Home Journals Articles Updates About
CN
image
收藏切换
Computational insights into the effects of reagent structure and bases on nucleophilic monofluoromethylation of aldehydes
收藏切换
PDF
Meng-Meng Zhenga, Hao-Dong Tana, Yueqian Sangb, Xiao-Song Xuea, b, *, Jin-Pei Chenga, c
Chinese Chemical Letters | 2022, 33(5) : 2387 - 2390
Less
收藏切换
Chinese Chemical Letters | 2022, 33(5): 2387-2390
• Communication •
Computational insights into the effects of reagent structure and bases on nucleophilic monofluoromethylation of aldehydes
Full
Meng-Meng Zhenga, Hao-Dong Tana, Yueqian Sangb, Xiao-Song Xuea, b, *, Jin-Pei Chenga, c
Affiliations
  • a State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
  • b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
  • c Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China
Published: 2022-05-15 doi: 10.1016/j.cclet.2021.11.045
Outline
收藏切换

Although fluorobis(phenylsulfonyl)methane (FBSM) and its cyclic analog 2-fluoro-1, 3-benzodithiole-1, 1, 3, 3-tetraoxide (FBDT) possess similar physicochemical properties, Shibata et al. found that FBSM failed to undergo nucleophilic monofluoromethylation of aldehydes regardless of the reaction conditions attempted (using various organic and inorganic bases). However, it was later discovered by Hu et al. that the nucleophilic monofluoromethylation could be accomplished by employing lithium hexamethyldisilazide (LiHMDS) as a base. Herein, we present an in-depth computational investigation into the intriguing effects of reagent structure and bases on the nucleophilic monofluoromethylation of aldehydes. The computations reveal the 1, 4-diazabicyclo[2.2.2]octane (DABCO) catalyzed nucleophilic monofluoromethylation of benzaldehyde with acyclic FBSM is a thermodynamically unfavorable process mainly due to the destabilizing O···O lone pair repulsions in FBSM product, whereas such repulsion could be largely avoided in FBDT product because of its constrained five-membered ring structure. Employing LiHMDS as a base can not only facilitate the nucleophilic monofluoromethylation via Li–O interactions but also render the monofluoromethylation of benzaldehyde with FBSM thermodynamically favored.

Nucleophilic monofluoromethylation  /  Fluoroalkylation reagent  /  DFT calculations  /  Thermodynamic effect  /  Lone pair repulsion
Meng-Meng Zheng, Hao-Dong Tan, Yueqian Sang, Xiao-Song Xue, Jin-Pei Cheng. Computational insights into the effects of reagent structure and bases on nucleophilic monofluoromethylation of aldehydes[J]. Chinese Chemical Letters, 2022 , 33 (5) : 2387 -2390 . DOI: 10.1016/j.cclet.2021.11.045
Full Text
Less
The increasing importance of the monofluoromethyl group in pharmaceuticals and agrochemicals as well as materials development has spurred tremendous efforts in the development of practical reagents for their incorporation into target molecules [1-17]. Among various fluoromethylating reagents, fluorobis(phenylsulfonyl)methane (FBSM) [18, 19] and its cyclic analog 2-fluoro-1, 3-benzodithiole-1, 1, 3, 3-tetraoxide (FBDT) [20] are popular nucleophilic reagents that have been widely used in monofluoromethylation reactions [21-29]. Interestingly, while FBSM and FBDT possess similar acidity (pKa of FBSM: 14.3 vs. FBDT: 13.5) [30] and their carbanions have comparable nucleophilicity (Mayr's nucleophilicity parameter (N) of FBSM: 17.46 vs. FBDT: 19.03) (Scheme 1a) [31], contrasting outcomes were observed in their reactions with aldehydes. In 2010, Shibata et al. found that the nucleophilic monofluoromethylation of aldehydes could proceed well with FBDT in the presence of 1, 4-diazabicyclo[2.2.2]octane (DABCO) (Scheme 1b), but no desired product was observed when the reagent was switched from FBDT to FBSM (Scheme 1c) [20]. However, Hu et al. subsequently demonstrated that employing an organometallic base lithium hexamethyldisilazide (LiHMDS) in combination with FBSM could enable the nucleophilic monofluoromethylation reaction of aldehydes at low temperatures (Scheme 1d) [32].
