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Redox Potential Tuning in Bio-relevant Heterocycles via (Anti)Aromaticity Modulated H-Bonding (AMHB)

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2019-0410.R1

Manuscript Type: Article

Date Submitted by the Author: 06-Jan-2020

Complete List of Authors: Kakeshpour, Tayeb; Michigan State University, ChemistryVan Wiemeersch, Adam; Michigan State University, ChemistryJackson, James; Michigan State University, Chemistry

Is the invited manuscript for consideration in a Special

Issue?:J Wuest

Keyword: Hydrogen Bonding; Aromaticity; Antiaromaticity; AMHB; Redox Tuning

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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Redox Potential Tuning in Bio-relevant Heterocycles via

(Anti)Aromaticity Modulated H-Bonding (AMHB)

Tayeb Kakeshpour, Adam Van Wiemeersch, James E. Jackson*

Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA

Email: [email protected]; Phone: 517-353-0504

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ABSTRACT

Hydrogen bonds are arguably the most important non-covalent interactions in chemistry

and biology, and their strength and directionality have been elegantly exploited in the rational

design of complex structures. We recently noted that the variable responses of cyclic -systems

upon H-bond formation reciprocally lead to modulations of the H-bonds’ strengths, a phenomenon

which we dubbed (anti)aromaticity-modulated hydrogen bonding (AMHB) [J. Am. Chem. Soc.

2016, 138, 3427-3432]. Species that switch from aromatic to antiaromatic or vice versa upon

changing -electron counts should be oppositely stabilized by the AMHB effects, so their redox

potentials should be significantly “tuned” by H-bond formation. Herein, using quantum chemical

simulations, we explore the effects of these H-bond induced -electron polarizations on the redox

potentials of (anti)aromatic heterocycles. The systems chosen for this study have embedded amide

groups and amidine moieties capable of forming two-point H-bonds in their cyclic -systems.

Thus, as the 4-electron and 6-electron -systems in redox-capable monocycles (e.g. quinones) can

be differentially stabilized, their redox potentials can be modulated by H-bond formation by as

much as 6 kcal/mol (258 mV for one electron transfer). In fused rings, the connectivity patterns

are as important as the -electron counts. Extending these ideas to flavin, a biologically relevant

case, we find that H-bonding patterns like those found in its crystals can vary its redox potential

by up to 1.3 kcal/mol.

KEYWORDS

Hydrogen Bonding; Aromaticity; Antiaromaticity; Redox; Computational Chemistry

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INTRODUCTION

James D. Wuest’s use of hydrogen bonding (H-bonding) interactions in the assembly of

complex and interesting structures has had a tectonic effect on the field of self-assembly and novel

non-covalent materials.1–12 One of us (JEJ) had the privilege of working with Professor Wuest as

an undergraduate at Harvard in the 1970s. Despite a complete lack of lab success, I came away

indelibly marked with the urge to understand and explore the rules and consequences of organic

molecules’ bonding patterns. In this vein, we recently showed that the aromatic and antiaromatic

stability patterns of heterocycles can couple to their H-bonding leading to modulation of their H-

bond strengths. This energetic effect, dubbed (anti)aromaticity-modulated hydrogen bonding

(AMHB),13,14 was quantified by comparing the calculated H-bond strengths of (anti)aromatic

heterocycles versus those of their non-(anti)aromatic counterparts in which the cyclic -systems

were breached via hydrogenation of one of their endocyclic -bonds. [Note: as used herein,

“(anti)aromatic” describes both species stabilized (aromatic) and those destabilized (antiaromatic)

by cyclic even-electron systems.] Calculations showed uniformly that H-bonds that enhance

aromaticity or relieve some antiaromaticity of heterocycles are strengthened, whereas those that

disrupt aromaticity or increase antiaromatic delocalization are weakened compared to their dihydro

reference compounds. Changes in (anti)aromaticity due to H-bond formation were computation-

ally assessed via dissected nucleus-independent chemical shift, NICS(1)zz,15 confirming the

inferred π-electronic perturbations in the form of changes in “ring current” upon H-bonding.

