The Utility of 1 , 5 , 7-triazabicyclo [ 4 . 4 . 0 ] dec-5-ene ( TBD ) as a Hydrogen Bond Acceptor in the Design of Novel Superbasic Guanidines – A Computational Study

New guanidine-derived superbases with TBD-functionalized alkyl side chains have been developed using a computational DFT approach. Exploiting the high hydrogen bond basicity of TBD allowed access to systems with strong charge-assisted intramolecular hydrogen bonds in the protonated state. The enhanced stability of such guanidines is mirrored in their gas-phase basicities, which cover the range from 1044−1168 kJ mol−1, depending on the number of alkyl side chains, the type of alkyl spacer and the hydrogen-bonding pattern.


INTRODUCTION
The past two decades have witnessed a growing interest in naturally occuring and synthetic guanidines. 1 The ubiquity of guanidine functionality in biological systems has guided research in bioorganic chemisty towards discovery and design of pharmacologically active guanidine compounds. 2On the other hand, the symmetry of the guanidinium cation and its potential to form hydrogen bonds have been exploited in crystal engineering, 3a supramolecular chemistry 3b and especially organocatalysis. 4Also, a number of guanidine derivatives, that are utilized as neutral organic superbases, are commercially available in the market (Scheme 1).
Among them, 1,5,7-triazabicyclo [4.4.0]dec-5-ene (TBD) and 7-methyl-1,5,7-triazabicyclo [4.4.0]dec-5ene (MTBD) are frequently selected as base catalysts to promote Knovenagel, 5a and Henry reactions, 5b Michael addition, 5c Wittig reaction, 5d transesterification of vegetable oils 5e etc.While TBD and MTBD are non chiral, the bicyclic scaffold can be functionalized to introduce chirality affording superbasic asymmetric catalysts. 6In general, the catalytic activity of bicyclic guanidines originates from their ability to form strong hydrogen bonds in the protonated state with acceptor molecules.As such, a combination of their high basicity and directionality of hydrogen bonds makes TBD a suitable template for the development of novel organosuperbases.
Recently, Coles et al. described the synthesis and basicity of bis(TBD)methane (bis-TBD, Scheme 2a). 7he calculated proton affinity (PA) of 1132.2 kJ mol −1 and the measured pK a value of 29.0 in acetonitrile reflect the cooperative effect between the two TBD units where the protonation of one unit induces a partial protonation in the second one through a strong intramolecular hydrogen bond (IMHB).The proton shuttles back and forth between the protonation sites in an almost barrierless process as evidenced by solid state CP-MAS 15 N NMR measurements and theoretical calculations. 7heme 1. Commercially available guanidine superbases.In a paper by Barić et al., 8 a series of superbasic heteroalkyl-substituted guanidines based on IMHB were modelled in silico.While the highest proton affinity (1227.2kJ mol −1 ) was achieved with phosphoruscontaining (e.g.phosphazene) termini as IMHB acceptors in the side chains, tetramethylguanidinyl terminus in tris-TMG (Scheme 2b) also significantly increased the gas-phase basicity of the central guanidine subunit relative to its unfolded conformation.A combined effect of high intrinsic gas-phase basicity of alkyl-tetramethylguanidine and its pronounced propensity to form hydrogen bonds resulted in PA(tris-TMG) value of 1197.5 kJ mol −1 and the estimated pK a 29.5 in MeCN.
High basicity of tris-TMG can be rationalised through hydrogen bond basicity expressed by the pK HB value 9 (pK HB = negative logarithm of the hydrogen bond association constant).For pentamethylguanidine (PMG), which is structurally equivalent to the alkyltetramethylguanidine fragment in tris-TMG, pK HB amounts 3.16.Such high pK HB value indicates strong internal solvation upon intramolecular hydrogen bond (IMHB) formation, particularly of the conjugate acid, and therefore a large increase in basicity with respect to the system without IMHB.The corresponding pK HB value for MTBD is 3.48, indicating even stronger tendency for this compound to act as a hydrogen-bond acceptor with respet to PMG.Bearing this in mind, we continue our research on guanidine superbases 10 containing substituents capable of forming IMHB by reporting the design and computational investigation of a series of new tris-alkyl substituted guanidines 1-3 (Scheme 3).TBD molecules, which play the role of strong hydrogen bond acceptors as suggested by the high pK HB value of MTBD, are appended at the termini of the side chains.Our main aim was to model a series of novel bases that will (a) approach the upper limit of the basicity scale and (b) to fill the region of GBs from 255 to 270 kcal mol −1 to increase the number of reference bases for future gas-phase measurements.This was achieved by varying the number and length of alkyl-substituents attached to the guanidine moiety using methylene (Me, n = 1), ethylene (Et, n = 2) and propylene (Pr, n = 3) spacers.The gas-phase basicities (GBs), pK a in acetonitrile and the relative stabilities of 1,3-(c1) and 1,1-(c2) hydrogen-bonded structures, as well as the unfolded ones (c3), were estimated by DFT approach.Since TBD and the central guanidine subunit are of similar basicity, the preferred protonation site in 1-3 depends on the appropriate molecular conformation and the spacer length.In this paper we show for the first time that the actual protonation position can be tuned by intramolecular hydrogen bonding.Such a systematic approach enabled us to design the most basic phosphorus-free all-guanidine superbase 3Et-c2, gas- Croat.Chem.Acta 87 (2014) 423.
phase basicity of which is estimated to 1168 kJ mol −1 (PA = 1205.0kJ mol −1 ) and with pK a as high as 33 pK a units.

