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Jun 17, 2016 - Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, Karnataka, India. •S Supporting Information...
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Computational Studies on Structural, Excitation, and ChargeTransfer Properties of Ureidopeptidomimetics Sherin Joy, Vommina V Sureshbabu, and Ganga Periyasamy* Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, Karnataka, India S Supporting Information *

ABSTRACT: Peptides with ureido group enclosing backbones are considered peptidomimetics and are known for their higher stabilities, biocompatibilities, antibiotic, inhibitor, and charge-transduction activities. These peptidomimetics have some unique applications, which are quite different from those of natural peptides. Hence, it is imperative to appreciate their properties at a microscopic level. In this regard, this work outlines, in detail, the charge transfer (CT) properties, holemigration dynamics, and electronic structures of various experimentally comprehended ureidopeptidomimetic models using density functional theory (DFT). Time-dependent DFT and complete active space self-consistent field computations on basic models provide the necessary evidence for the viability of CT from the end enfolding the ureido group to the other end with a carboxylate entity. This donor-to-acceptor CT has been reflected in excitation studies, in which the higher intensity band corresponds to CT from the π orbital of the ureido group to the π* orbital of the carboxylate entity. Further, hole-migration studies have shown that charge can evolve from the ureido end, whereas the hole generated at the carboxylate end does not migrate. However, hole migration has been reported to occur from both ends (amino and carboxylate ends) in glycine oligopeptides, and our studies show that the ability to transfer and migrate charge can be tuned by modifying the donor and acceptor functional groups in both the neutral and cationic charge states. We have analyzed the possibility of hole migration following ionization using DFT-based wave-packet propagation and found its occurrence on a ∼2−5 fs time scale, which reflects the charge-transduction ability of peptidomimetics.

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INTRODUCTION Energy transfer and charge transfer (CT) in biomolecules are robust and directional phenomena, accountable for countless functional as well as pathological cellular processes, including respiration, photosynthesis, signal transduction in proteins, and so forth.1,2 The observed CT in natural proteins3 led researchers to synthesize a number of artificial analogues that can mimic one or more functions of their natural counterparts.4,5 These synthetic analogues are called peptidomimetics and are potentially used in catalysis, biosensors, electronic devices, and drug synthesis on the basis of their conducting and CT natures.6,7 Peptidomimetics and their applications have been extensively studied using various experimental and theoretical methods.8,9 Ureidopeptidomimetics (UPs) are one among synthetic peptidomimetics,10 in which a peptide bond is replaced with a ureido group. The presence of a ureido group has proven to enhance the metabolic stability and probereceptor specificity for drug binding.11 UPs have also been found to act as HIV-1 protease inhibitors12,13 and are betterknown as antibiotics.4 UPs have been synthesized with various substituents, ranging from organic (carboxylic groups, amines, etc.)14,15 to inorganic (ferrocene units)16 functional groups. Their metabolic stability, permeability, and thus longer degrading time make these peptidomimetic compounds prospective candidates for drug development.17 Therapeutic © XXXX American Chemical Society

applications require a microscopic-level understanding of these mimetics, which can be achieved using density functional theory (DFT) methods. This work focuses on tracing the electronic structure, excitation properties, and hole-migration dynamics for a few experimentally realized UP models using computational tools. Many distinct functions of natural proteins, like energy transfer and signal transduction, are dominated by the CT process.18 CT happens either because of excitation of molecules by the absorbance of photons or as a result of the occurrence of some redox (oxidation/reduction) processes. In general, in biological systems, CT is predicted to happen via bond or space.19 The former involves transfer of electrons through regular bonds, and the latter involves weak interactions, like electrostatic interactions, hydrogen bonds, halogen bonds, van der Waals interactions, and so forth.19−22 In peptides, CT is believed to happen through the bonds from electron-rich to -deficient centers.23 In this respect, intra- and intermolecular CT through a large number of peptides and modified peptide systems have been investigated over the years.24 Specifically, in some bi- and tripeptide models, hole-migration dynamics have Received: March 2, 2016 Revised: June 10, 2016