Variable-temperature and -concentration NMR studies showed that the effects remained

significant across a range of solvent polarities (benzene, chloroform, dichloromethane and

acetonitrile; the three latter results are in preparation for publication), with energetic effects large

enough in some cases to shift self-association by two orders of magnitude.16

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In prior studies, we focused on modulation of H-bond strengths via the -electronic

patterns of (anti)aromaticity of heterocycles. In contrast, this work evaluates effects of H-bond

formation on tuning the redox potential energies of mono- and polycyclic heterocycles. These

species feature -systems containing amide or amidine functional groups capable of forming two-

point H-bonds that can polarize their -electrons. Figure 1 depicts such an example in a bicyclic

framework. With 8 electrons in its -system, compound 11 is weakly antiaromatic, but further

antiaromatic destabilization is induced upon H-bond formation with formic acid. In contrast, its

O,O-hydrogenated counterpart has 10 electrons, so that its H-bond formation enhances aromatic

delocalization and is thus favored by AMHB. Hence reduction should become more exothermic

in the presence of formic acid in Reaction II vs Reaction I (Figure 1). The main body of this

paper studies the effects of H-bonding on redox potentials in compounds analogous to 11 to

understand the generality of the concept and to quantify the extent of the effect.

11

N

O

H2

OO

11H2

Reaction I: Reduction of isolated compound 11

Reaction II: Reduction of 11, H-bonded to formic acid

HN

O

OHHO H

N

OH2

OO H

O

O

HN

O

OHHO H

O

O

H

H-bond formationincreases antiaromaticity

(destabilizing)

H-bond formationincreases aromaticity

(stabilizing)

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Figure 1. Illustration of opposing AMHB effects on starting material and product of a reduction

reaction that converts an antiaromatic to an aromatic -cycle.

RESULTS AND DISCUSSION

Modulation of redox potential via AMHB in single-ring heterocycles

The AMHB effect on reduction energies of single-ring heterocycles is most straightforward and is

thus discussed here first. To explore this effect, para- and ortho-benzoquinone frameworks (q1 and

q2 in Figure 2) were used. Replacement of one of the double bonds with an amide group leads to

compounds q3, q4 and q5 (compounds q3 and q5 are the same but they are named separately since

we consider their H-bonding at different sites). All are weakly antiaromatic as evidenced by their

calculated NICS(1)ZZ values of +2.1 to +5.4 ppm (i.e downfield, or paratropic shifts; green

numbers inside rings). The NICS(1)ZZ (Nucleus Independent Chemical Shift) method computes

the shielding or deshielding (due to diatropic aromatic or paratropic antiaromatic “ring current”

effects) that a proton would experience if placed 1 Å above the center of the ring in question; it

thus represents a measure of aromatic or antiaromatic -delocalization. Upon H-bond formation,

the antiaromaticity of these heterocycles is increased, as evidenced by the changes in their

calculated NICS(1)ZZ values. Reduction of q3, q4 and q5 forms the corresponding heterocycles

q3H2, q4H2 and q5H2; these are all aromatic, based on their electron count and calculated negative

NICS(1)ZZ values. Upon H-bonding to formic acid, their aromaticity is further enhanced as

indicated by the -2.3 to -4.1 ppm changes (upfield shifts) of their calculated NICS(1)ZZ values (see

numbers inside rings). The H-bond induced effects of destabilization by increasing antiaromaticity

in the starting material and enhancement of aromatic stabilization in the reduction product make

the reduction reaction more exothermic than in the isolated system by 3.04 to 4.79 kcal/mol in the

presence of formic acid (negative numbers in dashed boxes).

