Why does thionating a carbonyl molecule make it a better electron acceptor? †

The past decade has witnessed a surge of biomedical and materials applications of thiocarbonyl molecules (R 2 C Q S), such as in photodynamic therapy, organic field-eﬀect transistors, and rechargeable batteries. The success of these applications originates from thiocarbonyl’s small optical gap in the visible region and the enhanced electron aﬃnity compared to the carbonyl analogues (R 2 C Q O). Although these observations seem to be contrary to the implication based on a simple electronegativity consideration (2.58 for sulfur and 3.44 for oxygen), a natural bond orbital (NBO) analysis gives a straightforward explanation for the LUMO-lowering eﬀect of C Q O - C Q S substitution. In comparison to the valence (2p) C /(2p) O interactions in C Q O, the higher 3p orbital of sulfur and its weaker overlap with the 2p level of carbon result in a weaker antibonding interaction in p (cid:2) C ¼ S NBO, a prominent contributor to the LUMO. Such an analysis also provides a semi-quantitative understanding of the electronic eﬀect of substituents on or in p -conjugation with a (thio)carbonyl functionality. The intuitive concepts uncovered here oﬀer a simple rule to predict the electronic properties of p -conjugated molecules that incorporate heavy heteroelements and would facilitate materials development.


Introduction
The discovery of Lawesson's reagent 1,2 for replacing oxygen with sulfur in a carbonyl functionality marks the boost of research interests in thiocarbonyl molecules (R 2 CQS, also known as thiones) in the second half of the 20th century.5][6] While these seminal reports revealed the fundamental properties of thiocarbonyl compounds, their applications in biomedical and materials chemistry were only uncovered recently.
The rapid singlet-to-triplet intersystem crossing of photoexcited thiocarbonyl compounds enables their use to sensitise oxygen into the reactive singlet form ( 1 O 2 ) to induce targeted cellular damage.][9][10] Given the long lifetime and high energy of the triplet excited states, thiocarbonyl chromophores also display photocatalytic activities comparable to common organometallic photocatalysts. 11For materials applications, Seferos and co-workers reported that the carrier mobility of n-type organic field-effect transistors (OFET) based on perylene diimide derivatives can be enhanced by thionation. 12Subsequently, performance enhancement has been observed for OFET using other thionated organic semiconductors, such as naphthalene diimide [13][14][15] and iso-diketopyrrolopyrrole. 16,17][22] It is conceivable that the versatile applications of thiocarbonyl compounds stem from their low optical gap (usually in the visible region) and enhanced electron affinity compared to carbonyl materials.Both properties are related to the lower energy level of the lowest unoccupied molecular orbital (LUMO), which often manifests experimentally in the more positive electrochemical reduction potentials of thiocarbonyls.4][25][26] These results, together with some earlier electrochemical data of non-chromophoric thiocarbonyls, suggest that the enhanced electron affinity is a general feature for this class of molecule.However, besides a proposal based on polarity comparison, 27 there is no discussion on the origin of the LUMO-lowering effect by thionation to the best of our knowledge.][30][31] Since the electron affinity, photoredox driving force, or electron transportation mobility of these thiocarbonyl materials are critically related to the LUMO level, it is important to elucidate the origin of the enhanced electron-accepting power from a theoretical point of view.An insightful understanding will facilitate the development of high-performance materials.By recognising the LUMO of all molecules in Fig. 1 features p-antibonding between the C and O/S centres of (thio)carbonyl, we took a minimalist approach and focused on the construction of the p-antibonding orbital p Ã C¼X (X = O or S) using the natural bond orbital (NBO) analysis. 32The LUMO-lowering effect of thiocarbonyls was found to originate from the weak interaction between (2p) C and (3p) S orbitals.We also demonstrate that this simple analysis can provide instinctive rationalisation to the effect of p-conjugated substituents on the electron-accepting power of (thio)carbonyl derivatives.

