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Article

Complete Assignments of 1H and 13C NMR Chemical Shift Changes Observed upon Protection of Hydroxy Group in Borneol and Isoborneol and Their DFT Verification

by
Baohe Lyu
1,
Yoshikazu Hiraga
1,*,
Ryukichi Takagi
2 and
Satomi Niwayama
3,*
1
Graduate School of Science and Technology, Hiroshima Institute of Technology, 2-1-1 Miyake, Saeki-ku, Hiroshima 731-5193, Japan
2
Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan
3
Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto-cho, Muroran 050-8585, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(3), 597; https://doi.org/10.3390/molecules30030597
Submission received: 25 December 2024 / Revised: 23 January 2025 / Accepted: 24 January 2025 / Published: 28 January 2025
(This article belongs to the Special Issue Applications of NMR Spectroscopy to Problem Solving for Inorganic, Organometallic, and Organic Compounds)
Browse Figures
Versions Notes

Abstract

:
Complete assignments of the 1H and 13C NMR chemical shifts for the monoterpenes, borneol 1a and isoborneol 2a, as well as their derivatives (1b–1g and 2b–2g), in which the secondary hydroxy group is protected with various protecting groups, have been made in various solvents. Upon protection of the hydroxy groups in 1a and 2a, many protons and carbons within the bicyclic ring exhibited downfield or upfield shifts in their chemical shift values, facilitating the unambiguous assignments of these protons and carbons. These chemical shift values also showed excellent correlations with those obtained from density functional theory (DFT) calculations. Furthermore, the anisotropic effect of the benzene ring was estimated by the analysis of the iso-chemical shielding surface (ICSS) resulting from substituents introduced to the hydroxyl groups of 1a and 2a.

Graphical Abstract

1. Introduction

Borneol 1a and isoborneol 2a are chiral monoterpenoids abundant in nature and constitute components of plant essential oils (Scheme 1) [1,2,3,4,5,6,7,8]. These natural products consist of a bicyclic ring, and are epimers of each other in which the stereochemistry of the hydroxy group is different. Both of them have been utilized in a wide range of products such as pharmaceuticals, insect repellant, fragrance, and chiral ligands since many decades ago [9,10,11,12]. Therefore, their spectroscopic properties such as 1H and 13C NMR spectroscopic behaviors have been actively investigated for the last few decades [13,14,15,16,17,18,19].
NMR spectroscopy plays a key role for structure determination as well as obtaining information about various chemical environments of organic compounds in general, even distinguishing subtle structural differences. Although high resolution NMR spectroscopy made magnificent advancements recently, the complete assignments of 1H NMR and 13C NMR chemical shifts for these compounds have still been rather challenging, for isobrorneol 2a in particular, because of some overlapping peaks. In spite of the difficulties, we previously reported our complete assignments of 1H NMR chemical shifts of both borneol 1a and isoborneol 2a by protecting each hydroxy group with various protecting groups [20,21]. We found high-frequency shifts or low-frequency shifts (hereafter referred to as downfield shifts and upfield shifts, meaning deshielding and shielding, respectively) for many protons, including those distant from the protecting groups that have phenyl groups. This is likely to be attributed to anisotropic effects, facilitating the complete assignments.
Here, based on quantum chemical calculations, we investigated the change of the chemical shift values observed upon the protection of the hydroxy groups in 1a and 2a with various carbonyl-containing protecting groups or with silyl-protecting groups having a various number of phenyl rings. We optimized the most stable structures of 1a, 2a, and their derivatives (1b–1g and 2b–2g), all of which were adopted in the experiments, using density functional theory (DFT) calculations with the Gaussian 09 program [22]. We further predicted their 1H NMR and 13C NMR chemical shifts based on these structures and compared them with the experimental 1H NMR and 13C NMR chemical shifts. Furthermore, for quantitative investigation of the anisotropic effects arising from the carbonyl group or the phenyl group, we calculated the iso-chemical shielding surface (ICSS) [23], which is a real-space function closely related to the nucleus-independent chemical shift (NICS) [24,25,26,27,28,29] and can be applied to the evaluation of the aromaticity of cyclic molecules or local rings [30,31,32,33,34,35,36,37,38,39,40,41]. The ICSS method can clearly reveal the extent of magnetic shielding and deshielding effects at different regions due to the delocalized electrons, and therefore we have been able to explain the origin of the chemical shift changes observed upon the protection of each hydroxy group with the above protecting groups.