A

DOI: 10.1021/acs.jpcb.6b02210 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry B been studied and proven to occur within a 1.5 fs time scale.9 Although the phenomenon of CT has been known for a long time, experimental and computational realization of this phenomenon in biomolecules like proteins is a difficult task. This is due to the complexity in the structures of the bioentities and the ultrafast time scale in which charge is transfered.25,26 Hence, biomimetics, such as modified peptides,27 polypeptides,28 and peptide nucleic acids,29 have been synthesized and the CT mechanism explored, which provokes its comparison with signal transduction through a protein chain in biological systems.30 Charge is transferred from the donor end to the acceptor end through a bridge, which is a covalent linkage in this case.2 The CT phenomenon is significant because it can be applied to sensors and other electronic devices. Further, recent technological advancements have enabled monitoring of electron-/ hole-migration dynamics in a faster time scale (atto/femto).31 Keeping this in mind, we have attempted to probe the time scale for hole migration through peptidomimetics (UP) after immediate ionization. Further, the optical properties of these ureidopeptides have also been explored, which arise because of an electron-rich urea moiety at one terminal and a carboxylate entity at the other. Certain forms of UPs have already been synthesized and characterized.32 Some of their properties, like their ability to act as catalysts 7 and protease inhibitors, 13 self-assembly, 15 fragmentation pattern,33 and so forth, have been studied extensively.34 Nevertheless, a few others, including electronic structure, charge distribution, CT, and optical properties, have not been investigated. Hence, theoretical methods have been used to study these properties, which are important for understanding the nature of UPs.

population scheme56 has been used to analyze the charge distribution in optimized molecules. The oxidation properties of UPs are studied by calculating vertical ionization energy (VIE) and adiabatic ionization energy (AIE) values using the equations given below VIE = E′(N − 1) − E(N); AIE = E(N − 1) − E(N)

where E(N) is the energy of an optimized neutral molecule with N electrons, E′(N−1) is the energy of a cation present in the neutral (N electron) geometry, and E(N−1) is the energy of an optimized cation with (N − 1) electrons. Further, hole migration after ionization is explored by measuring the time scale for evolution of the hole created after vertical ionization.21,41 Time evolution of the hole created by ionization can occur at a much faster time scale than that for nuclear dynamics. Hence, frozen frame nuclei at the vertical ion (VI) point have been considered to solve the time-dependent Schrödinger equation. In this method, the cationic states are approximated by Kohn−Sham (KS) orbitals, resulting from solving cationic KS-DFT equations.42 Vertical ionization creates a localized hole in the molecule. Hence, the hole is created using neutral KS orbitals, most probably at the highest occupied molecular orbital (HOMO). However, this orbital of a neutral molecule is not the stationary orbital of the cation, and the hole charge density evolves in time. Time propagation of hole density can be monitored by projecting the HOMO of the neutral molecule on the stationary molecular orbitals of the cation at a fixed neutral geometry of the complex. This procedure of probing hole-migration dynamics was first introduced by Levine and Remacle, and we have closely followed their procedure.9 The molecular orbitals obtained using all three functionals for cationic and neutral states are alike. Moreover, the wave functions of both charge states are calculated using CASSCF methods, with an active space of 6 (neutral) or 5 (cation) electrons and 10 orbitals to validate the wave functions obtained using DFT methods. Comparisons of the neutral and cationic molecular orbitals of a model (M1) analyzed using three functional are given in Tables S3 and S4, respectively. The expression given below (eq 1) defines the initial nonstationary hole orbital, |ψ(0)|, in which N represents the number of atomic basis orbitals, which are stationary states of the λth molecular orbitals. ψMO is the molecular orbital of the neutral molecule in which the hole is generated (in the majority of cases it is the HOMO), whereas ϕλ is the λth cationic molecular orbital