Method
Since the electrochemical reduction potential (E RED ), as a measure of the electron-accepting power of a molecule, is empirically found to correlate with the energy of lowest unoccupied molecular orbitals (E LUMO ) computed by density functional theory (DFT), 33,34 we analyse the title question by examining the effect of CQO -CQS substitution on LUMO.This canonical molecular orbital can be expressed in terms of a complete orthonormal set of localised NBOs.For (thio)carbonyl compounds, such a combination can be explicitly written as: Furthermore, the p Ã C¼X NBO is composed of the natural atomic hybrid orbitals (NHOs) of carbon and oxygen/sulfur (h C and h X , respectively) of essentially pure (499%) p character (p p , which would be p z if the molecule is set at the xy plane): Similarly, here the coefficient c represents the percentage of the NBO on each atomic hybrid, and the minus sign indicates the antibonding combination.The NBO analysis was performed using NBO 7.0.10 35interfaced with Gaussian 09 36 on the geometryoptimised gas-phase molecules at the DFT level of oB97X-D/def2-TZVP.NBO keyword CMO was used to obtain the leading NBO contributions to the canonical LUMO, and FNHO or FNBO to output the Fock (Kohn-Sham) matrix elements in the NHO or NBO basis, respectively.VMD 37 was used for orbital visualisation.By defining the O/S atom and the rest of the molecule as two fragments, the composition of molecular orbitals (MOs) can alternatively be expressed in terms of fragment orbitals (FOs) in a linear combination of fragment orbitals (LCFO-MO) approach.Complementary to the NBO analysis, the effect of O/S on the LUMO was examined using this orbital composition analysis considering the entire molecule as opposed to the local (thio)carbonyl functionality.The analysis was performed using Multiwfn version 3.8(dev) 38 based on the same DFT-optimised molecules.][25][26] computed considering their respective spin configuration.FOs contribution to each MO was evaluated using the charge decomposition analysis (CDA) 39,40 module with the Mulliken method implemented in Multiwfn.
The electrochemical reduction potentials for discussion are the half-wave potentials quoted from the literature and referenced against the saturated calomel electrode (SCE), using known conversion factors, 41 if necessary, for values reported against other references, such as the ferrocenium/ferrocene couple.

Results and discussion
Since all the examples in Fig. 1 are aromatic (thio)imides and (thio)amides, we would like to first verify if structurally simpler thiocarbonyls also possess stronger electron-accepting power.Our analysis begins with propan-2-one (1a, acetone) and propan-2-thione (1b).Electrochemical reduction potentials of these two molecules have not been reported but can be estimated to be at E RED o À2.1 V for 1a 42 and E RED = À1.99V for 1b 43 (Table 1).Consistent with these values, DFT calculations at the level of oB97X-D/def2-TZVP reveal a higher LUMO energy for 1a (1.58 eV) than 1b (À0.05 eV).
Comparison between the LUMO and p Ã C¼X (X = O or S) clearly shows the predominant contribution of this antibonding NBO to LUMO (Fig. 2, 79% for 1a and 83% for 1b; see also Fig. S1, ESI † for the LUMO of other molecules).Analysis of the composing atomic hybrids to this NBO should reveal the origin of the lower p Ã C¼S energy (0.69 eV) compared to p Ã C¼O (2.62 eV).As illustrated in Fig. 3a, the energy of the atomic hybrids follows the sequence of h C 4 h S 4 h O (or basically (p p ) C 4 (p p ) S 4 (p p ) O ), in line with the common anticipation based on the electronegativity of these elements.The extent of interaction between the composing NHOs, represented by the off-diagonal Fock (Kohn-Sham) matrix element, is smaller between h C and h S (|hh C |F|h S i| = 5.44 eV for 1b, Table 1) than between h C and h O (|hh C |F|h O i| = 7.21 eV for 1a).The weaker interaction between h C and h S can be understood considering (i) the longer CQS bond length and (ii) mismatch between the (2p p ) C and (3p p ) S orbitals, resulting in the weaker (2p p ) C /(3p p ) S overlap, compared to the stronger (2p p ) C /(2p p ) O overlap.Consequently, the p Ã C¼S energy is lower than p Ã C¼O , resulting in a lower LUMO of 1b.
An alternative way to track the effect of O/S substitution on LUMO energy can be done by evaluating the contribution of the fragment orbitals (FOs) of O/S and the rest of the molecule to the overall molecular orbitals (MOs). 39,40We consider the O/S and propan-2-ylidene fragments both in the triplet configuration, without losing generality, to form the CQX double bond in 1a and 1b (Fig. 3b).The LUMO, composed of the FOs of the p symmetry, is raised above the highest singly occupied FO of propan-2-ylidene.The extent of energy increase (DE in Fig. 3b,