2. Results and Discussion

2.1. The Correlation Between the Experimentally Obtained and DFT-Calculated 1H and 13C NMR Chemical Shifts of Borneol 1a, Isoborneol 2a, and Their Derivatives 1b–1g and 2b–2g

The chemical shift changes in 1H NMR and 13C NMR upon the introduction of acyl (acetyl and benzoyl) or silyl protective groups to borneol and isoborneol were investigated. The NMR solvents used were CDCl3, C6D6, and CD3OD, and the differences due to the solvent effects were also examined. However, compounds 1d–1g and 2d–2g with the silyl groups were insoluble in CD3OD, and therefore, comparisons were made using CDCl3 and C6D6.
The assignments in the 1H NMR and 13C NMR spectra upon the introduction of an acetyl group or a benzoyl group to the hydroxyl group of borneol and isoborneol are shown in Tables S1–S4, and the assignments in the spectra upon the introduction of silyl groups with varying numbers of phenyl groups are shown in Tables S5–S8 [20,21]. Furthermore, the 1H NMR chemical shift changes caused by the difference in electron-withdrawing properties between acetyl and benzoyl groups are shown in Figure 1 for borneol 1a and its derivatives 1b–1c and in Figure S1 for isoborneol 2a and its derivatives 2b–1c. The chemical shift changes caused by the number of phenyl groups in silyl groups with varying numbers of phenyl groups are shown in Figure 2 for borneol derivatives 1d–1g and in Figure S2 for isoborneol derivatives 2d–2g.
The anisotropy and shielding effects of the phenyl group will be discussed in a later chapter. It was found that the introduction of an acetyl group induces downfield shifts for most protons in borneol derivatives and isoborneol derivatives, as in Figure 1 and Figure S1. Additional downfield shifts were also found upon the introduction of a benzoyl group. Additionally, regarding the solvent effects caused by the NMR solvent, similar chemical shifts were observed in CDCl3 and CD3OD. However, in C6D6, due to the anisotropic effects of the solvent [42], the methyl groups exhibited chemical shifts and chemical shift changes that were different from those in the other solvents, as shown in Figure 1 and Figure S1.
On the other hand, as shown in Figure 2 and Figure S2, the chemical shift changes observed upon introducing silyl protecting groups to borneol 1a and isoborneol 2a showed minimal differences regardless of the solvent. However, unlike the case of acyl groups, as the number of phenyl groups in the silyl protecting groups increases, not only did the protons of the compounds exhibit downfield shifts in the 1H NMR chemical shifts, but protons showing upfield shifts, such as the methyl protons at C-8, were also observed, as shown in Figure 2 and Figure S2. Therefore, we used quantum chemical calculations to investigate the changes in the chemical shifts of 1H NMR and 13C NMR when acyl groups or silyl groups were introduced into borneol 1a and isoborneol 1b.
The most stable structure of each compound was determined with the use of the Gaussian 09 program with DFT methods at the B3LYP/6-311+G(2d,p), ωB97XD/6-311+G(2d,p), and mPW1PW91/6-311+G(2d,p) levels [43,44,45,46,47], and GaussView 5 was utilized for the creation of the input files and analysis of the results [22]. The calculations of the NMR chemical shifts were performed with the use of the gauge, including the atomic orbital (GIAO) technique in combination with the mPW1PW91/6-311+G(2d,p) level [48,49,50,51,52]. In order to verify the solvent effects and validities of the chemical shifts of each compound in each solvent, we compared the chemical shift values obtained by the DFT calculations (GIAO/mPW1PW91/6-311+G(2d,p) level of theory with IEFPCM in the gas phase and several solvents) in each solvent and the spectroscopically observed values in each solvent [53,54,55,56,57,58,59,60].
The linear correlations between the experimental and calculated NMR chemical shifts for the bornyl and isobornyl skeletons were investigated. The results are shown in Figures S3 and S4 for borneol 1a and its derivatives 1b and 1c, as well as in Figures S5 and S6 for isoborneol 2a and its derivatives 2b and 2c.