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COMPUTATIONAL METHODS All of the models reported here are optimized using DFT, with a number of long-range electron−electron-interaction-corrected hybrid functionals, such as CAM-B3LYP,35 wB97XD,36 and M06-HF,37 and the 6-311++G** all-electron basis set, as implemented in the Gaussian 09 package.38 The structures are characterized as minima or maxima on the basis of frequency analysis. The presence of all real frequencies confirms the structures as minima. Various conformers are generated by changing the dihedral angles of significant bonds between 0 and 180°. Energetics are analyzed using all three functionals, and the lowest energy conformers are considered for CT studies (Table S1 in the Supporting Information). A comparison of computed structural parameters and energies using three functionals (CAM-B3LYP, wB97XD, M06-HF) is given in Table S2. The computed values show that changing the functional does not change the results considerably. Hence, we have discussed the results observed for the CAM-B3LYP functional in the following section. Excited-state calculations are carried out using the CAM-B3LYP functional with timedependent density functional theory (TDDFT).39 For similar types of molecules, like dipeptides, β-dipeptides, and tripeptides, CAM-B3LYP has proven to give better descriptions of excitation energies, without any correlation between error and spatial orbital overlap (λ values).40 Further, the first five excitation energies are computed using complete active space self-consistent field (CASSCF)55methods, with an active space of 6 electrons, 10 orbitals. Both the TDDFT and CASSCF methods are found to produce results that are comparable, and both are observed to follow the same trend. The natural

N

|ψ (0)⟩ =

∑ ⟨φλ|ψMO|φλ⟩

(1)

λ=1

After time t, the hole orbital can be represented by including a time-dependent phase factor, as shown in eq 2 N

| ψ (t )⟩ =

∑ ⟨φλ|ψMO⟩ exp(−iEλt /ℏ|φλ⟩ λ=1

(2)

The hole orbitals associated with α and β spins can be represented using the equations given below. |ψα(t)⟩ and |ψβ(t)⟩ are the hole orbitals associated with spins α and β, given in eqs 3 and 4, respectively, and both equations are applied to calculate hole migration. They reflect the same trend. Hence, hole migration on cation α orbitals are reported only in the results B

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|ψα(t )⟩ =

∑ ⟨φαλ|ψMO⟩ exp(−iEλαt /ℏ|φαλ⟩ λ=1

bond lengths and bond angles, for the lowest-energy conformers are given (Figures 2 and 3). Moreover, computed vibrational normal modes go hand in hand with the experimentally observed ones (Table 1).32,47,50 The slight differences observed are predicted to be due to the removal of protecting groups and lack of a physical environment for the computed models. 2. Similar to that reported for natural oligopeptides, charge separation at both ends is observed in these synthetic analogues. 3. Natural population analyses (NPA) have been carried out on the neutral state of the models to understand the atomic charge distribution and orbital populations of molecular-orbital wave functions.51 They show that the end holding the ureido group has an increased electronegativity in all UP models; hence, the ureido group has the capability of acting as a donor group (Table 2). 4. The computed higher Δ values (HOMO−LUMO, 8.00− 9.00 eV) indicate enhanced chemical stability of these molecules (Table 3). 5. In general, two types of excitations are observed in all neutral UP models, one that corresponds to the π to π* transition and another that corresponds to the n to π* transition. The former excitation is observed to be from the localized π orbital of the ureido group to the π* orbital on the carboxylate entity. The latter is from the lone pair of electrons on hetero atoms at the ureido moiety to the π* orbital (Table 4). Similar types of transitions with a single excitation peak are observed in CASSCF, and the computed excitation energies in both methods are comparable. 6. The VIEs and AIEs are calculated to understand the extent of structural variation after ionization. The energy differences between the VIE and AIE (Table 3) are very small, which shows the minimal structural difference due to the relaxation of ionized states. This is evident from the computed structural parameters of the neutral and cationic states (Table 5 and Figures S2 and S3). This supports probing hole-migration dynamics by the frozen nuclei approach, in which nuclear relaxation is ignored. 7. The computed AIEs for various UP models are around 8−9 eV, which is lower than those for basic alkyl amino acids (∼9−12 eV).52 Certain features that are unique to each model have been analyzed meticulously in the following section. Model 1 (M1). The study began with M1, which is similar to natural glycine peptides. It is experimentally synthesized as (Figure S1) an Nα-Fmoc-protected ureidopeptide (Fmoc− Ala−ϕ(NH−CO−NH)−Phe−OCH3). To reduce the computational cost, Fmoc protection is modeled as a CH3 group, and it has a ureido group at one end and carboxylate ester at the other, separated by one α-CH2 group (Figure 1). Steric hindrance in the folded conformer makes the linear structure with one strong intramolecular H-bonding interaction lower in energy by 2.2 kcal mol−1. Strong intramolecular H-bonding is observed in ureido N−H···O−carboxylate (2.225 Å). The presence of H-bonding increases the bond lengths of N−H (1.020 Å) and CO (1.213 Å) compared to those in free urea (1.008 Å) and carboxylate (1.202 Å), respectively. The observed structural change is also reflected in the computed vibrational frequencies, υN−H and υCO (Table 1). Molecular