PCCP Paper
signifying the antibonding character of LUMO) is smaller for 1b than 1a.This reflects a weaker overlap between (2p p ) C /(3p p ) S orbitals than (2p p ) C /(2p p ) O and is consistent with the NBO/NHO analysis discussed above.It is of interest to note that the HOMO of 1b is primarily contributed by the lone pair on sulfur.This unique characteristic should be a consequence of the higher 3p level of S than 2p of O, contributing to the rich photochemical processes of thiocarbonyl's 1 (n-p) excited state. 5,49Despite the wealth of information available in orbital interaction diagrams, we will, however, focus on NBO analysis in the rest of this study for its simple and straightforward chemical picture.
Fluoren-9-one (2a) and fluoren-9-thione (2b) were selected as the model system to analyse the effect of thionation on the electron-accepting power of aromatic molecules (Table 1).Due to conjugation with the aromatic units, the reduction potential of 2 is easier to measure under common electrochemical conditions; E RED = À0.82V was reported for 2b, which is less negative than 2a (E RED = À1.14V). 44 The easier reduction of the thiocarbonyl is, again, consistent with its lower LUMO energy (À0.71 eV for 2a and À1.44 eV for 2b).
Although the LUMO of 2 delocalises to the benzene units, since the p Ã C¼X NBO has a significant contribution (35% for 2a and 52% for 2b) and is the only differing NBO component contributing to LUMO, it is instructive to analyse the atomic hybrids of p Ã C¼X .Similar to the aliphatic (thio)carbonyl, a smaller |hh C |F|h S i| was found for 2b, resulting in the lower p Ã C¼S energy, in turn a lower LUMO compared to 2a.Analyses of aromatic imides 3 and 4 also reveal a smaller |hh C |F|h S i| D 4.8 eV than |hh C |F|h O i| D 6.8 eV of the (thio)carbonyl units.This result is consistent with that found for 1 and 2 and explains the lower LUMO and easier reduction of thioimides (Table 1 and Fig. 1).Furthermore, since 3b and 4b contain both CQO and CQS units in the same molecule, their NHO Fock matrix elements were evaluated on the same ground, adding to the reliability of the above comparison.It is worth noting that p Ã C¼S NBO often shows a high contribution to LUMO (B24% for p Ã C¼S , relative to B12% for p Ã C¼O in the case of 3 and 4; see also above for 2).The significant weight of p Ã C¼S reflects the pronounced LUMO-lowering effect by CQO -CQS substitution, and is consistent with the positive shift in g values of the radical anion of these molecules, resultant from a large spin density on the heavy sulfur atom. 45,46,50aken together, the NBO analysis of (thio)carbonyl 1-4 indicates that the LUMO-lowering of these molecules originates from weaker (2p p ) C /(3p p ) S interactions, despite sulfur in CQS being less electronegative than oxygen in CQO (see also Fig. S2-S4 in ESI † for the effect of electronegativity on molecular electrostatic potential surface and Mulliken charges).This analysis also confirms that thiocarbonyl's stronger electronaccepting power (or easier reduction) is a general phenomenon but not a result of particular substituent patterns.We should point out that we have chosen molecules with nearly planar structures.Such a selection is only for the ease of visualisation of NBOs of the s and p characters; it would not affect the discussion.Inspired by the effect of LUMO-lowering from p-type atomic hybrids, we wondered what the electronic effect would be if the O -S exchange takes place on a site p-conjugated to carbonyl but not on carbonyl itself.
Using methyl ester [RC(O)OCH 3 ] and methyl thioester [RC(O)SCH 3 ] as the example, our above query can be reformulated as comparing the electron withdrawing/donating power of -OCH 3 and -SCH 3 substituents.In this regard, it is conceivable that Hammett substituent constants s p could be used for estimation, since these substituents are p-conjugated with the carbonyl functionality.It was reported that -OCH 3 (s p = À0.27)displays a moderate electron-donating character, whereas -SCH 3 (s p = 0.00) in comparison is somewhat electron withdrawing.This observation is, again, contrary to the simple consideration based on electronegativity.
To investigate the electronic effect of conjugated O/S, we used isochromen-1-one (5a) and isothiochromen-1-one (6a), whose reduction potentials have been reported, as the model system for comparison (Table 2). 46The ''thioester'' version of the isochromenone derivative (6a) displays a noticeably less negative E RED = À1.27V compared to E RED = À1.41V for ''ester''  While the p Ã C¼O NBO contributes significantly to the LUMO of 5a and 6a (20%, along with other antibonding CQC NBOs), the lone-pair NBO of the conjugated O/S atom also has 5-9% importance.This lone-pair orbital orients perpendicular to the molecular plane, adopting the p symmetry, and can mix with the (2p p ) C of carbonyl (Fig. 4). 51The off-diagonal Fock matrix elements between these p-symmetric atomic hybrid h C of carbonyl and h O 2/h S 2 of s-bonded O/S is smaller for 6a (|hh C 1|F|h S 2i| = 3.16 eV) than for 5a (|hh C 1|F|h O 2i| = 4.11 eV), reflecting again the weaker (2p p ) C /(3p p ) S overlap (Table 2).This smaller |hh C 1|F|h S 2i| results in a lower LUMO energy, an interpretation derived similarly to the above NHO Fock matrix analysis for CQO/CQS molecules (1-4).Therefore, even the S lone-pair orbital of ''thioester'' is not formally part of p Ã C¼O as the Lewis structure represents, its weaker coupling to the carbonyl still makes the LUMO lower compared to the ''ester'' analogue (Section 5 in ESI †).While d p -p p interactions have been proposed for sulfur-containing molecules, 52 such an effect is not obvious in all molecules under investigation, likely due to the high energy of sulfur's 3d level.The possibility of such an interaction will be probed in our future study.We also note that using the planar and cyclic model system simplifies the visualisation and avoids conformation complexity; we can generally expect thioester-type molecules to have a stronger electronaccepting power based on this analysis.
In comparison to CQO -CQS replacement, the effect on E RED /LUMO is weaker for -C(O)O---C(O)S-, as the O/S atom is not directly modifying the p Ã C¼X orbital.Therefore, among the four possible S-replaced isochromenone derivatives, E RED was found to be 6b 4 5b 4 6a 4 5a, with doubly thionated 6b displaying the greatest electron-accepting power.The effect on the LUMO of these formally s-bonded O/S decreases, as one would expect, when it is further away from the carbonyl.Using xanthen-9-one (7a) and thioxanthen-9-one (8a) for illustration, the |hh C 2|F|h S 2i| between the p hybrids of the heteroatom and the directly attached carbon is smaller for 8a, consistent with the above analysis (Table 2); however, the E RED and E LUMO are found to be comparable for these two molecules. 47,48Such a similarity indicates marginal enhancement of the electronaccepting power by thionation at this remote position.In fact, the lone-pair NBO of the conjugated O/S atom shows a minimal contribution to LUMO (2-3% for 7 and 8, see also the small MO lobes on sulfur in Fig. 4e).This comparison highlights the limitation of thionation for LUMO-lowering and the explanation power of simple NBO analysis.2 and the anticipation for the weaker 2p/3p orbital interactions.Furthermore, a wide range of k CQO = 1-2 can be found in the collection of HMO parameters curated by Purcell and Singer. 54The ambiguity in parameter selection obscures the use of HMO method in the present study.We therefore recommend using the DFT-based NBO/NHO analysis to obtain a more reliable understanding of the electronic effect of heteroatom substitution on p-conjugated molecules.This computationally economic analysis provides intuitive and clear chemical insights similar to what one might obtain from HMO without the aforementioned problems.

