**1. Introduction**

The name "hydrogen bonding" was used for the first time by Linus Pauling in 1929 [1], although the interactions associated with a hydrogen bond had been described for the first time more than a century ago, by W.M. Latimer and W.H. Rodebush, in a paper published in 1920 [2]. Since 1934, the year in which Pauling and Brockway experimentally confirmed that carboxylic acids could indeed form hydrogen bonds [3], hydrogen bonding became one of the most fruitful concepts in chemistry, being behind a huge amount of stabilizing intermolecular interactions [4–15]. In addition, in the 1920s, the existence of intramolecular interactions that, nowadays, we know as intramolecular hydrogen bonds (IHBs), were described in the literature. Indeed, the first paper on the coordination of hydrogen to explain the abnormal solubilities of some benzene derivatives was published in 1924 [16]. The intramolecular hydrogen bond was actually described in a 1926 publication by H.E. Amstrong [17], making reference to a paper of T.M. Lowry on the anomalies of the optical rotatory dispersion of tartaric acid published the same year [18], as a "bigamous hydrogen". Almost a century has elapsed since the publication of these articles, and the presence of IHBs is very often shown to be behind many different phenomena in chemistry, physics, in particular in photophysics, material science, and biochemistry, to the point that IUPAC dedicated a specific paper to the definition of this chemical interaction [19]. Let us mention here a few suitable examples, drawn from a huge number of publications,

**Citation:** Lamsabhi, A.M.; Mó, O.; Yáñez, M. Perturbating IntramolecularHydrogen Bonds through SubstituentEffects or Non-Covalent Interactions. *Molecules* **2021**, *26*, 3556. https:// doi.org/10.3390/molecules26123556

Academic Editor: Mirosław Jabło ´nski

Received: 27 May 2021 Accepted: 8 June 2021 Published: 10 June 2021

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such as the substituent effects on the IHB of malonaldehyde [20], or the role of IMHBs on: protonation and deprotonation processes [21], NMR chemical shifts [22], bond dissociation enthalpies [23,24], or their influence on the role of aromaticity in chemical reactions [25]. They are also crucial to understand excited-state intramolecular proton transfers [26–28], or the control of photosubstitution phenomena in metal complexes [29], or the control of emissive properties of different organic compounds [30]. IMHBs are also behind the high chemical stability of metal-organic frameworks [31] and the excellent electroluminescence of some organic light-emitting diodes (OLEDs) [32], and related with linear and nonlinear electric properties [33] or with the thermodynamic properties of compounds like pyridinol derivatives [34]. In biochemistry, they are responsible for proton shuttle mechanisms in certain lipase-catalyzed reactions [35]. IMHBs between hydroxyl and amino groups of a serinol function, characteristic of an important lipid, sphingosine, seem to be responsible for its existence, as neutral at the physiological pH [36], IMHBs allow also for designing novel peptide inhibitors [37], and play an important role as far as the molecular conformation of amino acids is concerned [38]. In addition, important properties are associated with the so-called intramolecular charge-inverted hydrogen bonds [39,40].

Since the pioneering studies by microwave spectroscopy on 2-aminoethanol [41] and by infrared spectroscopy on *trans*-8a and -8b-decahydroquinilinol reveal the important role of IMHBs in their stability, the interest in amino-alcohols increased significantly. The first ab initio calculations showed that 2-aminoethanol, 3-aminopropanol, and 4-aminobutanol were indeed stabilized by OH···N IMHBs, this stabilization being larger the longer the chain [42]. Very recent microwave experiments in parallel with MP2 ab initio calculations confirmed that, in both 3-aminopropanol [43] and 4-aminobutanol [44], the ground state is stabilized through the formation of an OH···N IMHB with O-N internuclear distance of 2.856 and 2.954 Å, respectively. In addition, a recent and rather complete study [45] using FTIR measurements, 1H NMR spectroscopy, density functional theory (DFT) calculations, and molecular dynamics (MD) on 3-aminopropan-1-ol, 3-methylaminopropan-1-ol, and 3-dimethylaminopropan-1-ol, unambiguously showed that the methylation at the N atom results in a systematic enhancement of the OH···N IMHB, reflecting a decrease of the s-character of the nitrogen lone pair orbital.

These results clearly indicate that the effects of substituents directly attached to the active sites of the OH···N IMHB have a significant effect in its strength, but, to the best of our knowledge, not much is known on the effects induced by substituents that are at the α-position of both the hydroxyl or the amino group, or what the effects are when any of these two groups are also actively participating in a non-covalent interaction with a second body. Hence, one of the aims of this paper is to investigate, through the use of high-level ab initio calculations, the characteristics of the OH···N IMHB in the series of HOCHX(CH2)nCH2NH2 and HOCH2(CH2)nCHXNH2 (*n* = 0–5) with substituted aminoalcohols being X = H, F, Cl, Br. As mentioned above, there is an alternative way in which the strength of an IMHB can be altered, and this is through non-covalent interactions in which either the proton donor or the proton acceptor is engaged. Among the many possible non-covalent interactions capable of interacting with IMHBs, the so-called beryllium bonds [46] are particularly interesting. A good and rather complete compilation on the coordination chemistry of beryllium was reported recently by Perera et al. [47]. Beryllium bonds have been found to compete with dihydrogen bonds [48], and they are able to modulate the strength of tetrel bonds [49]. They can also be formed when interacting with other electron deficient systems, such as boron derivatives [50] or with noble gases [51]. Although there are previous studies on the mutual interaction of intermolecular hydrogen bonds and beryllium bonds [52,53], very little has been done dealing with IMHBs. In this respect, a recent theoretical study must be mentioned describing how intramolecular hydrogen bonds are able to enhance tetrel bonds [54], or the competition between pnictogen bonds and intramolecular hydrogen bonds in protonated systems [55]. Here, we have decided to investigate this phenomenon when the system interacting with the aminoalcohol is an electron deficient compound. To achieve this goal, we will investigate the

characteristics of the complexes between HOCH2(CH2)nCH2NH2 (*n* = 0–3) when they interact, either through the amino group or the hydroxyl group, with BeF2 molecules, yielding the corresponding beryllium bonds [46].