(3)

N

|ψβ(t )⟩ =

∑ ⟨φβλ|ψMO⟩ exp(−iEλβt /ℏ|φβλ⟩ λ=1

(4)

Hole migration, studied in this work using peptide models, occurs over covalent bonds, and the contributions of weak (long-range and H-bonding) interactions are minimal. Hence, DFT-based approximations seem appropriate to probe this migration. Moreover, the computed excitation energies and patterns, with more than 80% contribution from a single orbital excitation, are similar to TDDFT results, which supports the use of DFT-based wave-packet propagation methods for these molecules. The models studied are listed in Figure 1.

Figure 1. Schematic representation of the various UP models studied in this work (corresponding synthesized molecules and their complete structures are given in Figure S1).

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RESULTS AND DISCUSSION Urea is a nitrogen-enriched molecule that can easily be prepared and expended. The ureido group holds an amide unit with a peptide bond, which can replace the same in natural proteins.43 With its lone pair of electrons present above and below the molecular plane, urea is found to behave as a donor or acceptor, depending on the groups to which it is attached in its CT complexes and clusters.44,45 Urea is also a known example of a hydrogen-bond donor and acceptor and thus is used in molecular self-assembly. This property makes it interact with protein structures effectively and causes denaturation of proteins and even nucleic acids in aqueous medium.20,45 Consequently, peptide bonds replaced with urea can be expected to interact more efficiently with proteins. These features can be inherited by ureido analogues, which have a proficiency at transferring charge. This interaction may increase or decrease with respect to the nature of the moieties, which can influence the phenomenon of CT and the time scale for hole migration through them. Herein, we have chosen models that have been synthesized by various groups.46−49 The similarities in properties, observed for all UP models studied in this work, are illustrated below. 1. Various conformers are optimized using dispersioncorrected CAM-B3LYP, wB97XD, and M06-HF hybrid functionals. Computed structural parameters, such as C

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Figure 2. Optimized structures of different UP models in the neutral and cationic charge states. Important structural parameters (bond distances (Å) and bond angles (°)) are shown.

Figure 3. Optimized structures of derivatives of M1. Important structural parameters (bond distances (Å) and bond angles (°)) are shown. Note that M1a and M1b molecules have two conformers within a 1 kcal mol−1 energy difference, and the stabilities of the conformers have been swapped in the M06-HF functional; hence, both conformers are considered for CT analysis.

orbital analyses of the neutral entity indicate that the valence orbitals are localized at the ureido and carboxylate functional

units (Figure 4), which suggests the possibility for a local ionization. The larger difference in natural charge between the D

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The Journal of Physical Chemistry B Table 1. Computed Vibrational Frequencies (cm−1) for Different UP Modelsa

a

models

υC−O (ureido group) (cm−1)

υN−C (cm−1)

υN−H (cm−1)

urea M1 M1a-1 M1a-2 M1b-1 M1b-2 M1c M2 M3 M4 M5 M6

1826/1610* 1783 1790 1783 1791 1788 1790 1775 1766/1667* 1765/1646* 1766 1784

1439/1242* 1593 1587 1592 1584 1590 1584 1593 1511 1526 1509 1489

3618/3396* 3625 3642 3674 3641 3688 3659 3645 2792/3431* 2793 2801 2821

υC−O (carboxylate) (cm−1) 1830 1836 1831 1834 1835 1833 1824 1795 1754 1818

Experimental values are given in italics.