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On the other hand, if one of the double bonds of the quinones is replaced with an amidine

group, heterocycles q6, q7 and q8 are formed which are antiaromatic since they have 4 electron

counts in their cyclic -systems. Upon H-bond formation, their antiaromaticity is slightly relieved

by delocalization out of the ring, as illustrated by the resonance structures in Figure 2 and

confirmed by their NICS(1)ZZ value changes (+0.07 to +0.8). The aromaticity of the corresponding

hydrogenated products q6H2, q7H2 and q8H2 is weakened by this exocyclic delocalization upon H-

bond formation. In this case, the antiaromaticity relief of the starting azaquinones and disruption

of aromaticity in their reduction products again act in opposite directions, but this time they narrow

the gap, disfavoring the reduction reaction by 0.91 to 5.05 kcal/mol (positive numbers in dashed

boxes) in the presence of formic acid. Thus, energetic and magnetic calculations both support the

notion that H-bonding can modulate the redox energetics of heterocycles via AMHB.

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Figure 2. Examples demonstrating the AMHB effect on redox active heterocycles. Energies (in

kcal/mol) were calculated at the CCSD(T)/CBS//MP2/aDZ level. Numbers inside rings are

NICS(1)ZZ values calculated at mPWPW91/6-311++G(3df,3pd)//MP2/aDZ.

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Modulation of redox potentials via AMHB in fused ring heterocycles

Analysis of the AMHB redox modulation of fused ring systems requires consideration of

resonance in both the directly contacted ring, and the second remote ring to understand how H-

bond formation perturbs the whole -system. Figure 3A shows an example illustrating this issue.

When 1 dimerizes (the second monomer is not shown), resonance Form I is enhanced which

increases the aromaticity of the first ring. However, this resonance picture does not help to

understand the perturbation of the -electrons of the second ring. By rotating the -electrons

around the first ring, resonance Form II is obtained that highlights the 6π electron delocalization

(also known as Clar sextet)17 in the second ring. Hence, 1 should have a stronger H-bond,

compared to a reference compound that is not capable of increasing aromaticity in both rings upon

H-bond formation. An estimate of the energetic magnitude of this effect is obtained by considering

the reference compounds 1’ and 1” (Figure 3B, Case A), in which one of the two bonds in the

second ring is hydrogenated, breaching its aromatic Clar sextet. Indeed, the H-bonded dimerization

energies of both 1’ and 1” are about the same and about 4 kcal/mol weaker than that of 1. In

contrast to 1, in 2 and 3, the aromaticity of the second ring’s Clar sextet is weakened upon H-bond

formation. Thus, the H-bond strengths of 2 and 3 are 2-3 kcal/mol weaker than their reference

compounds (2’, 2”, 3’ and 3”). These calculations provide strong evidence for the polarization of

remote aromatic rings via AMHB, an effect that acts in both directions and cannot be described by

simply counting -electrons. As in the previous cases, variations in NICS(1)ZZ values support the

above resonance-based rationalizations.

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Figure 3. Interpreting AMHB in fused rings. A) An example where the AMHB effect is further

enhanced by the presence of the second aromatic ring; B) Two further examples evaluating the

magnitude of the AMHB effect in fused rings where the disruption of the second ring’s aromaticity

disfavors H-bonding when the second ring is fully unsaturated. Calculations were performed at the

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DF-MP2/aQ5Z//MP2/aDZ level. Aromatic Clar sextets are shown in red. The H-bonds form via

dimerization, and the dimers are not fully shown.

Based on the hypothesis described in the introduction, the reduction of compound 4 should

be favored in the presence of H-bonding to formic acid. The calculated H-bond energy of 4 to

formic acid is -16.41 kcal/mol (Figure 4, blue number). For 4H2, the reduced form of 4, this

association is 3.84 kcal/mol stronger (Figure 4, right column). This energy difference can also be

interpreted as the amount the reduction reaction is favored in the presence of H-bonding to formic

acid. The numbers under the reaction arrows show the reduction reaction energies in the absence

(black) and presence (blue) of H-bonding to formic acid. The NICS(1)ZZ value changes (numbers

inside rings) upon H-bond formation suggest that the paratropicity (antiaromaticity) of both rings

in 4 are increased, whereas the diatropicity (aromaticity) of those of 4H2 are increased consistent

with the hypothesized (anti)aromaticity changes using the AMHB concept. The numbers next to

each ring show the corresponding calculated NICS(1)ZZ values. Similarly, the changes in reduction

energetics for compounds 5-11 in the presence of H-bonding to formic acid can be explained by

the increased aromaticity of both rings in the 5H2-11H2 upon H-bond formation. As in 4, in 5, 6, 9

and 11 the antiaromaticity of both rings is amplified upon H-bonding. In 7, 8, and 10, however,

the two rings are not cross-conjugated, so they act more independently like the monocycles in