As a continuation of our research efforts on the structure−reactivity relationship and mechanism of fluorination/fluoroalkylation reagents [30, 33-51], we report herein a computational study of these important nucleophilic monofluoromethylation reactions with an aim of understanding: (a) why the two monofluoroalkylating reagents FBDT and FBSM gave completely different results under identical conditions despite possessing similar physicochemical properties (Scheme 1b vs. 1c)? (b) why changing the base from DABCO to LiHMDS could successfully promote the FBSM monofluoromethylation reaction (Scheme 1c vs. 1d)?
Density functional theory (DFT) calculations were performed at the M06–2X/6–311+G(2d, p)−SMD//M06–2X/6–31G(d, p)−SMD level of theory (see Supporting information for computational details). The computed free energy profiles of nucleophilic monofluoromethylation of benzaldehyde with FBDT and FBSM are summarized in Fig. 1. The first step is deprotonation of the reagent by DABCO to generate the hydrogen bond stabilized α-fluorocarbanion. The barrier for the deprotonation is slightly lower for FBDT (TS1a: 8.7 kcal/mol) than for FBSM (TS1b: 9.5 kcal/mol), in accord with our recent observation that the C-H bond is slightly more acidic in FBDT than in FBSM [30]. Then, nucleophilic attack of the resulting α-fluorocarbanion (Int1) on benzaldehyde via TS2, in which [DABCOH]+ simultaneously interacts with both sulfone and carbonyl moieties via hydrogen-bonding interactions, yields the products. The activation energy of nucleophilic addition for FBDT carbanion (12.6 kcal/mol) is slightly lower than that for FBSM carbanion (14.2 kcal/mol), in agreement with their nucleophilicity [31]. To review the overall energy profiles, the nucleophilic addition is the rate-determining step. The overall free energy barrier for FBDT is only 1.9 kcal/mol lower than that for FBSM, suggesting the observed experimentally contrasting outcomes are less likely a result of the kinetic effect. On the other hand, the nucleophilic monofluoromethylation of benzaldehyde by FBSM is a thermodynamically unfavorable process (ΔG = 3.5 kcal/mol), whereas it is a slightly favorable process by FBDT (ΔG = −0.1 kcal/mol). Therefore, the distinct behavior between FBDT and FBSM under DABCO catalysis is primarily a result of the thermodynamic, rather than kinetic, effects.
Scrutiny of the structure of monofluoromethylation product Pb revealed that the O···O distances between the carbonyl and sulfonyl oxygen are close to the sum of their van der Waals radii (Fig. 2). Indeed, the computed electrostatic potential map indicates the destabilizing O···O lone pair repulsions in Pb. Such repulsions should be much weaker in Pa due to the increased O···O distances as a result of the constraint of the five-membered ring in FBDT. Thus, the difference in the behavior of FBDT and FBSM can be mainly ascribed to the key difference in their structure (cyclic vs. acyclic) that results in different O···O lone pair repulsions in products.
Next, we explored why the nucleophilic addition of FBSM on benzaldehyde could be successfully promoted by changing the base from DABCO to LiHMDS. Computations of possible LiHMDS complexes suggest that the LiHMDS-benzaldehyde dimer is a stable complex that could work as a base (Scheme S1 in Supporting information for other higher energy LiHMDS complexes). As shown in Fig. 3, the dissociation of LiHMDS-benzaldehyde dimer assisted by FBSM to form Int0c is endergonic by 5.2 kcal/mol. The deprotonation of FBSM via TS1c, generating Li-coordinated α-fluorocarbanion Int1c, is exergonic by 13.5 kcal/mol. The barrier for the LiHMDS-deprotonation is 7.8 kcal/mol lower than that for DABCO-deprotonation. The following nucleophilic attack of α-fluorocarbanion to C=O double bond via TS2c leads to lithium carbinolate Int2c with a barrier of only 4.4 kcal/mol, much lower than that of the DABCO-catalyzed process. This can be attributed to the greater stabilization of nucleophilic attack transition state by the Li–O interactions [32] as compared to hydrogen-bonding interactions. Then, the protonation of lithium carbinolate Int2c by CF3CO2H gives product Pb. The overall process is calculated to be exergonic by 27.2 kcal/mol, with a very low barrier of 7.8 kcal/mol (from Subb to TS1c). Clearly, the use of LiHMDS could not only significantly reduce the barrier of nucleophilic monofluoromethylation (24.4DABCO vs. 7.8LiHMDS kcal/mol), but also render the reaction to be a highly thermodynamically favorable process (+3.5DABCO vs. −27.2LiHMDS kcal/mol). This explains why the nucleophilic monofluoromethylation could be accomplished by employing lithium hexamethyldisilazide (LiHMDS) as the base. In fact, the organic base DABCO participates in the reaction as a catalyst (Scheme 2a), while the organometallic base LiHMDS serves as both reactant and activator (Scheme 2b).
