D. Roth (2004) Contemporary Drug Synthesis, Hoboken:Wiley-Interscience, 118.
- PMID 20622857.
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- ^ Choudhary et al. (2010), pp. 655–657.
Bibliography
- Choudhary, A.; Kamer, K.J.; Powner, M.W.; Sutherland, J.D.; Raines, R.T. (2010). "A stereoelectronic effect in prebiotic nucleotide synthesis". ACS Chem. Biol. 5 (7): 655–657. PMID 20499895.
- Cieplak, A.S. (2008) [1994]. "Organic Addition and Elimination Reactions; Transformation Paths of Carbonyl Derivatives [Ch. 6]". In Bürgi, Hans-Beat; Dunitz, Jack D. (eds.). Structure Correlation. Vol. 1. Weinheim, GER: VCH. pp. 205–302, esp. 270–274. ISBN 978-3-527-61608-4. Retrieved 1 March 2016.
- Evans, D.A. (2006), Carbonyl and Azomethine Electrophiles [Lectures 21, 22] (PDF), Chemistry 206, Advanced Organic Chemistry, Cambridge, MA, USA: Harvard University Chemistry Department, pp. 91–99, 106–110, 116, retrieved 5 December 2015[dead link]
- Fleming, Ian (2010). Molecular Orbitals and Organic Chemical Reactions (Reference ed.). John Wiley and Sons. pp. 214–215. ISBN 978-0-470-74658-5.
- Heathcock, C.H. (1990). "Understanding and controlling diastereofacial selectivity in carbon-carbon bond-forming reactions" (PDF). Aldrichimica Acta. 23 (4): 94–111. Archived from the original (PDF) on 2014-01-06. Retrieved 5 January 2014.
- Koskinen, A.M.P. (2012). Asymmetric Synthesis of Natural Products. Chichester, UK: John Wiley and Sons. pp. 3–7f.
- Mahrwald, Rainer (1999). "Diastereoselection in Lewis-Acid-Mediated Aldol Additions" (PDF). Chem. Rev. 99 (5): 1095–1120, esp. pp. 1099, 1102, 1108. PMID 11749441. Retrieved 5 December 2015.