Figure 2. In the latter group, ring I gains some aromaticity while ring II becomes more

antiaromatic upon H-bond formation. This explains the smaller effect (-2.18 to -2.72 kcal/mol) in

the latter group than in the former (-3.84 to -6.37 kcal/mol). Evidently, the reason the two rings

cannot act independently in the former set is that their -systems are “interlocked” by exocyclic

double bonds in opposite directions at the ring junctions.

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The AMHB modulations of redox potentials of compounds 12-24 can be analyzed in a

similar fashion. In 12H2-24H2, the aromaticity of ring I is enhanced upon H-bond formation as is

evident from their large and negative NICS(1)zz values (see numbers inside rings). However, the

NICS(1)ZZ values of ring II in these compounds only suggest a small increase of aromaticity

upon H-bonding, in contrast to the aromaticity change anticipated from AMHB. Similar problems

with NICS(1)ZZ calculations on fused rings have been mentioned in the literature.18 Despite this

ambiguity, the AMHB effect on the redox energetics in 12-24 can be understood. In these cases,

since the aromaticity of the two rings is not uniformly enhanced upon H-bonding in the reduced

forms 12H2-24H2, the favorability of the reduction reaction upon H-bond formation needs a more

detailed analysis of the starting materials 12-24. Among these, in 12, 13, 16, and 21, while the

aromaticity of ring I is enhanced upon H-bonding, the antiaromaticity of ring II is relieved, which

favors these oxidized forms and hence disfavors the reduction reaction (positive numbers in the

right column). Compounds 22 and 24 also belong to this group, yet for them, reduction is favored

by H-bonding. Presumably the proximity of the OH groups of ring II to the H-bond acceptor of

formic acid in 22H2 and 24H2 enhances H-bonding in these cases compared to, e.g. 21H2. Again,

the opposing NICS(1)zz values are not consistent with the anticipated antiaromaticity relief for

the reasons described above. For 14, 15, 17, 18, 19, 20 and 23 the antiaromaticity of both rings is

increased upon H-bonding which disfavors the starting material and thus favors the reduction

reaction as seen from the negative H-bond-induced reduction energy changes in the right column.

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Figure 4. Examples describing the AMHB effect on redox potential of fused rings. Energies

were calculated at CCSD(T)/CBS//MP2/aDZ. Black numbers bellow arrows are reduction

energies of the heterocycles without (black) and with (blue) H-bonded formic acid. Green and

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red numbers below rings represent diatropic and paratropic NICS(1)ZZ values, respectively while

numbers inside the rings show the NICS(1)ZZ values upon H-bonding with formic acid.

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Figure 4. Cont’d.

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Figure 4. Cont’d.

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The flavin nucleus is a biologically relevant cofactor whose redox chemistry might be modulated

via AMHB as explored in this paper. A quick survey of the protein data bank (PDB) reveals that

flavin H-bonds in different ways in different proteins’ active sites. Four examples19–22 of such

complexes are shown in Figure 5.

(a) flavin oxidoreductase (b) monooxygenase

(c) flavin reductase PheA2 (d) oxidoreductase from Helicobacter pylori

Figure 5. Four examples of flavin forming H-bonds in active sites of proteins.

Flavin can H-bond in two modes which are shown as cases I and II (Figure 6). In case I, the

aromaticity of rings II and III is increased upon H-bonding. This is consistent with the calculated

negative ∆NICS(1)zz values for these rings (see numbers inside the corresponding rings). A

resonance form consistent with these magnetic changes is shown in Figure 6. In this resonance

form, the sum of rings II and III is similar to naphthalene, a bicyclic 10 electron aromatic

compound. This favorable interaction with the oxidized form stabilizes the starting flavin,

disfavoring the reduction by 0.32 kcal/mol. Conversely, in case II, H-bond formation favors a

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resonance form in which the rings II and III are not aromatic, again consistent with the calculated

∆NICS(1)ZZ values (see numbers inside rings). As a result, the starting material’s -system is

destabilized while the product is stabilized, favoring reduction by 1.67 kcal/mol. Thus, the active

site binding modes found in the protein pockets of various flavin binding enzymes could

potentially adjust the redox potential over this nontrivial range via the AMHB mechanism.