nm (Table 4). Excitation at a higher wavelength corresponds to the π to π* transition from HOMO − 1 localized at the ureido group to LUMO + 2 localized at the carboxylate entity (Figure 4). A lower wavelength is related to the n to π* transition from HOMO − 2 to LUMO + 2, which substantiates the possibility of urea being the donor and carboxylate being the acceptor. Following this, hole migration, followed by redox processes (ionization), is monitored by generating a localized hole at both the ureido and carboxylate ends and propagating it on stationary orbitals of the cation at a fixed neutral geometry. To justify the cation wave functions and geometries, groundstate cation geometries are reoptimized using CASSCF calculations, and the results are given in the Supporting Information. DFT and CASSCF wave functions of cations are comparable, as reported for M1 in Table S4. The spin densities at the vertical and adiabatic ionization states are studied using all three functionals and found to be predominantly located on the ureido group (Table S5). Subsequently, the dynamics of hole migration is studied after immediate ionization by ignoring the nuclear relaxation, as proposed by Levine and Remacle.9 Ionization of a neutral molecule (singlet) at a given point of time produces a doublet cationic state, which has a localized spin density on the ureido group (π-orbital, t = 0 in Figure 5). The hole formed at the ureido group is seen to migrate from the ureido group to the carboxylate entity in 1.5 fs and remain there until 2.3 fs. It starts migrating back and reaches the initial point at 2.9 fs (Figure 5). The hole-density picture proposes the participation of energetically low-lying carboxylate orbitals in this migration process. To understand the possibility of charge migration in the reverse direction, a hole is created at the carboxylate end and propagated over the time scale. The results show that the hole created at the carboxylate end does not migrate to the ureido end because of the ureido group being more negatively polarized (Figure S4), which contradicts the reported bidirectional charge flow in glycine oligopeptides.27 In other words, our results show that the hole cannot evolve when created at the carboxylate end. The time scale of 2.9 fs for hole migration from the ureido end to the carboxylate end in M1 is slightly longer than that reported for oligopeptides, 1.5 fs.9 To correlate these differences, the model is modified by diverse substitutions at both ends. Initially, the α-carbon is modified (M1a−M2), followed by alteration of the functional units at both terminals. The influence of these reformations has been discussed below.

Table 2. Computed NPA Values of Both Ureido and Carboxylate Groups in Different UP Models Carried Out Using the CAM-B3LYP Functional models

ureido group

carboxylate group

M1 M1a-1 M1a-2 M1b-1 M1b-2 M1c M2 M3 M4 M5 M6

−0.202 −0.230 −0.229 −0.202 −0.230 −0.197 −0.192 −0.191 −0.245 −0.188 −1.074

0.001 −0.021 0.001 0.006 0.003 0.008 0.011 0.057 −0.206 −0.007 −0.213

Table 3. Computed Δ (LUMO−HOMO), VIE, and AIE Values for Different UP Models Using the CAM-B3LYP Functionala models

Δ, (eV) (LUMO−HOMO)

VIE (eV)

AIE (eV)

time scale for one cycle (fs)

M1 M1a-1 M1a-2 M1b-1 M1b-2 M1c M2 M3 M4 M5 M6

9 9 9 9 9 9 8 9 7.5 9 9

9.208 9.011 9.056 9.034 9.044 9.000 9.014 9.023 9.112 9.005 9.019

8.933 8.831 8.247 8.634 8.520 8.607 8.731 8.235 8.250 8.551 8.621

2.9 2.5 5 2.6 5.2 2 2.4 1.8

a

The time scale for evolution of hole through cation stationary orbitals of different models are shown. For M4, M5, and M6 the holemigration studies are not carried out.

functional units at both ends propose a CT from the electronrich ureido group to the electron-deficient carboxylate entity. The lowest unoccupied molecular orbital (LUMO) is seen to be localized at the carboxylate end. This orbital picture further supports a probability for end-to-end CT. To understand CT due to absorption of light, excitation energies are calculated for neutral stable conformers using the TDDFT and CASSCF methods. Excited-state computations show the presence of two intense peaks around 173 and 184 E