As for 13C NMR chemical shifts, a good correlation was observed between the calculated values in the gas phase and the observed values in each solvent (CDCl3, C6D6, or CD3OD) for both borneol 1a and isoborneol 2a, as well as for their derivatives 1b, 1c, 2b, and 2c, as shown in Figures S3 and S5. However, for the calculated values of 1H NMR chemical shifts in the gas phase, some variation was observed in the high-field region depending on the measurement solvent. Therefore, the correlations between the calculated values of 1H NMR chemical shift with IEFPCM in each solvent and the corresponding observed values were examined. As shown in Figures S4 and S6, far better correlations were found in these solvents than in the gas phase. In particular, good correlations were observed in chloroform and in methanol for all these compounds, especially for isoborneol 2a and its derivative 2c (Figure S6). As a result, excellent correlations were found between the chemical shift values obtained by the calculations and those observed by 1H and 13C NMR spectroscopy in each solvent. In general, it is considered difficult to estimate the extent of anisotropic effects by theoretical calculations, but these results are likely to indicate that quantum chemical calculations at the GIAO/mPW1PW91/6-311+G(2d,p) level with IEFPCM in solvent (CDCl3, C6D6, or CD3OD) can properly estimate the 1H and 13C NMR chemical shift values for these uniquely strained bicyclic molecules.
Next, in order to verify the changes in the chemical shifts observed in the 1H and 13C NMR spectra of borneol 1a and isoborneol 2a and their derivatives 1d–1g and 2d–2g protected with silyl groups having various numbers of phenyl groups in CDCl3 or C6D6 solutions, we compared the experimental 1H NMR and 13C NMR chemical shifts in these solutions with those estimated by quantum chemical calculations based on the most stable structures in the gas phase.
Figures S7 and S8 show the correlation between the experimental 1H and 13C NMR chemical shifts for the bornyl skeleton in CDCl3 and C6D6 solutions and the calculated 1H and 13C NMR chemical shifts in the gas phase for borneol 1a and its silyl-protected derivatives 1d–1g. They were insoluble in CD3OD, as noted previously. Very good correlations were observed between the experimental 1H and 13C NMR chemical shifts in CDCl3 or C6D6 and the calculated 1H and 13C NMR chemical shifts, respectively, for the same set of compounds. These results suggest that the expected 13C NMR chemical shift values calculated from the most stable structures reflect the experimentally observed values even after the introduction of the silyl group and the increase in the number of phenyl groups within the silyl groups. It is also suggested that the most stable structures are all valid, and the 1H NMR and 13C NMR shielding calculations derived from these most stable structures are also proper. Furthermore, as shown in Figure S8, concerning the 1H NMR chemical shift correlation, a slightly better linear correlation between the calculated values and the observed values was observed in C6D6 than in CDCl3. Therefore, we believe that the most stable structures in this case properly reflect the experimentally observed anisotropic effects from the phenyl groups in C6D6 solution [61,62,63,64,65,66].
Figures S9 and S10 show the correlation between the experimental 1H and 13C NMR chemical shifts for the isobornyl skeleton in CDCl3 and C6D6 solutions, for isoborneol 2a and its silyl-protected derivatives 2d–2g, and the calculated 1H and 13C NMR chemical shifts in the gas phase. As with the results for borneol 1a and its derivatives 1d–1g, very good correlations were found between the experimental 13C NMR chemical shifts and the calculated 13C NMR chemical shifts for isoborneol 2a and its derivatives 2d–2g in CDCl3 or C6D6. Notably, although isoborneol 2a possesses a very crowded exo hydroxy group at C-2, good correlations between the experimental chemical shifts and calculated ones were still detected even after the introduction of the silyl groups, verifying the most stable conformations.
From the above results, the experimental values of 1H NMR chemical shifts in the gas phase, some variation was observed in the high-field region depending on the measurement solvent, as shown in Figures S7 and S9. Therefore, the correlations between the calculated values of 1H NMR chemical shift with IEFPCM in each solvent and the corresponding observed values were examined. As shown in Figures S8 and S10, far better correlations were found in these solvents than in the gas phase.