Figure 6. AMHB modulation of redox potential for the flavin case. Energies were calculated at

CCSD(T)/CBS//MP2/aDZ.

In related chemical studies, Breinlinger et al. have shown that three-point H-bond formation with

various 2,6-diaminopyridines can modulate the experimental one-electron redox potential of flavin

by up to 155 mV.23 Though we have not explored the one-electron redox processes discussed in

their elegant paper, such substantial shifts in redox potential are consistent with the energetics

computed herein and rationalized via the AMHB concept.

CONCLUSIONS

Modulations of the redox potential of heterocycles can be explained and potentially rationally

engineered using the AMHB concept. While these modulations can be as large as 6 kcal/mol, they

are small enough in other cases that other competing effects, such as other intramolecular hydrogen

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bonds, may dominate their energy landscapes (cf. 22 and 24). For flavin, with its tricyclic polyaza

heterocyclic structure, the AMHB/redox potential effect is discernable and consistent with related

studies of H-bonding. However, the effects are modest and their interpretation and attribution to

AMHB is not as straightforward as in the simpler mono- and bicyclic cases examined herein.

Nonetheless, the AMHB notion offers a tool for design of H-bonding systems of varying strengths

which we hope will be of use to those building self-assembling systems.

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COMPUTATIONAL DETAILS

All the geometries were optimized at the MP224–28/aDZ29–33 level of theory, with the core

electrons frozen. Frequency calculations were performed to confirm the stationary nature of the

minima; most final structures satisfied the default geometry convergence criteria in Gaussian1634

after frequency calculations. These default values for Maximum Force, RMS Force, Maximum

Displacement, and RMS Displacement were , , , and 4.5 × 10 ―4 3.0 × 10 ―4 1.8 × 10 ―3 1.2 ×

respectively. In cases where not all the four criteria were converged, if the Maximum Force 10 ―3

and RMS Force were smaller than and the geometries were accepted as 4.5 × 10 ―4 3.0 × 10 ―4

optimized. This exception was only used in cases where even optimizations with calculation of a

new Hessian at each point did not resolve the issue and Gaussian16 itself accepted those

geometries.

Using the optimized geometries, the wavefunction-based scheme recommended by Burns

et al.35 was used to obtain reference H-bonding interaction energies in the gas-phase.

𝐸𝐶𝐶𝑆𝐷(𝑇)𝑎𝑝𝑝𝑟𝑜𝑥. = 𝐸𝐷𝐹 ― 𝐻𝐹/𝑎𝑄𝑍

𝑒𝑙𝑒𝑐. + 𝐸𝐷𝐹 ― 𝑀𝑃2/𝑎𝑄5𝑍𝑒𝑥𝑡𝑟𝑎𝑝𝑜𝑙. + 𝛿𝐶𝐶𝑆𝐷(𝑇)/𝑎𝐷𝑍

𝑀𝑃2/𝑎𝐷𝑍

The scheme is based on density-fitted36–44 Hartree-Fock (DF-HF)45 electronic energies calculated

at DF-HF/a5Z, , DF-MP2 correlation energies extrapolated from aQZ to a5Z (abbreviated EHF/aQZelec.

as DF-MP2/aQ5Z), , and CCSD(T) 46–50/aDZ additional correlation energies, EMP2/aQ5Zextrapol.

, added on top of those of DF-MP2. The sum of these three components gives an δCCSD(T)/aDZMP2/aDZ

approximation of the CCSD(T) energies extrapolated to the complete basis limit (CBS), denoted

as in the above equation. The extrapolation scheme used for the DF-MP2 calculations is ECCSD(T)approx.

that of Halkier et al.51 in the form below

Ecorr.n = Ecorr.