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Table 4. Computed Excitation Energies (eV) and Wavelengths (nm) of Different Models Using TDDFT and CASSCF Methods TDDFT n to π*

models M1 M1a-1 M1a-2 M1b-1 M1b-2 M1c M2 M3 M4 M5 M6

7.155 7.093 7.099 7.186 7.232 7.156

CASSCF π to π*

(173) (172) (175) (173) (175) (173)

6.712 6.442 6.351 6.821 6.944 7.032 6.498 6.521 5.975 6.989

6.912 (179)

n to π*

(184) (192) (195) (194) (192) (176) (191) (190) (208) (177)

7.299 8.150 8.274 8.628 7.528 8.579

π to π*

(170) (152) (150) (144) (165) (145)

6.933 (179) 6.276 (198) 6.345 (195)/6.090 (204) 7.021 (177) 7.123 (175) 8.015 (155) 7.094 (175) 6.383 (194) 7.740 (160) 7.442 (167)

7.395 (168)

5.461 (227)/5.295 (234)

5.828 (213)/4.526 (274)

Table 5. Computed Structural Parameters for Neutral and Ionized States of Different Models Using the CAM-B3LYP Functional models

functionals

N−H (Å)

N−C (Å)

C−O (urea) (Å)

C−O (carboxylate) (Å)

N−C−N (°)

M1

neutral cation neutral cation neutral cation neutral cation neutral cation neutral cation

1.012 1.019 1.008 1.011 1.016 1.026 1.030 1.015 1.030 1.032 1.021 1.024

1.373 1.361 1.374 1.371 1.402 1.401 1.395 1.395 1.408 1.434 1.411 1.431

1.226 1.204 1.228 1.227 1.232 1.248 1.222 1.223 1.223 1.223 1.211 1.212

1.212 1.214 1.213 1.212 1.218 1.226 1.221 (urea′) 1.222 (urea′) 1.222 1.202 1.207 1.211

115 114 115 115 116 122 115/115 115/114 115 114 114 115

M2 M3 M4 M5 M6

Figure 4. Computed excitation wavelength (nm); the molecular orbitals involved in the excitation of M1 are shown (orbitals are plotted with an isocontour value of 0.04 Å−3).

Figure 5. Snapshots of the evolution of hole density from the HOMO orbital of M1, which migrates back in 2.9 fs (densities are plotted with an isocontour value of 0.002 Å−3).

Models M1a-1, M1a-2, M1b-1, M1b-2, and M1c. The length between the donor and acceptor ends has been increased in M1a, as the length of the peptide chain is considered a parameter to evaluate the constancy of CT/hole migration as electrons travel across large distances in biological systems.53 Electronic structure calculations point out that the presence of three sp3 carbons constituting the bridge leads to two lowestenergy conformers within an energy difference of 1 kcal mol−1, a straight chain conformer (M1a-1) and a bent chain (folded) conformer (M1a-2), as shown in Figure 3. They vary from each other in terms of the presence of an intramolecular H-bonding

interaction (2.814 Å) between the ureido and carboxylate ends present in M1a-2. Both terminals align themselves in a stacking position to form this H-bond, which results from a rotational change in the β-sp3 carbon of the bridge. Additionally, the molecular orbitals lose their localized nature completely because of this Hbonding. Although they possess different electronic structures and orbital patterns, similar excitation patterns are observed in both conformers, with two prominent peaks for the neutral charge state. The peak around 172 nm corresponds to the transition from the lone pair (n) orbital of the end with the ureido group to the π* orbital of the carboxylate end, whereas F

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Figure 6. Computed excitation wavelengths and orbital pictures of conformers M1a-1 (a) and M1a-2 (b), respectively (orbitals are plotted with an isocontour value of 0.04 Å−3). The latter shows orbital delocalization due to H-bonding.