COMPUTATIONAL DETAILS
The geometry optimizations were carried out using the Gaussian09 suite of programs 11 employing the density functional theory hybrid functional B3LYP  16 pK a values were obtained using linear relationship between pK a and ΔG * (BH + ) a,sol as described previously. 16Geometries of the optimized structures were generated and visualized by MOLDEN 5.0. 17All relative stabilities are expressed as the relative Gibbs energies.Both relative Gibbs energies and the gasphase basicities are given in kJ mol −1 .

RESULTS AND DISCUSSION
In order to identify the most stable minima, three conformations of the neutral and protonated forms of trisubstituted guanidines 1-3 were optimized (Scheme 3).Conformation c1 corresponds to 1,3-hydrogen bonding motif between the donor nitrogen atom in the substituent and the proton on the neighbouring nitrogen atom of the central guanidine subunit.This motif was found in the crystal structure of N,N',N''-tris-(3dimethylaminopropyl)guanidinium hexafluorophosphate 18 and was also predicted to be the most stable in the 2-(2-pyridyl)ethyl substituted guanidine derivatives. 19Next, the 1,1-hydrogen bonding motif, present in c2 conformation, results from IMHB between the TBD-imino nitrogen atom and the proton located at the same nitrogen atom where the alkyl-TBD substituent is attached.Finally, the unfolded conformation c3, without any IMHB, was considered as well.Additionally, for each conjugate acid the structures protonated at the central guanidine and the TBD moiety were optimized.
The geometry optimization of the unfolded structures with methylene spacer proved to be a problematic case.The fully optimized minimum on the potential energy surface was found only in the case of neutral 1Me-c3 base.Attempts to fully optimize the geometries of its protonated form as well as of higher derivatives 2Me-c3 and 3Me-c3, led to the formation of hydrogen bonded structures.On the other hand, the geometry optimization of the unfolded structures with ethylene and propylene spacers were successfully conducted.

