The Strong β-CF3 Shielding Effect in Hexafluoroisopropanol and 100 Other Organic Solvents Revisited with 17O NMR Spectroscopy.

An 17O NMR spectroscopy survey of more than 100 ubiquitous organic solvents and compounds, including some typical oxofluorinated solvents such as hexafluoroisopropanol, trifluoroethanol, trifluoroacetic acid, and others, is presented with D2O as a reference. A strong alternating α,β-CF3-substituent chemical shift effect was thus observed. This alternating deshielding-shielding effect is suspected to have a role in the exceptional properties of these oxofluorinated solvents, notably in oxidative cross-coupling reactions.

The fluorinated alcohols hexafluoroisopropanol (HFIP), trifluoroethanol (TFE), and related compounds have recently shown remarkable solvent properties, notably for cross‐dehydrogenative coupling reactions (Scheme 1).1 However, these solvent‐accelerating effects, often at mild temperatures or at room temperature, are still not well understood. Thus, in this work, a comparative 17O NMR spectroscopy study of these compounds is proposed. In general, 17O NMR spectroscopy remains largely underappreciated for the routine characterization of organic molecules, in contrast to 1H NMR, 13C NMR, 31P NMR, 19F NMR, and 15 n NMR spectroscopy. Very few exhaustive studies exist,2 and even fewer include organic oxofluorinated compounds.3 This is surprising, because oxygen and oxidation processes are at the heart of organic processes. This characterization technique, which is reputed to be very sensitive to electronic and steric environments,2, 3, 4 has been notably well developed in other fields of chemistry5 despite the relatively low abundance of 17O (0.04 % on earth). A selection of 100 ubiquitous organic compounds, including notorious HFIP and TFE, is thus herein revisited by 17O NMR spectroscopy with the aim of revealing what makes those oxofluorinated solvents so special. Another objective of this work is to provide an updated 17O NMR spectroscopy table of organic compounds with comparable measuring conditions,6 which could arguably be useful for the development of oxidative coupling reactions.7 All spectra are provided in the Supporting Information.

Scheme 1

A selected cross‐dehydrogenative coupling reaction enabled by HFIP.1e

In all cases, D2O was chosen as a δ=0.0 ppm chemical‐shift reference. All measurements were performed with a standard, either D2O (δ=0.0 ppm) or alternatively CD3OD (δ=−35.3 ppm), in a melted glass capillary, which was placed inside every NMR tube. Neat results are reported in Table 1. In general, the margin of error is considered to be Δδ±0.4 ppm or less (Bruker FT‐NMR Avance I, 1H: 600 MHz, 17O: 81.4 MHz) on the basis of certain selected entries that were measured multiple times (see the Supporting Information). For the 17O NMR lines that are described as broad (br) however, a precautionary Δδ±1 ppm precision should be considered. In a few broadest cases (very br), the values were rounded up to the nearest integer and a precautionary Δδ±2 ppm precision should be considered. The measuring temperature was 22 °C for all samples. The average 17O NMR spectrum contains typically 4096 scans, representing an acquisition time of approximatively 20 min. Indicatively, in the case of methanol (Table 1, entry 3), the neat sample had a molarity of approximatively 24.7 mol L−1. For convenience, only compounds that are liquid at 22 °C were considered.

Table 1

17O NMR (17O: 81.4 MHz, T=22 °C, relaxation delay of 50 ms, at least 2048 scans) neat chemical shifts from D2O (δ=0.0 ppm).[a]