2.2. Relationship Between the Changes in 1H NMR Chemical Shifts of Borneol 1a, Isoborneol 2a, and Their Derivatives Containing an Acetyl Group or a Benzoyl Group 1b–1c or 2b–2c and the Iso-Chemical Shielding Surface (ICSS)

To investigate the changes in the 1H NMR chemical shifts of the ring protons and the three methyl groups in borneol 1a and isoborneol 2a upon the introduction of an acetyl group or a benzoyl group, we performed the Iso-chemical Shielding Surface (ICSS) calculations based on the most stable structure of each compound 1b–1c and 2b–2c in the gas phase [23].
The results are shown in Figure 3. The values of the 1H NMR chemical shifts shown in the top row represent the changes in CDCl3, those in the middle row represent changes in C6D6, and those in the bottom row represent changes in CD3OD. For each compound, the change in the 1H NMR chemical shift of each proton is expressed relative to unprotected 1a or 2a, respectively. The chemical shifts of protons that exhibited upfield shifts due to the introduction of the protecting group are indicated in red, while those that showed downfield shifts are indicated in blue. The ICSS is represented by a pink color for regions where ICSS = −0.2 ppm, while regions where ICSS = −0.5 ppm are shown in a yellow-brown color.
Figure 3a illustrates the relationship between the 1H NMR chemical shift changes and the ICSS regions for bornyl acetate 1b. In bornyl acetate 1b, a small region where ICSS = −0.2 ppm was observed, along with a tiny region where ICSS = −0.5 ppm around the carbonyl group. Therefore, the influence of the anisotropic effect due to the carbonyl group is considered to be small. As shown in Figure 1 and Figure 3a, the introduction of an acetyl group into borneol 1a resulted in downfield shifts in the 1H NMR chemical shifts of the H-2exo, H-3endo, H-3exo, and H-6exo protons in all solvents. These changes are probably attributed to the electron-withdrawing nature of the acetyl group. Furthermore, it is believed that these protons exhibit downfield shifts due to the additional small deshielding effect of the carbonyl group, as indicated by the ICSS data shown in Figure 3a [67,68]. The other protons showed similar changes in CDCl3 and CD3OD. However, in C6D6, protons such as H-5endo, H-6endo, and the H-8 methyl group exhibited upfield shifts. These changes are likely to be due to the anisotropy effects from the solvent.
The introduction of an acetyl group to the hydroxyl group of borneol 1a caused most protons to exhibit downfield shifts. Furthermore, as shown in Figure 3b, which exhibits large ICSS regions around the benzoyl group, when a benzoyl group was introduced to borneol 1a, most protons exhibited downfield shifts in all solvents. In particular, the H-2exo, H-3endo, H-3exo, and H-6endo protons showed significant downfield shifts due to the introduction of the benzoyl group. These changes can be attributed not only to the electron-withdrawing nature of the benzoyl group, but also to the ring-current effect caused by the benzene ring according to the ICSS results.
Figure 3c shows the relationship between the chemical shifts and the ICSS regions for isobornyl acetate 2b. As observed with bornyl acetate 1b, there was almost no region where ICSS = −0.5 ppm, and the region where ICSS = −0.2 ppm was present near the carbonyl group. Similar to borneol acetate 1b, the ring protons excluding the methyl group showed a similar downfield-shift trend in CDCl3 and CD3OD, while in C6D6, they exhibited chemical shift changes toward upfield shifts. Especially, H-2endo, H-3endo, and H-6endo showed downfield shifts in all solvents as shown in Figure 3c. These changes are likely attributed to the additional deshielding effect of the carbonyl group combined with the electron-withdrawing property of the acetyl group as inferred from the ICSS region of the carbonyl group.
Figure 3d shows the relationship between the 1H NMR chemical shift changes and the ICSS regions for isobornyl benzoate 2c. Similar to bornyl benzoate 1c, the H-2endo, H-3endo, H-3exo, and H-6endo protons, which are located near the deshielded region of the benzene ring as calculated by the ICSS, showed downfield shifts in all solvents. These chemical shifts are considered to be due to the anisotropic effect of the benzene ring. Furthermore, the downfield shifts observed for the hydrogen atoms of the H-10 methyl group is thought to be due to their proximity to the deshielded region of the benzene ring.
The methyl groups of isoborneol derivatives 2b and 2c exhibited a mixture of upfield and downfield shifts upon the introduction of acetyl or benzoyl groups to isoborneol 2a, as shown in Figure 3c,d.

2.3. Relationship Between the Changes in 1H NMR Chemical Shifts of Borneol 1a, Isoborneol 2a, and Their Derivatives Containing Various Silyl Protective Groups 1d–1g and 2d–2g and the Iso-Chemical Shielding Surface (ICSS)

