Flippin–Lodge angle
In that projection, the vector (arrow) pointing from :Nu to the carbon of the carbonyl is mirrored across plane I to make clear that the nucleophile can approach from either above or below this plane (with resulting differences in the stereochemistry of reaction products, see text).
—describe the "trajectory" or "angle of attack" of the nucleophile as it approaches the electrophile, in particular when the latter is planar in shape.
This is called a nucleophilic addition reaction and it plays a central role in the biological chemistry taking place in many biosyntheses in nature, and is a central "tool" in the reaction toolkit of modern organic chemistry, e.g., to construct new molecules such as pharmaceuticals.
Because chemical reactions take place in three dimensions, their quantitative description is, in part, a geometry problem.
is an angle that estimates the displacement of the nucleophile, at its elevation, toward or away from the particular R and R' substituents attached to the electrophilic atom (see image).
is the angle between the approach vector connecting these two atoms and the plane containing the electrophile (see the Bürgi–Dunitz article).
Reactions addressed using these angle concepts use nucleophiles ranging from single atoms (e.g., chloride anion, Cl–) and polar organic functional groups (e.g., primary amines, R"-NH2), to complex chiral catalyst reaction systems and enzyme active sites.
These nucleophiles can be paired with an array of planar electrophiles: aldehydes and ketones, carboxylic acid-derivatives, and the carbon-carbon double bonds of alkenes.
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 synthetic studies of the outcome of carbon-carbon bond-forming reactions in solution.
Studies invoking Flippin–Lodge angles in synthetic chemistry have improved the ability of chemists to predict outcomes of known reactions, and to design better reactions to produce particular stereoisomers (enantiomers and diastereomers) needed in the construction of complex natural products and drugs.
[2][3][4] Nucleophiles in this addition reaction may range from single atoms (hydride, chloride), to polar organic functional groups (amines, alcohols), to complex systems (nucleophilic enolates with chiral catalysts, amino acid side chains in enzyme active sites; see below).
Planar electrophiles include aldehydes and ketones, carboxylic acid-derivatives such as esters, and amides, and the carbon-carbon double bonds of particular alkenes (olefins).
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.
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).
, describes the Nu-C-O bond angle and was named after crystallographers Hans-Beat Bürgi and Jack D. Dunitz, its first senior investigators (see that related article).
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.
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
required to provide optimal overlap between HOMO and LUMO reflect the complex interplay of energetic contributions described with examples above.
, is modified to include further complex, electrophile-specific attractive and repulsive electrostatic and van der Waals interactions that can alter
,[5]—though not in crystallographic structure correlation approaches as gave birth to the BD concept.
Finally, in constrained environments (e.g., in enzyme and nanomaterial binding sites), these angles, when characterized, appear to be quite distinct, an observation conjectured to arise because reactivity is not based on random collision, and so the relationship between orbital overlap principles and reactivity is more complex.
[8][a][14] For instance, while a simple amide addition study with relatively small substituents gave an
of ≈50° in solution,[2] the crystallographic value determined for an enzymatic cleavage of an amide by the serine protease subtilisin gave an
values for the same reaction in different catalysts clustered at 4 ± 6° (i.e., only slightly offset from directly behind the carbonyl, despite significant dissymmetry of the substrate electrophiles).
angle values from the careful literature compilation clustered at 89 ± 7° (i.e., only slightly offset from directly above or below the carbonyl carbon).
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.
The trajectory of the nucleophile approaching a center flanked by two large substituents is more limited, i.e. the Flippin–Lodge angle is smaller.
[citation needed] Thus, from the perspective of simpler electrophile systems where only steric bulk come into play, the attack trajectories of the classes of nucleophiles studied makes clear that as the disparity in size between the substituent increase, there is a perturbation in the FL angle that can be used to provide higher stereoselectivities in designed reaction systems;[citation needed] while the patterns become more complex when factors other than steric bulk come into play (see section above on orbital contributions),[2][5] Flippin, Lodge, and Heathcock were able to show that generalizations could be made that were useful to reaction design.
[1][2][3] A surpassing area of application has been in studies of various aldol reactions, the addition of ketone-derived enol/enolate nucleophiles to electrophilic aldehydes, each with functional groups varying in size and group polarity;[3] the way that features on the nucleophile and electrophile impact the stereochemistry seen in reaction products, and in particular, the diastereoselection exhibited, has been carefully mapped (see the steric and orbital description above,[1][2][3] the aldol reaction article, and David Evans' related Harvard teaching materials on the aldol[16]).
These studies have improved the chemists' abilities to design enantioselective and diastereoselective reactions needed in the construction of complex molecules, such as the natural product spongistatins[17] and modern drugs.