∞ + An ―3

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in which is the cardinal number of the Dunning basis set, is the calculated correlation energy n Ecorr.n

using that basis set, is a constant, and is the extrapolated correlation energy at a cardinal A Ecorr.∞

number of infinity. By using two basis sets with consecutive cardinal numbers of n and n+1, the

equation can be solved for Ecorr.∞

Ecorr.∞ =

(n + 1)3Ecorr.n + 1 ― n3Ecorr.

n

(n + 1)3 ― n3

In our case where cardinal numbers n = 4 and n + 1 = 5 are used, the equation simplifies as follow

EDF ― MP2/aQ5Zextrapol. = Ecorr.

∞ = 125 × Ecorr.

a5Z ― 64 × Ecorr.aQZ

61

After calculating the for each monomer and dimer, the electronic dimerization energies, ECCSD(T)approx.

, were calculated as∆dimE

∆dimE = ECCSD(T)approx. (dimer) ― 2 ECCSD(T)

approx. (monomer)

in which the denotations are obvious. For the structures in Figure 1, the was not 𝛿𝐶𝐶𝑆𝐷(𝑇)/𝑎𝐷𝑍𝑀𝑃2/𝑎𝐷𝑍

calculated due to the large size of the systems. The energy calculations were performed using

Molpro.52,53

was used as an index of (anti)aromaticity throughout this work. Here, the NICS(1)zz

number 1 means that the probe is placed 1 Å above the center of the ring and the zz subscript

means that only the zz tensor of the calculated magnetic shielding is considered, minimizing the

contributions of the sigma electrons.15 The calculations were performed at the NICS(1)zz

mPWPW91/6-311++G(3df,3pd) level of theory. Since these calculations are essentially NMR

calculations, the choice of method was guided by benchmark study of 1H NMR calculations by

Lodewyk et al.54 These authors have shown that the root mean square deviation (RMSD) of

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chemical sifts calculated at mPWPW91/6-311+G(2d,p) is only 0.16 ppm from a wide range of

experimental 1H NMR values. Here, the larger basis set 6-311++G(3df,3pd) was used.

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ACKNOWLEDGMENTS

This research was supported by National Science Foundation (award number CHE-

1362812). We thank the staff at Michigan State University’s Institute of Cyber-Enabled Research

(iCER) for their technical support.

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Figure 1. Illustration of opposing AMHB effects on starting material and product of a reduction

reaction that converts an antiaromatic to an aromatic -cycle.

Figure 2. Examples demonstrating the AMHB effect on redox active heterocycles. Energies (in

kcal/mol) were calculated at the CCSD(T)/CBS//MP2/aDZ level. Numbers inside rings are

NICS(1)ZZ values calculated at mPWPW91/6-311++G(3df,3pd)//MP2/aDZ.

Figure 3. Interpreting AMHB in fused rings. A) An example where the AMHB effect is further

enhanced by the presence of the second aromatic ring; B) Two further examples evaluating the

magnitude of the AMHB effect in fused rings where the disruption of the second ring’s aromaticity

disfavors H-bonding when the second ring is fully unsaturated. Calculations were performed at the

DF-MP2/aQ5Z//MP2/aDZ level. Aromatic Clar sextets are shown in red. The H-bonds form via

dimerization, and the dimers are not fully shown.

Figure 4. Examples describing the AMHB effect on redox potential of fused rings. Energies

were calculated at CCSD(T)/CBS//MP2/aDZ. Black numbers bellow arrows are reduction

energies of the heterocycles without (black) and with (blue) H-bonded formic acid. Green and

red numbers below rings represent diatropic and paratropic NICS(1)ZZ values, respectively while

numbers inside the rings show the NICS(1)ZZ values upon H-bonding with formic acid.

Figure 5. Four examples of flavin forming H-bonds in active sites of proteins.

Figure 6. AMHB modulation of redox potential for the flavin case. Energies were calculated at

CCSD(T)/CBS//MP2/aDZ.

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