Next, we examined the relationship between the 1H NMR chemical shift changes of borneol 1a and isoborneol 2a on the protection of the hydroxy groups with silyl-protecting groups having varying numbers of phenyl groups and the ICSS calculated from the most stable structures of the silyl-protected derivatives 1d–1g and 2d–2g (Figure 4 and Figure 5). In these figures, the values of the chemical shifts in the upper row represent the changes in CDCl3, while the values in the lower row represent the changes in C6D6. As in the previous section, the chemical shifts of hydrogens that exhibited upfield shifts due to the introduction of the protecting group are indicated in red, those that showed downfield shifts are indicated in blue, and those with almost no change (±0.02 ppm) are shown in black.
In bornyl TBDMS 1d, with the introduction of a TBDMS group, which lacks a benzene ring, all of the 1H NMR chemical shifts of protons except for the H-6endo proton shifted upfield in CDCl3 and downfield in C6D6. These chemical shift changes were opposite to those observed in bornyl derivatives with the carbonyl-containing protective groups, particularly the acetyl group, as shown in Figure 4a. As depicted in Figure 4a, no region where ICSS = −0.5 ppm was present in bornyl TBDMS 1d, and there was only a small region where ICSS = −0.2 ppm was observed around the oxygen atom of the silyl moiety. Therefore, the chemical shift changes observed in bornyl TBDMS 1d are attributed to changes in electron density due to the introduction of the TBDMS silyl protecting group to the hydroxyl group of borneol 1a.
Figure 4b shows the chemical shift changes and ICSS regions of bornyl DMMPS 1e. Due to the presence of a benzene ring in the DMMPS group, a deshielding region was observed around the benzene ring. Among the 1H NMR chemical shift changes in bornyl DMMPS 1e, both the H-3exo and H-9 methyl group protons exhibited upfield shifts in both CDCl3 and C6D6. These changes can be attributed to the anisotropic effect of the benzene ring as these protons are located in the shielding region of the benzene ring as indicated by the ICSS calculations. On the other hand, both the H-3endo and H-6endo protons showed downfield shifts, which are attributed to the ring current effect resulting from their proximity to the deshielding region of the benzene ring in the DMMPS group.
Figure 4c shows the ICSS regions and chemical shift changes of bornyl TBDPS 1f, which contains a TBDPS group with two benzene rings. The protons H-3exo, H-4exo, the H-8 methyl group, and the H-9 methyl group of 1f, which are located above the plane of the benzene rings, exhibited upfield shifts in both solvents due to the anisotropic effect of the benzene rings. Similarly, the downfield shifts observed for the H-2exo and H-6endo protons in 1f can be attributed to their proximity to the deshielding region of the benzene rings in the TBDPS group.
Figure 4d shows the ICSS regions and chemical shift changes of bornyl TPS 1g, which contains three benzene rings in the TPS group. Similar to 1f, the protons H-3exo, H-4exo, the H-8 methyl group, and the H-9 methyl group of 1g, which are located above the shielding region of the benzene rings, exhibited upfield shifts in both solvents. Conversely, the H-2exo, H-3endo, H-5endo, and H-6endo protons, which are close to the deshielding region of the benzene rings, showed downfield shifts. These observations demonstrate that the changes in 1H NMR chemical shifts when borneol 1a is protected with silyl groups containing different numbers of phenyl groups can be understood by considering the shielding and deshielding regions indicated by the ICSS, as determined from the most stable structure of each borneol derivative.
As depicted in Figure 5a, similar to bornyl TBDMS 1d in Figure 4a, no ICSS = −0.5 ppm region was observed for isobornyl TBDMS 2d, and only a small −0.2 ppm region was present around the oxygen atom. Furthermore, when isoborneol 2a was protected with a TBDMS group, chemical shift changes similar to those of bornyl TBDMS 1d were observed. These changes were attributed to the change in electron density of isoborneol 2a due to the protection with TBDMS, as indicated by the ICSS analysis results similar to bornyl TBDMS 1d.
Figure 5b shows the relationship between the chemical shift changes of isobornyl DMMPS 2e containing a benzene ring and the ICSS regions. Upfield shifts were observed for the H-3endo proton in both solvents. Considering the shielding regions of the benzene ring depicted by the ICSS, the upfield shifts of the H-3endo proton are thought to be due to their positions within the shielding region of the benzene ring. On the other hand, the downfield shifts observed for the H-3exo proton and the H-9 methyl group protons could be attributed to their proximity to the deshielding region of the benzene ring in the DMMPS group.
Figure 5c shows the correlation between the chemical shift changes and the ICSS regions of isobornyl TBDPS 2f, which contains two benzene rings. The chemical shift changes of the H-2endo proton differed from those observed for the H-2endo proton of 2d and 2e with downfield shifts observed in both solvents. According to the ICSS analysis, this chemical shift change of H-2endo of 2f can be attributed to the benzene rings of the TBDPS group being located in the deshielding region. Similarly, the upfield shifts observed for the H-3endo, H-4exo, H-5endo, H-5exo, H-6endo, and H-6exo protons are attributed to their positions within the shielding region of the benzene rings, while the downfield shifts observed for the H-3exo and H-9 methyl group protons are presumed to result from their proximity to the deshielding region of the benzene rings.
Finally, Figure 5d shows the correlation between the chemical shift changes of the hydrogen atoms observed in isobornyl TPS 2g and its ICSS. As shown in Figure 5d, the chemical shift changes observed in isobornyl TPS 2g exhibited a pattern similar to those observed in isobornyl TBDPS 2f. In the isoborneol derivatives 2e–2g, which have silyl protecting groups containing one to three benzene rings, the H-9 methyl group exhibited downfield shifts in both solvents, while the H-8 and H-10 methyl groups showed similar changes as shown in Figure 5b–d. Based on the ICSS analysis, the downfield shifts of the H-9 methyl group are considered to be due to the ring current effects of the benzene rings, whereas those of the H-8 and H-10 methyl groups are not due to the influence by the benzene ring.
In conclusion, it has been demonstrated that the behavior of the 1H NMR chemical shifts of hydrogen atoms in bornyl and isobornyl derivatives containing benzoyl groups or silyl groups with varying numbers of benzene rings can be explained by consideration of the shielding and deshielding regions of the benzene rings based on ICSS analysis of the most stable structure of each compound.

3. Materials and Methods

3.1. Chemicals

(–)-Borneol 1a, purity > 95% (GC), and (±)-isobornel 2a, purity > 90% (GC) were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), and were used without further purification. The deuterated solvents, CDCl3, C6D6, and CD3OD and other reagents were purchased from Fujifilm Wako Chemicals Co., Ltd. (Osaka, Japan). Borneol derivatives 1b–1g and isoborneol derivatives 2b–2g were prepared from 1a and 2a, respectively, according to the reported procedure [20,21].

