molecules Review Noncovalent Bonds through Sigma and Pi-Hole Located on the Same Molecule. Guiding Principles and Comparisons Wiktor Zierkiewicz 1,* , Mariusz Michalczyk 1,* and Steve Scheiner 2 1 Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeze˙ Wyspia´nskiego27, 50-370 Wrocław, Poland 2 Department of Chemistry and Biochemistry, Utah State University Logan, Logan, UT 84322-0300, USA; [email protected] * Correspondence: [email protected] (W.Z.); [email protected] (M.M.) Abstract: Over the last years, scientific interest in noncovalent interactions based on the presence of electron-depleted regions called σ-holes or π-holes has markedly accelerated. Their high directionality and strength, comparable to hydrogen bonds, has been documented in many fields of modern chemistry. The current review gathers and digests recent results concerning these bonds, with a focus on those systems where both σ and π-holes are present on the same molecule. The underlying principles guiding the bonding in both sorts of interactions are discussed, and the trends that emerge from recent work offer a guide as to how one might design systems that allow multiple noncovalent bonds to occur simultaneously, or that prefer one bond type over another. Keywords: molecular electrostatic potential; halogen bond; pnicogen bond; tetrel bond; chalcogen bond; cooperativity Citation: Zierkiewicz, W.; Michalczyk, M.; Scheiner, S. Noncovalent Bonds through Sigma and Pi-Hole Located on the Same 1. Introduction Molecule. Guiding Principles and The concept of the σ-hole, introduced to a wide audience in 2005 at a conference in Comparisons. Molecules 2021, 26, Prague by Tim Clark [1], influenced a way of thinking about noncovalent interactions 1740. https://doi.org/10.3390/ that prevails to this day. Early experimental findings [2–5] of unusual halogen·halogen molecules26061740 contacts were explained in part by the anisotropic distribution of electronic density around a halogen atom when linked to an electron-withdrawing group. Already in 1992, it had Academic Editor: Teobald Kupka been learned that electronegative atoms from Groups 14–17 have regions of positive molecular electrostatic potential (MEP) on their outer surfaces, along an extension of a Received: 5 March 2021 covalent bond, which may attract an incoming Lewis base [6]. This observation led to Accepted: 17 March 2021 σ Published: 20 March 2021 the further computational studies which resulted in formulation of the -hole idea [7] which was further generalized in later works [7–17]. These ideas concerning the halogen bond were successfully adapted to atoms from other families of the periodic table, which Publisher’s Note: MDPI stays neutral σ with regard to jurisdictional claims in were later grouped into the category of -hole bonds. This general sort of noncovalent published maps and institutional affil- bond has been subdivided by the specific family from which the bridging atom is drawn, iations. i.e., chalcogen [18–23], pnicogen (pnictogen) [24–28], or tetrel bonds [29–31]. The former, along with the halogen bond, has been formally recognized and detailed in recent IUPAC recommendations [32,33]. Quite the opposite from representing exotic or unusual contacts, these bonds make important contributions to numerous fields of chemistry and biology. As examples, un- Copyright: © 2021 by the authors. derstanding the forces behind crystal engineering and supramolecular chemistry benefits Licensee MDPI, Basel, Switzerland. σ This article is an open access article from a knowledge of -hole interactions due to their directionality, strength, and self- distributed under the terms and organization properties which promote formation of adducts in the solid state [34–52]. The conditions of the Creative Commons importance of σ-hole bonding has also been verified in the context of anion recognition Attribution (CC BY) license (https:// processes [53–61], materials chemistry [62–72], or biochemistry [73–81]. An early work creativecommons.org/licenses/by/ connecting σ-hole bonds with crucial concepts in chemistry occurred when Grabowski 4.0/). Molecules 2021, 26, 1740. https://doi.org/10.3390/molecules26061740 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 21 Molecules 2021, 26, 1740 2 of 21 processes [53–61], materials chemistry [62–72], or biochemistry [73–81]. An early work recognizedconnecting thatσ-hole tetrel bonds bonds with can crucial be thought concepts of asin achemistry preliminary occurred stage ofwhen the veryGrabowski important SrecognizedN2 reaction that [82 tetrel]. bonds can be thought of as a preliminary stage of the very important SN2 reactionAs ideas [82]. concerning the σ-hole were proliferating, it was recognized that density depletionAs