Relative Stabilities
In the first part of the discussion we shall compare the relative stabilities of the conformers of neutral and protonated forms separately.In all cases, the 1,3conformers were taken as a reference since this conformation has been previously found in a structurally similar compound. 18The relative stabilities of all these structures are given in Table 1.
The values were found to depend on the spacer length.Thus, for methylene spacer, the 1,3-conformer is preferred for both neutral and protonated forms, while in the case of propylene spacer the 1,1-conformers were found to be the most stable structures.With an ethylene spacer, the neutral and protonated forms show different preference for intramolecular hydrogen bonding.Whereas the formation of a larger ring (1,3-hydrogen bonding) is energetically favourable in neutral bases, the 1,1-hydrogen bonding motif is preferred in their conjugate acids, irrespectively of the protonation site.The calculated relative stabilities of these isomers also show that the unfolded structures are not the most stable structures in neither of considered three isomers although our calculations predict that for the propylene derivatives, unfolded structures of the neutral bases are more stable than the "1,3" conformers.

Gas-phase Basicity
Although different conformers of the neutral and protonated species proved to be the lowest energy minima, the gas-phase basicities were calculated using the neutral base and its conjugate acid in the same conformation.The results obtained in this way provide an insight into dependence of the basicity on the size of the ring formed upon closure of IMHB.The GB values of all considered conformers for compounds 1-3 are compared in Table 2.The modelled 3Et-c2 and 3Pr-c1 guanidines, with their GB values above 1155 kJ mol −1 belong to the most basic neutral non-phosphorus all-guanidine bases and their gas-phase basicity is comparable to recently published bis-imidazolydene guanidine derivatives 20 and aforementioned bis-TBD. 7Together with the analogues bearing 4-dimethylaminopyridine 21 or TMG subunit, 8 our compounds approach the region of the GB values where a spontaneous proton transfer from superacids 22  achieved.Additionally, bis-substituted derivatives 2 fall in the borderline region of the currently measured GBs for organic bases and are desirable for future extension of the experimental GB scale.
However, in the protonated forms of 1-3 we observed a competition between the two basic imino nitrogen atoms: one located in the central guanidine subunit and the second one in TBD moiety, as shown in Figure 1.b) ΔGB(B) = GBTBD(B) − GBgu(B) As expected, the calculated gas-phase basicities of the hydrogen bonded conformers are significantly higher than of the unfolded ones.The formation of IMHB in mono-TBD-substituted derivatives 1 leads to an increase in GBs of both basic sites by 16−43 kJ mol −1 depending on the conformation and the protonation site (p1 or p2).Generally, the effect is more pronounced for the central guanidine subunit than for the TBD part of the molecule although the TBD imino nitrogen atom remains to be the most basic position (Tables 1 and 2).The GBs become more strongly affected by introducing the second and the third substituent capable of forming IMHB.The increase in GBs with respect to c3 conformers is in the range 27−63 kJ mol −1 and 47−75 kJ mol −1 for 2 and 3 derivatives, respectively.Also, the preferred protonation site in 2 and 3 series is changed in comparison with the basicity trend in 1.For example, on going from 1Et-c1 to 2Et-c1 conformer, the increase in GB gu amounts 47 kJ mol −1 , while GB TBD rises by 22 kJ mol −1 .These changes are sufficient to make the guanidine imino nitrogen atom the most basic position in the molecule.This could be rationalized by dividing 2EtH + -c1 structure into two fragments separated by the ethyl spacer (Scheme 4).
The first fragment is TBD (unit 1) while the second fragment is guanidine containing one hydrogenbonded TBD-substituent (unit 2).The latter fragment has the same structure as compound 1 and, if considered separately, unit 2 is more basic than TBD alone.Therefore, the switch in the preferred protonation site for hydrogen bonded structures on going from 1 to 2 series is not surprising.
The length of the spacer also affects the order of GBs for the two hydrogen bonded conformers.Comparison of the relative energies of c1 and c2 conformers with ethylene spacer shows that higher GB of the 1,1-hydrogen-bonded structure c2 is a consequence of two effects: destabilization of the neutral form and stabilization of the protonated form with respect to the 1,3-conformer (Table 1).However, this is not the case in c1 and c2 conformers with a propyl spacer where c2 is more stable, whether neutral or protonated structures are compared.Consequently, GB values of these two conformers are very similar.It is interesting to note that the switch from ethyl to propyl slightly attenuated the basicity what could be ascribed to the larger change in G rel for neutral molecules than for the protonated structures upon spacer elongation.