3.2. NMR Measurements

All NMR spectra were recorded using a JEOL JNM-ECZ400S NMR spectrometer (1H: 399.9 MHz, 13C: 100.5 MHz, JEOL Ltd., Tokyo, Japan) at 298 K with 5 mm (o.d.) Pyrex glass tubes. 1H and 13C NMR chemical shifts were measured with reference to the residual 1H and 13C signals of the deuterated solvents (CDCl3: δH 7.260, δC 77.01; C6D6: δH 7.156, δC 128.03, CD3OD: δH 3.306, δC 49.04) [69]. The 1H and 13C NMR chemical shifts of borneol 1a and isoborneol 2a and their derivatives 1b–1g and 2b–2g in CDCl3, C6D6 and CD3OD are listed in Tables S1–S8, respectively.

3.3. Computational Methods

Conformational search of borneol 1a, isoborneol 2a, and their derivatives (1b–1g and 2b–2g) was performed with the use of the Spartan’06 molecular modeling program [70] with the semi-empirical method, AM1. Each compound was structurally optimized at the B3LYP/3-31G(d) level with the Gaussian 09 program from the conformers obtained by the scan of dihedral angles on the potential energy surface. The most stable structures of borneol 1a, isoborneol 2a, and their derivatives (1b–1g and 2b–2g) were further optimized at the B3LYP/6-311+G(2d,p) level in the gas phase. The 1H NMR and 13C NMR chemical shifts of the compounds calculated at the GIAO/B3LYP/6-311+G(2d,p) level, GIAO/ωB97XD/6-311+G(2d,p) level, and GIAO/mPW1PW91/6-311+G(2d,p) level with the use of the integral equation formalism model of the polarizable continuum model (IEFPCM) at the same theory level, were referenced with respect to the standard TMS that was optimized at the same level [48,49,50,51,52,53,54,55,56,57,58,59,60]. The calculations of anisotropic effects are based on the nucleus independent chemical shift (NICS) concept, and the iso-chemical shielding calculations were performed with the GIAO method with the use of the HF/6-31G(d) level in the gas phase [23]. The generation of the Gaussian input files for the NICS calculations and the analysis of ICSS were performed with the use of Multiwfn 3.8 [71]. The iso-chemical surface maps were rendered by means of Visual Molecular Dynamics (VMD) software [72] based on the files exported from Multiwfn.