Conclusions
The origin of the superior electron affinity of thionated carbonyls was elucidated by NBO analyses.The use of localised orbitals (NBOs and NHOs) for analysing global molecular properties (electron-accepting power) is semi-quantitatively satisfactory as the p Ã C¼X NBO contributes predominantly to the LUMO of (thio)carbonyl molecules.Despite the lower electronegativity of sulfur (hence higher atomic orbital levels), the smaller (2p p ) C /(3p p ) S interaction results in the weaker antibonding character in p Ã C¼S , lower LUMO level, and less negative reduction potential of thiocarbonyl molecules compared with the corresponding carbonyls.This chemically straightforward interpretation/analysis can be extended to understand the enhanced electron-accepting power of carbonyl derivatives with p-conjugated sulfur atoms.The focus on p-symmetric atomic hybrids in this NBO analysis shares the same philosophy as the Hu ¨ckel theory but avoids relying on the empirical parameters.Therefore, the present strategy can be applied to a broader range of heteroatom-containing molecules or materials. 55,56Once the effect of heteroatom is evaluated and understood at the atomic level using a model system, this knowledge will provide a useful basis for rapid estimation of the molecular reactivity and electronic property induced by uncommon functional groups, such as acyl metalloids and phosphine sulfides, 57,58 and facilitate materials discovery.
where p Ã C¼X (X = O or S) is the antibonding p* NBO of the (thio)carbonyl functional group, and f NBO i are other NBOs of the molecule, often also of the p* antibonding character or lone-pair orbitals of the p symmetry.The coefficient c i represents the percentage (100 Â c i 2 ) of each NBO to LUMO.