Estimation of the GB for 1Pr and 3Pr Derivatives
Recently, we have found that the calculated GBs correlate well with combination of pK HB and σ 4B parameters indicating possible usage of pK HB as a general experimental descriptor of the molecular properties for the systems with intramolecular hydrogen bonds in their structure. 21This could be beneficial for further improvement of quantitive structure/property relationship (QSPR) approaches.The equations obtained for a series of N'-substituted N,N' ' 24.24 p 1.99 1063.0 0.956 where σ 4B is the difference in Gibbs energies between the unfolded conformer of the base in question and N'propyl-N,N''-dimethylguanidine (Eq. 1) or N,N',N''tripropylguanidine (Eq.2).pK HB is a tabulated value 9 characteristic for the hydrogen bond accepting group -TBD in our case.For 1Pr the estimated GB amounts 1085 kJ mol −1 what is in an excellent agreement with the directly calculated GB value of c1 conformer (1084 kJ mol −1 , Table 2).For 3Pr, GB est amounts 1182 kJ mol −1 and it deviates from the calculated GB by 25 kJ mol −1 (Table 2).It has been shown earlier that r 2 value for Eq. 2 is significantly lower than for Eq. 1 and these new results confirm the necessity for its improvement.

Unfolded Derivatives
The preferential protonation at the TBD unit was also found in the unfolded conformer c3 of 1 and 2 series.The effect of substituent replacement can be assessed in the same way as for the hydrogen bonded conformers c1 and c2.In the case of 1Et-c3, the increase in basicity of 27 and 30 kJ mol −1 was achieved for guanidine and TBD moieties, if compared with the GB values of isolated N,N',N''-trimethylguanidine (1016 kJ mol −1 ) and MTBD (1038 kJ mol −1 ). 19These values could also be considered as a result of the replacement of one methyl group located on trimethylguanidine or MTBD with either TBDethyl or dimethylguanidine-ethyl subunit, respectively.The replacement of the second and third methyl groups located at the guanidine moiety with TBD-ethyl groups enhances the basicity of the guanidine part by 26 and 24 kJ mol −1 , respectively, while the basicity of the TBD subunit rises by ca 10 kJ mol −1 per additional TBD-ethyl substituent added.It appears that the stepby-step substituent change increases GB gu in approximately additive manner.
On the other hand, the introduction of the second and third substituent contributes to the GB TBD significantly lower than the first one.This is expected since the three-fold structural change occurs quite apart from the TBD subunit.Slightly smaller changes leading to the same general trend were also found for structures with the propyl spacer.Although the effect of the substituent change on the GB gu is almost two-fold lower than in hydrogen bonded conformers, it is still large enough to change the preferential protonation site, but only when three alkyl-TBD groups are attached to the central guanidine moiety.