In summary, we have performed a computational study on the effects of reagent structure and bases on nucleophilic monofluoromethylation of aldehydes. The contrasting outcomes between cyclic FBDT and acyclic FBSM in DABCO-catalyzed nucleophilic monofluoromethylation of benzaldehyde are primarily a result of the thermodynamic effect. The nucleophilic monofluoromethylation of benzaldehyde with acyclic FBSM is a thermodynamically unfavorable process due to the O···O lone pair repulsions in the product. Such repulsions can be largely avoided in the FBDT product due to its cyclic structure. The use of LiHMDS can not only facilitate the nucleophilic monofluoromethylation via Li–O interactions, but also render the nucleophilic monofluoromethylation reaction thermodynamically favored. The insights obtained regarding reagent structure and bases on nucleophilic monofluoromethylation should be valuable in future efforts towards the design of new reactions.
Declaration of competing interest
Less
The authors declare no competing financial interest.
Acknowledgments
Less
This work was supported by the Natural Science Foundation of China (Nos. 22122104, 21933004 and 21702098). We thank professor Faguang Zhang at Tianjin University for helpful discussions.
Supplementary materials
Less
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2021.11.045
References
Less
[1]
G.K.S. Prakash, J. Hu, Acc. Chem. Res.40 (2007) 921–930.
[2]
N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry19 (2008) 2633–2644.
[3]
J. Hu, W. Zhang, F. Wang, Chem. Commun. (2009) 7465–7478.
[4]
J. Nie, H.C. Guo, D. Cahard, J.A. Ma, Chem. Rev. 111 (2011) 455–529.
[5]
G. Landelle, A. Panossian, S. Pazenok, J.P. Vors, F.R. Leroux, Beilstein J. Org. Chem. 9 (2013) 2476–2536.
[6]
J. Zhang, C. Jin, Y. Zhang, Chin. J. Org. Chem. 34 (2014) 662–680.
[7]
J.H. Lin, J.C. Xiao, Tetrahedron Lett. 55 (2014) 6147–6155.
[8]
C. Ni, M. Hu, J. Hu, Chem. Rev. 115 (2015) 765–825.
[9]
X. Yang, T. Wu, R.J. Phipps, F.D. Toste, Chem. Rev. 115 (2015) 826–870.
[10]
C. Ni, L. Zhu, J. Hu, Acta Chim. Sinica73 (2015) 90–115.
[11]
C. Ni, J. Hu, Chem. Soc. Rev. 45 (2016) 5441–5454.
[12]
N. Shibata, Bull. Chem. Soc. Jpn. 89 (2016) 1307–1320.
[13]
H.X. Song, Q.Y. Han, C.L. Zhao, C.P. Zhang, Green Chem. 20 (2018) 1662–1731.
[14]
T. Koike, M. Akita, Org. Biomol. Chem. 17 (2019) 5413–5419.
[15]
F.G. Zhang, X.Q. Wang, Y. Zhou, et al., Chem. Eur. J. 26 (2020) 15378–15396.
[16]
M. Reichel, K. Karaghiosoff, Angew. Chem. Int. Ed. 59 (2020) 12268–12281.
[17]
Y. Liu, C. Li, J. Meng, et al., Chin. J. Org. Chem. 40 (2020) 2322–2337.
[18]
C. Ni, Y. Li, J. Hu, J. Org. Chem. 71 (2006) 6829–6833.
[19]
T. Fukuzumi, N. Shibata, M. Sugiura, et al., Angew. Chem. Int. Ed. 45 (2006) 4973–4977.
[20]
T. Furukawa, Y. Goto, J. Kawazoe, et al., Angew. Chem. Int. Ed. 49 (2010) 1642–1647.
[21]
S. Mizuta, N. Shibata, Y. Goto, et al., J. Am. Chem. Soc. 129 (2007) 6394–6395.
[22]
G.K.S. Prakash, S. Chacko, S. Alconcel, et al., Angew. Chem. Int. Ed. 119 (2007) 5021–5024.