Fig. 3
Fig. 3 (a) Development of bonding p C¼X and antibonding p Ã C¼X NBOs of a (thio)carbonyl functional group from their atomic hybrids h C and h X NHOs.Left: X = O, right: X = S.(b) Orbital interaction diagrams for the formation of frontier MOs of 1 considering the FOs of O/S atom and propan-2-ylidene.Dashed lines connect MOs to FOs that show contributions greater than 415%.

a
Superscripted 1 and 2 in the chemical structure are for indexing purpose.b Natural hybrid orbital h C of the (thio)carbonyl C 1 atom.c h C of the aromatic C 2 atom.Paper PCCP 5a.The enhancement in the electron-accepting power by -C(O)O---C(O)S-is clear and consistent with the implication of the Hammett substituent constants s p of -OCH 3 and -SCH 3 and the relative LUMO energy.
Finally, it is worth pointing out that the use of p-symmetric NHO h C,O,S in this study is reminiscent of the Hu ¨ckel molecular orbital (HMO) theory.In the Hamiltonian matrix of HMO calculations, the Coulomb integral a C represents the energy of individual (2p p ) c atomic orbital of carbon, and the resonance integral b CC characterises the coupling between the neighbouring (2p p ) c orbitals.By modifying the integral values of carbon through a X = a C + k X Â b CC and b XY = k XY Â b CC , the property of the frontier orbitals of heteroatom-containing p systems can be estimated in the Hu ¨ckel framework (k X and k XY are proportional constants for heteroatom X).The resonance integral b CQX of (thio)carbonyl can be conceptually related to hh C |F|h X i in the present study.Values of b CQO = 1.06bCC and b CQS = 0.81b CC have been suggested by Van-Catledge.53The smaller b CQS is in agreement with the smaller |hh C |F|h S i| in Tables1 and 2, and the ratio of |hh C |F|h O i|/|hh C |F|h S i| similar to b CQO /b CQS .Therefore, it may be suggested that the HMO analysis of the title problem could provide a qualitative understanding with sufficient accuracy.Despite the simplicity and elegance of the HMO method, its treatment of heteroatom relies heavily on the parameters it uses and the underlying assumptions.For instance, in the same report byVan-Catledge, b C-O = 0.66b CC and b C-S = 0.69b CC were suggested between p p orbitals of singly-bonded C and O/S atoms; 53 the larger b C-S is contrary to the Fock matrix elements in Table

Table 1
Off-diagonal Fock matrix elements of (thio)carbonyl p* NBO in the NHO basis, LUMO energy, and reduction potential for 1-4 |hh C |F|h O i| (eV) |hh C |F|h S i| (eV) E LUMO (eV) E RED (V vs. SCE) Ref.

Table 2
Off-diagonal Fock matrix elements of (thio)carbonyl p* NBO in the NHO basis, LUMO energy, and reduction potential for 5-8 with O/S pconjugated with (thio)carbonyl a