Entry	Compound	δ [ppm]	Description
1	H2O	+3.1	–
2[b]	H2O	+3.5	–
3	MeOH	−32.9	m
4	EtOH	+9.4	–
5[b]	PrOH	+3.0	–
6[b]	CF3(CH2)2OH	−2.3	–
7[b]	BuOH	+2.8	–
8[b]	Me(CH2)4OH	+4.7	–
9[b]	Me(CH2)5OH	+3.5	br
10	iPrOH	+42.5	br
11	(CF3)2CHOH (HFIP)	−8.5	br
12	CF3CH2OH (TFE)	−20.2	–
13[b]	HCF2CH2OH	−20.5	–
14[b]	CCl3CH2OH (TCE)	+18	very br
15	(CF3)3COH	+4.5	–
16	tBuOH	+67.6	br
17	BnOH	+7.9	br
18[b]	glycol	−5.5	br
19[b]	1,3‐propanediol	−1	very br
20[b]	cyclobutanol	+45.3	br
21[b]	cyclopentanol	+37	very br
22[b]	diethylene glycol	−2	very br
23	2‐methoxyethanol	−22.4, −5.4	–
24	allyl alcohol	+1.9	–
25	propargyl alcohol	+3.3	–
26	Et2O	+17.1	–
27[b]	CF3CH2OCH2CF3	−26.0	–
28	(iPr)2O	+63.6	–
29	tBuOMe	+19.9	–
30	cyclopentyl methyl ether	+5.1	–
31	THF	+19.5	–
32	tetrahydropyran	+12.1	–
33	1,4‐dioxane	+2.4	–
34	morpholine	+7.0	–
35	1,2‐dimethoxyethane	−21.2	–
36	diglyme	−21.1	–
37	MeOCHCl2	+68.9	–
38	anisole	+50.6	–
39	PhOCF3	+113.6	–
40	PhOCF2H	+118.4	‐
41	1,2‐dimethoxybenzene	+37.2	br
42	enflurane[c]	+127.7	m
43	HC(Cl)(F)CF2OMe	+41.1	–
44	HCF2OCH(Cl)CF3	+97.3	–
45	MeOCH2CF3	−35.6	lowest δ of table
46	HCF2CF2OMe	+38.4	–
47	2‐bromotetrafluoroethyl trifluorovinyl ether	+98.8	–
48	perfluoro(propyl vinyl ether)	+98.5	–
49	furan	+240.1	t, 2 J O,H≈15 Hz
50	2‐ethylphenol	+76	very br
51	3‐(trifluoromethyl)phenol	+82	very br
52	2‐bromophenol	+82.4	br
53	2‐fluorophenol	+55.3	br
54	3‐fluorophenol	+80	very br
55	3‐chlorophenol	+74.5	br
56	3,5‐bis(trifluoromethyl)phenol	+80	very br
57	formic acid	+260.8	–
58	acetic acid	+258.1	–
59	trifluoroacetic acid	+243.9	–
60	Ac2O	+273.8	–
61	propionic acid	+251.9	–
62	CF3CH2CO2H	+259.5	–
63	butyric acid	+254.0	–
64	isobutyric acid	+248.9	–
65	acetyl chloride	+509.7	–
66	propanoyl chloride	+501.4	–
67	pentanoyl chloride	+504.8	–
68	benzoyl chloride	+487.3	–
69	oxalyl dichloride	+524.3	–
70	ethyl chlorformate	+172.9,+351.2	–
71	isobutyric acid	+248.9	–
72	triflic acid	+147.0	–
73	MeOAc	+141.0,+363.3	–
74	EtOAc	+171.8,+364.7	–
75	BuOAc	+167.2,+365.8	–
76	tBuOAc	+205.1,+377.8	–
77	iPrOAc	+196.8,+365.1	–
78	PhOAc	+202.0,+372.8	br
79	tBuOAc	+205.1,+377.8	–
80	methyl isobutyrate	+134.2,+353.2	–
81	MeOCOCH(CF3)2	+149.1,+375.4	–
82	dimethyl carbonate	+92.7,+240.6	–
83	diethyl carbonate	+122.5,+241.4	–
84	DMF	+326.4	–
85	dimethyl acetamide	+345.4	–
86	N‐methylpyrrolidin‐2‐one	+301.3	–
87	DMPU[d]	+234.7	–
88	DMI[e]	+207.9	–
89	γ‐butyrolactone	+179.5,+338.6	–
90	BrCF2COOEt	+157.6,+345.4	–
91	propanal	+587.6	–
92	isobutyraldehyde	+580.7	–
93	benzaldehyde	+562.5	–
94	p‐anisaldehyde	+68, +542	very br
95	salicylaldehyde	+84.7, +506.0	–
96	furfural (2‐furaldehyde)	+238.1,+530.7	–
97	trans‐cinnamaldehyde	+569.2	br
98	acetone	+575.5	–
99	hexachloroacetone	+539.3	br
100	2‐butanone	+564.4	–
101	4,4,4‐trifluorobutan‐2‐one	+582.0	–
102	3‐pentanone	+551.9	–
103	acetophenone	+553.3	–
104	α,α,α‐trifluoroacetophenone	+548.5	–
105	pivalophenone	+568.0	br
106	cyclohexanone	+563.7	–
107	acetylacetone	+579.7,+278.6	(two tautomers)
108	dipivaloylmethane[f]	+270.8	–
109	DMSO	+18.4	–
110	nitromethane	+610.0	–
111	nitrobenzene	+573.8	–
112	(tBuO)2	+270.3	–
113	tBuO2H	+209, +249	very br
114	(MeO)3P	+46.4	d, 1 J O,P=156 Hz
115	(MeO)3PO	+23.0,+75.5	d, 1 J O,P=160 Hz
116	PhNCO	+115.9	–
117	EtNCO	+91.1	–

[a] D2O as standard. [b] D2O standard replaced by CD3OD. [c] 2‐Chloro‐1,1,2,‐trifluoroethyl‐difluoromethyl ether. [d] 1,3‐Dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone. [e] 1,3‐Dimethyl‐2‐imidazolidinone. [f] 2,2,6,6‐Tetramethyl‐3,5‐heptanedione.