[23]
C. Ni, L. Zhang, J. Hu, J. Org. Chem. 73 (2008) 5699–5713.
[24]
C. Ni, J. Hu, Tetrahedron Lett. 50 (2009) 7252–7255.
[25]
M. Ogasawara, H. Murakami, T. Furukawa, T. Takahashi, N. Shibata, Chem. Commun. (2009) 7366–7368.
[26]
G.K.S. Prakash, F. Wang, N. Shao, et al., Angew. Chem. Int. Ed. 48 (2009) 5358–5362.
[27]
G.K.S. Prakash, S. Chacko, H. Vaghoo, et al., Org. Lett. 11 (2009) 1127–1130.
[28]
T. Furukawa, J. Kawazoe, W. Zhang, et al., Angew. Chem. Int. Ed. 50 (2011) 9684–9688.
[29]
H. Ma, K. Matsuzaki, Y.D. Yang, et al., Chem. Commun. 49 (2013) 11206–11208.
[30]
H. Zheng, Z. Li, J. Jing, X.S. Xue, J.P. Cheng, Angew. Chem. Int. Ed. 60 (2021) 9401–9406.
[31]
Z. Zhang, A. Puente, F. Wang, et al., Angew. Chem. Int. Ed. 55 (2016) 12845–12849.
[32]
X. Shen, L. Zhang, Y. Zhao, et al., Angew. Chem. Int. Ed. 50 (2011) 2588–2592.
[33]
M. Li, X.S. Xue, J.P. Cheng, Acc. Chem. Res. 53 (2020) 182–197.
[34]
M. Li, H. Zheng, X.S. Xue, J.P. Cheng, Tetrahedron Lett. 59 (2018) 1278–1285.
[35]
M. Li, J. Guo, X.S. Xue, J.P. Cheng, Org. Lett. 18 (2016) 264–267.
[36]
B. Zhou, T. Yan, X.S. Xue, J.P. Cheng, Org. Lett. 18 (2016) 6128–6131.
[37]
M. Li, X.S. Xue, J. Guo, Y. Wang, J.P. Cheng, J. Org. Chem. 81 (2016) 3119–3126.
[38]
X.S. Xue, Y. Wang, M. Li, J.P. Cheng, J. Org. Chem. 81 (2016) 4280–4289.
[39]
T. Yan, B. Zhou, X.S. Xue, J.P. Cheng, J. Org. Chem. 81 (2016) 9006–9011.
[40]
M. Li, X.S. Xue, J.P. Cheng, ACS Catal. 7 (2017) 7977–7986.
[41]
M. Li, B. Zhou, X.S. Xue, J.P. Cheng, J. Org. Chem. 82 (2017) 8697–8702.
[42]
J.D. Yang, Y. Wang, X.S. Xue, J.P. Cheng, J. Org. Chem. 82 (2017) 4129–4135.
[43]
B. Zhou, X.S. Xue, J.P. Cheng, Tetrahedron Lett. 58 (2017) 1287–1291.
[44]
M. Li, Y. Wang, X.S. Xue, J.P. Cheng, Asian J. Org. Chem. 6 (2017) 235–240.
[45]
B. Zhou, M.K. Haj, E.N. Jacobsen, K.N. Houk, X.S. Xue, J. Am. Chem. Soc. 140 (2018) 15206–15218.
[46]
J. Zhang, J.D. Yang, H. Zheng, et al., Angew. Chem. Int. Ed. 57 (2018) 12690–12695.
[47]
M. Li, Y. Sang, X.S. Xue, J.P. Cheng, J. Org. Chem. 83 (2018) 3333–3338.
[48]
M. Li, H. Zheng, X.S. Xue, J.P. Cheng, Tetrahedron Lett. 59 (2018) 1278–1285.
[49]
M. Li, H. Kang, X.S. Xue, J.P. Cheng, Acta Chim. Sinica76 (2018) 988–996.
[50]
J.D. Yang, M. Li, X.S. Xue, Chin. J. Chem. 37 (2019) 359–363.
[51]
H. Kang, B. Zhou, M. Li, X.S. Xue, J.P. Cheng, Chin. J. Chem. 38 (2020) 130–134.
Appendix
Less
Year 2022 volume 33 Issue 5
PDF
44
24
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.cclet.2021.11.045
  • Receive Date：2021-09-18
  • Online Date：2025-12-19
  • Published：2022-05-15
Article Data
Affiliations
History
  • Received：2021-09-18
  • Revised：2021-11-13
  • Accepted：2021-11-15
Affiliations
    a State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
    b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
    c Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China
References
Share
https://castjournals.cast.org.cn/joweb/ccl/EN/10.1016/j.cclet.2021.11.045
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House