4. Conclusions

In conclusion, complete assignments of both 1H and 13C NMR chemical shifts for borneol 1a, isoborneol 2a, and their derivatives 1b–1g and 2b–2g, in which the hydroxy groups were protected with various protecting groups, were made in two solvents, and the validity of these assignments has further been confirmed by quantum chemical calculations at the GIAO/mPW1PW91/6-311+G(2d,p) level. The origins of the chemical shift changes upon protection of the hydroxy groups were further investigated by the ICSS method. The ICSS results suggest some regions may have been affected by the anisotropic effects from the phenyl rings or the carbonyl groups in the protecting groups. To our knowledge, this is the first study reporting the complete assignments of 1H and 13C NMR chemical shifts of borneol 1a and isoborneol 2a and their derivatives in various solvents and also reports their strong correlations with those predicted by quantum chemical calculations.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30030597/s1, Figure S1. 1H NMR chemical shift changes of isoborneol 2a and its derivatives 2b–2c in different solvents (CDCl3, C6D6 or CD3OD); Figure S2. 1H NMR chemical shift changes of isoborneol 2a and its derivatives 2d–2g in different solvents (CDCl3 or C6D6); Figure S3. Correlations between the experimental 1H and 13C NMR chemical shifts of borneol 1 and its derivatives 1b–1c in different solvents (CDCl3, C6D6, or CD3OD) and their calculated values (in the gas phase) at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S4. Correlations between the experimental 1H NMR chemical shifts of borneol 1 and its derivatives 1b–1c in different solvents (CDCl3, C6D6, or CD3OD) and their calculated values in the corresponding solvent at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S5. Correlations between the experimental 1H and 13C NMR chemical shifts of isoborneol 2a and its derivatives 2b–2c in different solvents (CDCl3, C6D6, or CD3OD) and their calculated values (in the gas phase) at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S6. Correlations between the experimental 1H NMR chemical shifts of isoborneol 2a and its derivatives 2b–2c in different solvents (CDCl3, C6D6, or CD3OD) and their calculated values in the corresponding solvent at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S7. Correlations between the experimental 1H and 13C NMR chemical shifts of bornyl derivatives 1d–1g in different solvents (CDCl3 or C6D6) and their calculated values (in the gas phase) at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S8. Correlations between the experimental 1H NMR chemical shifts of bornyl derivatives 1d–1g in different solvents (CDCl3 or C6D6) and their calculated values in the corresponding solvent at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S9. Correlations between the experimental 1H NMR and 13C NMR chemical shifts of isobornyl derivatives 2d–2g in different solvents (CDCl3 or C6D6) and their calculated values (in the gas phase) at the GIAO/mPW1PW91/6-311+G(2d,p) level; Figure S10. Correlations between the experimental 1H NMR chemical shifts of isobornyl derivatives 2d–2g in different solvents (CDCl3 or C6D6) and their calculated values in the corresponding solvent at the GIAO/mPW1PW91/6-311+G(2d,p) level; Table S1. 1H NMR chemical shifts for borneol 1 and its derivatives 1b–1c in different solvents; Table S2. 13C NMR chemical shifts for borneol 1 and its derivatives 1b–1c in different solvents; Table S3. 1H NMR chemical shifts for isoborneol 2a and its derivatives 2b–2c in different solvents; Table S4. 13C NMR chemical shifts for isoborneol 2a and its derivatives 2b–2c in different solvents; Table S5. 1H NMR chemical shifts of borneol 1a and its derivatives 1b–1e in CDCl3 and C6D6; Table S6. 13C NMR chemical shifts of borneol 1a and its derivatives 1b–1e in CDCl3 and C6D6; Table S7. 1H NMR chemical shifts of isoborneol 2a and its derivatives 2b–2e in CDCl3 and C6D6; Table S8. 13C NMR chemical shifts of isoborneol 2a and its derivatives 2b–2e in CDCl3 and C6D6; Table S9: Optimized coordinates, energies, and calculated NMR chemical shifts of borneol 1a; Table S10: Optimized coordinates, energies, and calculated NMR chemical shifts of isoborneol 2a; Table S11: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl acetate 1b; Table S12: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl benzoate 1c; Table S13: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl acetate 2b; Table S14: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl benzoate 2c; Table S15: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl TBDMS 1d; Table S16: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl DMMPS 1e; Table S17: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl TBDPS 1f; Table S18: Optimized coordinates, energies, and calculated NMR chemical shifts of bornyl TPS 1g; Table S19: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl TBDMS 2d; Table S20: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl DMMPS 2e; Table S21: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl TBDPS 2f; Table S22: Optimized coordinates, energies, and calculated NMR chemical shifts of isobornyl TPS 2g; Table S23: Comparison of the coefficient of determination (r2) and RMS between experimental and calculated 1H NMR chemical shifts for compounds 1a–1c and 2a–2c using various calculation methods; Table S24: Comparison of the coefficient of determination (r2) and RMS between experimental and calculated 1H NMR chemical shifts for compounds 1d–1g and 2d–2g using various calculation methods; Table S25: Comparison of the coefficient of determination (r2) and RMS between experimental and calculated 13C NMR chemical shifts for compounds 1a–1c and 2a–2c using various calculation methods; Table S26: Comparison of the coefficient of determination (r2) and RMS between experimental and calculated 13C NMR chemical shifts for compounds 1d–1g and 2d–2g using various calculation methods. Video S1: 1b-Bornyl-Acetate.mp4; Video S2: 1c-Bornyl-Acetate.mp4; Video S3: 1d-Bornyl-TBDMS.mp4; Video S4: 1e-Bornyl-DMMPS.mp4; Video S5: 1f-Bornyl-TBDPS.mp4; Video S6: 1g-Bornyl-TPS.mp4; Video S7: 2b-Isobornyl-Acetate.mp4; Video S8: 2c-Isobornyl-Acetate.mp4; Video S9: 2d-Isobornyl-TBDMS.mp4; Video S10: 2e-Isobornyl-DMMPS.mp4; Video S11: 2f-Isobornyl-TBDPS.mp4; Video S12: 2g-Isobornyl-TPS.mp4.

Author Contributions

Conceptualization, Y.H. and S.N.; methodology, Y.H. and S.N.; investigation, Y.H., S.N., B.L. and R.T.; writing original draft preparation, Y.H., S.N. and B.L. All authors have read and agreed to the published version of the manuscript.

Funding

We acknowledge the financial support from The Ogasawara Toshiaki Memorial Foundation Grant, Fukuoka Naohiko Memorial Foundation Grant, and Grants-in-Aid for Scientific Research (22K05106).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, and further inquiries can be directed to the corresponding author.

Acknowledgments

The JEOL NMR was purchased with a grant from the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (S1413002).