Model 2 (M2). The presence of a side chain at the α-carbon does not yield any new lowest-energy conformer, leaving the linear chain with one side bar. Similar to that in M1, an intramolecular H-bonding interaction with a 2.328 Å distance is observed in M2. Steric hindrance created by an ethyl side chain increases the H-bonding distance by 0.1 Å compared to that in M1. The excited-state transition observed in neutral M2 shows a small shift in wavelength for the π to π* transition. There is believed to be a contribution from the side chain toward the π orbital from which the transition is observed (Table 4 and Figure 7).

the other excitation corresponds to the π to π* transition. An increase in linker length shifted the wavelength of the π to π* transitions from 184 nm in M1 to 195 nm (Figure 6). Excitation studies show the possibility of a donor to acceptor CT. Similarly, the presence of a H-bond tunes the molecular orbitals of a cation, which is expected to affect the chargemigration process after ionization. Hence, hole-migration dynamics has been examined for other models after vertical ionization. In M1a-1, hole migration happens in 2.5 fs, which is lesser than the time scale required for M1. In M1a-2, the hole density reaches the other end, starting from the ureido group, within 0.9 fs, stays there until 3.6 fs, and returns within 5 fs, which is a longer time scale compared to that for other models studied in this work (Figure S5). The probable change is due to the structural bending of the molecule, which results in the requirement of a longer time scale for the orbitals to overlap. The effect of such rotational changes on polypeptides had already been reported.54 Distinctively, hole migration occurs through covalent bonds, and the presence of H-bonding only alters the energies of the orbitals that delay the phenomenon. Subsequently, the linker length is increased to check whether there is any change in the present scenario. Similar to M1a, M1b prefers two conformers and follows the same trend in hole-migration dynamics. However, further increase in the linker length reduces the possibility of folded conformers due to the presence of many sp3-hybridized carbon atoms constituting the bridge. As a result, the distance between the donor and acceptor is beyond the limit for a H-bond. Increasing the length of the chain by adding four CH2 groups did not alter the excitation energies and patterns of peaks considerably (Figures S6 and S7). After ionization, the hole in cationic M1c is seen to migrate from the ureido group to the carboxylate entity in 1.4 fs, return in 1.8 fs, and reach the initial point in 2.0 fs. Hence, the effect of linker is implicit, and it is suggested that the linear chain can facilitate hole migration via appropriate linear combinations of atomic orbitals overlap. To prove this fact further, a side chain is introduced at the αcarbon.

Figure 7. Computed excitation wavelength (nm) and orbital picture of M2 (orbitals are plotted with an isocontour value of 0.04 Å−3).

After ionization, the spin density is seen to be localized on the ureido group. The hole formed at the ureido group is seen to migrate from the ureido group to the carboxylate group in 1.6 fs; it remains there until 2.1 fs, then starts migrating back and reaches the initial point in 2.4 fs (Figure S8). Smooth migration of the hole from the ureido group to the carboxyl unit is disturbed by the presence of a side chain. The hole initially moves to the side-chain alkyl group, then to the G

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As hole migration is observed in M3, it is important to cognize the cause behind it. Hence, the −NHCOOCH3 and ureido groups in M3 are replaced with −CONH2 in M5 and an amide-substituted ureido group in M6. M3 and M5 differ from each other in the mode of coordination between NH and CO. M6 differs from M3 with regard to the presence of an extra NH2 group at the end with the ureido group. Excitation studies of these two neutral molecules, M5 and M6, demonstrate peak formation due to π to π* and n to π* transitions at 177/167 and 227/231 nm, respectively (Table 4). The orbitals involved in these transitions are delocalized over the molecules, which shows that both the ureido end and carboxylate end have similar energies. Hence, the possibility of a local ionization becomes marginal. This has been further supported by the presence of delocalized spin density at vertically ionized states (Figure S11). Thus, it is not possible to carry out holemigration studies for these molecules.