Basicity in Acetonitrile
To investigate the potential usage of TBD-containing guanidine derivatives as bases or basic catalysts we calculated their pK a values in acetonitrile.For this purpose, only the most stable conformers of neutral or protonated form of each base were considered.More precisely, in the case of methylene and propylene spacers, c1 and c3 conformations of base and its conjugated acid were used.Only in the case of ethylene spacer (n = 2) c1 conformation was taken for neutral and c2 conformation for protonated form.For 1Me-1Pr series, protonation on the TBD subunit was assumed while for other two series, protonation at the central guanidine moiety was found to be the most probable.Additionally, pK a of bis-TBDH + and tris-DMAPAH + (tris-DMAPAH + = N,N',N''-tris-(3 di-methylaminopropyl)guanidinium cation) was also calculated at the same level of theory and compared with compounds studied in this work.
In pK a calculation, a thermodynamic cycle was used as described previously 23 (Figure 2) which draws the relation between the gas-phase basicity of base B and the Gibbs energy of deprotonation of its conjugate acid BH + [Δ(G * a,sol (BH + )].
Absolute pK a (BH + ) in solution is calculated using Eq.3: or, after several simple mathematical operations described in Ref. 16: where while paramers a and b were obtained from the linear regression between the experimentally measured pK a 's and calculated ΔG' a,sol (BH + ) for a set of 57 various nitrogen bases.In this way, G sol (H + ) needs not to be known as it is hidden in the intercept of linear function given in Eq. 4. The results are listed in Table 3. Calculated pK a 's for bis-TBDH + and tris-DMAPAH + derivatives as reference compounds indicate that the approach using IPCM solvation model gives better agreement with the experimental data than the IEFPCM approach.Therefore, we consider IPCM results for compounds 1MeH + -3PrH + as more reliable.
The obtained pK a values for all bases cover the range from 27 to 33 pK a units with 3MeH + -c1 derivative being more basic than bis-TBDH + and tris-DMAPAH + by ca. 4 and 6 pK a units, respectively.In contrast to the gas-phase, methylene spacer was found to be optimal for maximizing the pK a values in acetonitrile, irrespectively of the number of intramolecular hydrogen bonds.The reason for this lies in an increased overall solvation contribution (Δ(ΔG°) sol in derivatives with methylene spacer which overcomes their slightly lower GB.The pK a s of derivatives with one and two TBDspacer substituents (1MeH + -2PrH + ) fall in between the values obtained for the two reference compounds.Based on these results one can expect that all investigated derivatives are indeed strong bases in the gas-phase and solution.However, the basicity in protic solvents could be somewhat attenuated by intermolecular hydrogen bonding with solvent molecules since it depends on the presence of IMHB.

CONCLUSION
By utilizing the concept of basicity increase through the formation of IMHB, and the high propensity of TBD to participate in hydrogen bonding as an acceptor, we successfully designed novel guanidine superbases with the estimated GB values of 1044−1168 kJ mol −1 .Optimization of the structural parameters such as the number of alkyl side chains (1, 2 or 3), the type of alkyl spacer (Me, Et or Pr) and the hydrogen-bonding pattern (1,3-and 1,1-motif), revealed 3Et-c2 as one of the most basic phosphorus-free guanidine superbase reported so far.In acetonitrile solution, the predicted pK a values span from 27−33 units with 3MeH + -c1 as the strongest base.Additionally, the preferred protonation site (TBDor central guanidine imino nitrogen) depends on the number of alkyl substituents and the spacer length.We hope these results will foster further theoretical investigations in the field of neutral organic superbases, as well as encourage experimental chemists to develop synthetic routes to these compounds and explore their potential application as organocatalysts.b) pKa = 0.14627  G°a,sol(BH + ) − 154.1.Linear function between pKa and G°a,sol(BH + ) was obtained from correlation between the experimental and calculated pKa's for 57 nitrogen bases in the same way as in Ref. 16. (c) pKa = 0.13026  G°a,sol(BH + ) − 133.5.b) c3 conformers of the protonated bases with methylene spacers converged to the hydrogen bonded forms and they were not used in this work. (d) TriMG = N,N',N''-trimethylguanidine

BFigure 2 .
Figure 2. Thermodynamic cycle used for calculation of the solution phase Gibbs energy of deprotonation (ΔG*a,sol(BH + )) of the bases investigated in this work.

Table 1 .
The relative stabilities of different conformers (c1, c2 and c3) for mono-(1), bis-(2) and tris-(3) TBD-substituted guanidines in their neutral and protonated states depending on the spacer length (Me, Et and Pr) (a)p1 and p2 relate to the protonation at imino nitrogen atom of the central guanidine or TBD subunit, respectively.

Table S1 .
Energies of the conformers and proton affinities (PA) of the two most basic sites in the investigated guanidine derivatives with methylene spacer calculated using B3LYP/6-311+G(2df,p) //B3LYP/6-31G(d) level of theory(a,b)