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 30 00597 sch001
Scheme 1. Borneol 1a, isoborneol 2a, and their derivatives 1b–1g and 2b–2g.
Scheme 1. Borneol 1a, isoborneol 2a, and their derivatives 1b–1g and 2b–2g.
Molecules 30 00597 sch001
Molecules 30 00597 g001
Figure 1. 1H NMR chemical shift changes of borneol 1a and its derivatives 1b–1c in different solvents (CDCl3, C6D6 or CD3OD).
Figure 1. 1H NMR chemical shift changes of borneol 1a and its derivatives 1b–1c in different solvents (CDCl3, C6D6 or CD3OD).
Molecules 30 00597 g001
Molecules 30 00597 g002
Figure 2. 1H NMR chemical shift changes of borneol 1a and its derivatives 1d–1g in different solvents (CDCl3 or C6D6). The number in parentheses under the compound number indicates the number of phenyl groups.
Figure 2. 1H NMR chemical shift changes of borneol 1a and its derivatives 1d–1g in different solvents (CDCl3 or C6D6). The number in parentheses under the compound number indicates the number of phenyl groups.
Molecules 30 00597 g002
Molecules 30 00597 g003
Figure 3. (a) Bornyl acetate 1b; (b) Bornyl benzoate 1c; (c) Isobornyl acetate 2b; (d) Isobornyl benzoate 2c. The changes in 1H NMR chemical shifts of borneol 1a, isoborneol 2a, and their derivatives containing acetyl and benzoyl groups 1b–1c and 2b–2c, along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Middle row, C6D6; Bottom row, CD3OD. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
Figure 3. (a) Bornyl acetate 1b; (b) Bornyl benzoate 1c; (c) Isobornyl acetate 2b; (d) Isobornyl benzoate 2c. The changes in 1H NMR chemical shifts of borneol 1a, isoborneol 2a, and their derivatives containing acetyl and benzoyl groups 1b–1c and 2b–2c, along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Middle row, C6D6; Bottom row, CD3OD. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
Molecules 30 00597 g003
Molecules 30 00597 g004
Figure 4. (a) Bornyl TBDMS 1d; (b) Bornyl DMMPS 1e; (c) Bornyl TBDPS 1f; (d) Bornyl TPS 1g. The changes in 1H NMR chemical shifts of borneol 1a and its derivatives containing various silyl protective groups 1d–1g along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Bottom row, C6D6. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
Figure 4. (a) Bornyl TBDMS 1d; (b) Bornyl DMMPS 1e; (c) Bornyl TBDPS 1f; (d) Bornyl TPS 1g. The changes in 1H NMR chemical shifts of borneol 1a and its derivatives containing various silyl protective groups 1d–1g along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Bottom row, C6D6. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
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Figure 5. (a) Isobornyl TBDMS 2d; (b) Isobornyl DMMPS 2e; (c) Isobornyl TBDPS 2f; (d) Isobornyl TPS 2g. The changes in 1H NMR chemical shifts of isoborneol 2a and its derivatives containing various silyl protective groups 2d–2g, along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Bottom row, C6D6. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
Figure 5. (a) Isobornyl TBDMS 2d; (b) Isobornyl DMMPS 2e; (c) Isobornyl TBDPS 2f; (d) Isobornyl TPS 2g. The changes in 1H NMR chemical shifts of isoborneol 2a and its derivatives containing various silyl protective groups 2d–2g, along with their Iso-chemical Shielding Surface (ICSS). Color of ICSS: pink, ICSS = −0.2 ppm; yellow-brown, ICSS = −0.5 ppm. Solvent used for the chemical shift values: Top row, CDCl3; Bottom row, C6D6. Color of changes in chemical shifts: Red, upfield shift upon the protection; Blue, downfield shift upon the protection; Black, less than ±0.02 ppm upon the protection.
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MDPI and ACS Style

Lyu, B.; Hiraga, Y.; Takagi, R.; Niwayama, S. Complete Assignments of 1H and 13C NMR Chemical Shift Changes Observed upon Protection of Hydroxy Group in Borneol and Isoborneol and Their DFT Verification. Molecules 2025, 30, 597. https://doi.org/10.3390/molecules30030597

AMA Style

Lyu B, Hiraga Y, Takagi R, Niwayama S. Complete Assignments of 1H and 13C NMR Chemical Shift Changes Observed upon Protection of Hydroxy Group in Borneol and Isoborneol and Their DFT Verification. Molecules. 2025; 30(3):597. https://doi.org/10.3390/molecules30030597

Chicago/Turabian Style

Lyu, Baohe, Yoshikazu Hiraga, Ryukichi Takagi, and Satomi Niwayama. 2025. "Complete Assignments of 1H and 13C NMR Chemical Shift Changes Observed upon Protection of Hydroxy Group in Borneol and Isoborneol and Their DFT Verification" Molecules 30, no. 3: 597. https://doi.org/10.3390/molecules30030597

APA Style

Lyu, B., Hiraga, Y., Takagi, R., & Niwayama, S. (2025). Complete Assignments of 1H and 13C NMR Chemical Shift Changes Observed upon Protection of Hydroxy Group in Borneol and Isoborneol and Their DFT Verification. Molecules, 30(3), 597. https://doi.org/10.3390/molecules30030597

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