carboxylate entity. This provides additional proof for the preference of hole migration through bonds in these moieties. As noticed in M1, all of the models (M1a, M1b, M1c, and M2) prefer hole migration from the ureido group to the carboxylate entity. Similarly, the hole created at the carboxylate end does not migrate to the ureido group. Subsequently, donor and acceptor functional groups are varied on the basis of synthetic models and are studied. Model 3 (M3). In M3, the carboxylate group has been modified as −NHCOOCH3. N-Boc-N′-carbamoyl-gem-diaminoalkyl derivatives were synthesized and their crystal structures studied. The folded conformers are predicted to have the lowest energy compared to that of the linear structure. There are three N−H bonds, which are trans to the existing carbamoyl group, that are found to result in intramolecular and bidirectional intermolecular H-bonding (Figure 2). The intramolecular hydrogen bonding observed is between the ureido N−H···O−carboxyl (1.956 Å) closing an eight membered pseudo cycle. The computed IR frequencies are comparable to the experimental ones.46 The calculated HOMO−LUMO gap is 9 eV, similar to that for molecules in M1 and M2. Tuning of the acceptor end polarized the structure, which set a similar trend for charge separation at the donor and acceptor sites as that in the models mentioned above. Further, excitation studies show that there is a possible π to π* transition at 190 nm (Table 4), possibly due to loss of degeneracy of the π orbital localized at the end with the ureido group (Figure S9). The spin density is predominantly located at the end with the ureido group compared to the −NHCOOCH3 end, although it is delocalized to some extent on the bridge. This confirms the removal of an electron from the ureido group. The cationic αHOMO is seen to be delocalized, which provides a chance for the hole density to propagate from one end to the other, as reported for similar molecules.9 The hole is seen to migrate from the ureido group and reach the carboxylate entity in 1 fs. It stays there for 0.2 fs and returns to the donor group in 1.8 fs (Figure S10). This is the fastest time scale compared to that for other models studied in this work and might be appropriate for experimental studies. The faster time scale is suggested to be due to the suitable energy difference between the donor and acceptor ends. Although a H-bond is present in the structure, the trend in hole migration shows that it crosses each atomic orbital in covalent linkage before reaching either terminal. Other Models (M4, M5, and M6). Along with the studied models, other experimentally recognized models have been studied.47,48 In pace with the models mentioned above, the computed structural parameters for these molecules are comparable to the reported values. M4 has a ureido group at one end and a ureido-pyrimidinone unit at the other end, separated by two sp3 carbons. Although the functional units are different and one end is stabilized by a H-bonding interaction (1.984 Å) between the N−H group of pyrimidinone and the O group of ureido, both functional ends have similar energies. As a result, the molecular orbitals at the valence shells in neutral geometries are delocalized. In excitation studies, the observed peak corresponds to the transition from the delocalized π molecular orbital to the π* molecular orbital. Natural charge analysis further supports their delocalized nature, illustrating similar charge distributions at both ends. As a result, the possibility for localized ionization becomes minimal. This is apparent from the computed spin-density plot for the cationic state. Hence, hole-migration studies are not carried out for M4.

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CONCLUSIONS The computational study on various UP models shows that they possess similar electronic and structural properties and charge distributions. As previously observed in peptides, Hbonding interactions are found to stabilize the molecular orbitals of respective functional units. Excitation studies based on TDDFT and CASSCF computations proposed the obvious n to π* and π to π* CTs. The dynamics of hole migration has been verified using the DFT-based simple wave-packetpropagation algorithm. All UP models prefer hole migration from the ureido group to the carboxylate entity, and its occurrence in the other direction is not observed. The computed time scale for hole migration is reasonable. M3, with ureido group at one end and −NHCOOCH3 at the other end, possesses a smaller time scale compared to that in all other models. As mentioned earlier, the presence of delocalized orbitals prevents the possibility for local ionization and hole migration from one end to the other.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b02210. (i) Experimentally reported molecules for the models considered in this study; (ii) structural parameter comparison for three functionals; (iii) computed optimized structure of positively charged models with important structural parameters; (iv) computed cation orbitals and spin-density plots; (v) excitation plot along with wave function pictures for models M1b, M1c, and M3; and (vi) hole-migration plots for models M1a-2, M2, and M3 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the UGC-Major Research Project (UGC-MRP), DST-SERB, Junior Research Fellowship (JRF), and Faculty Recharge Programme (FRP) for funding. We also thank Dr. Atanu Bhattacharya (Department of Inorganic and Physical H

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Chemistry, Indian Institute of Science, Bangalore, India) for his support.

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