ideas is not concerning necessarily the limitedσ-hole were only proliferating, to the extensions it was ofrecognized covalent that bonds. density Depletions de- canpletion also is occur not necessarily above planar limited groups only to as the well, extensions as for example of covalent above bonds. a carbonyl Depletions or can phenyl group.also occur Linear above systems planar groups such as as HCN well, canas for also example suffer above from a low carbonyl density or phenyl off the group. molecular axis.Linear Because systems of such their as locationHCN can and also associationsuffer from withlow densityπ-electronic off the systems,molecular these axis. regionsBe- ofcause density of their depletion location andand positiveassociation electrostatic with π-electronic potential systems, have these come regions to be calledof densityπ-holes. Asdepletion one specific and positive example, electrostatic tricoordinated potential triel have atoms come typically to be called occur π-holes. at the center As one of spe- a planar triangle,cific example, with tricoordinated a π-hole located triel above atoms the typically central occur triel at atom the center [13,83 of–87 a ],planar and thetriangle, resulting trielwithbond a π-hole [88 –located95] falls above into the the central category triel ofatom a π [13,83–87],-hole bond. and The the resultingπ-hole situated triel bond above the[88–95] C atom falls ofinto a the carbonyl category group of a π-hole offers bond. another The common π-hole situated example, above whose the C presenceatom of a was manifestedcarbonyl group in early offers work another of common Burgi and example, Dunitz whose [96]. Proteinpresence structures was manifested can also in early involve participationwork of Burgi of andπ-hole Dunitz bonds [96]. [97 Protein,98], as structures is also true can of also self-assembling involve participation systems [of99 π-hole]. As work bonds [97,98], as is also true of self-assembling systems [99]. As work has progressed, has progressed, there has been recognition of π-holes as providing a means by which an there has been recognition of π-holes as providing a means by which an aerogen bond aerogen bond (involving rare gas atoms) can form [100–104]. Other newly introduced (involving rare gas atoms) can form [100–104]. Other newly introduced types of σ/π- hole types of σ/π- hole directed interactions are alkali and alkaline earth bond (e.g., beryllium directed interactions are alkali and alkaline earth bond (e.g., beryllium bond, magnesium bond, magnesium bond) in which atoms of 1st and 2nd groups contribute [105–109] or bond) in which atoms of 1st and 2nd groups contribute [105–109] or regium and spodium regium and spodium bonds which employ transition metals from 11th (regium [110–115]) bonds which employ transition metals from 11th (regium [110–115]) or 12th (spodium or[105,116–119]) 12th (spodium groups [105 of,116 the–119 periodic]) groups table. of The the periodicfull range table. of these The sorts full rangeof bonds, of these along sorts ofwith bonds, their alongdesignations, with their is summarized designations, in isFigure summarized 1. in Figure1. FigureFigure 1.1. Family of of σσ andand π-holeπ-hole interactions. interactions. ThereThere have been been a a number number of of earlier earlier reviews reviews addressing addressing the theissue issue of σ-hole of σ-hole and π- and π- holehole bondsbonds [[13,49,51,52,81,84,105,120,121].13,49,51,52,81,84,105,120,121 ].However, However, little little attention attention has hasbeen been devoted devoted to to situationssituations where both both hole hole types types are are present present on on a single a single molecule, molecule, and and the thecompetition competition betweenbetween thethe twotwo forfor a a nucleophile. nucleophile. Indeed,Indeed, itit is is also also of of intense intense interest interest to to examine examine the the result whenresult bothwhen of both these of bonds these bonds are present are present at the sameat the time.same Astime. has As already has already been explored,been ex- the tunability of single σ or π-holes enables the construction of interesting assemblies with desired properties [122–124]. The possibilities multiply when both types of bonds are present and influence one another. The driving goal for this work is to review with a critical eye what is known about systems offering both σ and π-holes to an approaching nucleophile. Are there rules that can be used to predict which will be preferred? Is there a distinction depending on whether Molecules 2021, 26, x FOR PEER REVIEW 3 of 21 plored, the tunability of single σ or π-holes enables the construction of interesting assem- blies with desired properties [122–124]. The possibilities