With the aim of producing a useful set of data and to illustrate the high chemical‐shift sensitivity of 17O NMR spectroscopy, proximal isotopic effects were also studied (Table 2). Clearly, in comparison to other nuclei such as 13C, 17O NMR spectroscopy is very susceptible to isotope chemical‐shifting effects. D2O and H2O are, for example, separated by a full Δδ=3.3 ppm. For comparison, the 13C NMR signal of CD2Cl2 (δ=+53.84 ppm) and that of CH2Cl2 (δ=+54.24 ppm) are separated by only Δδ=0.4 ppm.6 CDCl3 and CHCl3 are moreover separated by only Δδ=0.3 ppm.6 In contrast, even remote isotopic differences can be detected with 17O NMR spectroscopy (notably in [D6]DMSO, 13CD3OD, and Ph15NO2; see Table 2).

Table 2

17O NMR (Bruker 600, 17O: 81.4 MHz, RT: 22 °C) chemical shifts of some isotopically enriched compounds compared to natural abundance analogues.[a]

Entry	Compound	δ [ppm]	Δδ [ppm]
1[b]	D2O/H2O	+0.0/+3.3	−3.3
2[b]	CD3OD/MeOH	−35.3/−32.9	−2.4
3	13CD3OD/CD3OD	−35.8/−35.3	−0.5
4[b]	[D8]THF/THF	+17.7/+19.5	−1.8
5[b]	AcOD/AcOH	+257.4/+258.1	−0.7
6[b]	[D6]acetone/acetone	+576.2/+575.5	−0.7
7[b]	[D6]DMSO/DMSO	+16.1/+18.4	−2.3
8[b]	CD3NO2/MeNO2	+609.9/+610.0	−0.1
9	Ph15NO2/PhNO2	+573.3/+573.8	−0.5

[a] D2O as standard. [b] The chemical shift of this compound is the average of five different measuring experiments, see the Supporting Information.

Before discussing the chemical‐shift trends in more detail, notably, as a result of the general broadness of the signals, spin–spin NMR couplings are seldom observed. In one exceptionally sharp case, for example, that of furan, a rare 2 J could be simulated, which is depicted in Figure 1. Given the general broadness of the signals, however, such an NMR coupling should be taken with caution. Moreover, the steric environment of the oxygen atom is well known to impose a very large effect on the 17O NMR chemical shift.4 This is conspicuous in Table 1 upon comparing methyl, ethyl, isopropyl, and tert‐butyl substituents, in stark contrast to linear alkyl chains (see Figure 2). Some explanative theories have been developed in the past that suggest intramolecular β C−H⋅⋅⋅O interactions.4 Fluorine substituent effects, however, have been less documented.3 Those differ considerably from non‐fluorinated alkyl chains (Figure 2, red plot). Moreover, their position with respect to the oxygen atom is decisive. In Figure 3, some α and β CF3 substituents are compared frontally to their Me analogues. Clearly, whereas an α‐positioned trifluoromethyl group (such as in CF3−O) will have, as expected, a strong deshielding effect on the oxygen atom owing to a strong withdrawing inductive effect, exactly the reverse occurs on the β position (CF3−C−O). This causes solvents such as HFIP and TFE to possess extremely shielded oxygen atoms (δ=−8.5 and −20.2 ppm, respectively) in comparison to their non‐fluorinated analogues. A few other similar cases are illustrated in Figure 3.

Figure 1

The limits of spin–spin NMR couplings: experimental (—) and simulated (—) 17O NMR profile (81.4 MHz) of furan, δ=+240.1 ppm, and the detectable 2 J ≈15 Hz (triplet).

Figure 2

Substituent chemical shift (SCS) effects: 17O NMR chemical shift from D2O (vertical axis) versus number of carbon atoms (horizontal axis).

Figure 3

α, β, and γ CX substituent chemical shift (SCS) effects compared to a non‐halogenated analogue, Δδ chemical shift (17O NMR, vertical axis, ppm).

It should be noted here that β−CF3 shielding effects are not restricted to 17O NMR spectroscopy. 13C NMR spectroscopy is also susceptible, although to a lesser extent. A CF3 substituent will typically deshield an α‐carbon atom but shield a β‐carbon atom. The case of isopropanol versus trifluoroisopropanol illustrates this point.8

Comparing CF3 with CCl3 and CF2H

Interestingly, hexachloroacetone and HFIP display similarly strong 17O NMR β‐shielding effects (Δδ=−36.2 and −51.0 ppm, respectively). Surprisingly, however, β‐trichloroethanol behaves very differently form β‐trifluoroethanol (Δδ=+8.4 and −29.6 ppm, respectively). A reasonable interpretation could arise from the involvement of chlorine atoms in significant intra‐ and intermolecular H‐bonding networks (O−H⋅⋅⋅Cl). Indeed, chlorine is a better H‐bond acceptor than fluorine, and this difference may account for a greater deshielding of the oxygen atoms in chloroalcohols. The two latter solvents may thus possess very different solvation and catalytic properties.

In contrast, trifluoroethanol (TFE) and difluoroethanol have very close chemical shifts, δ=−20.2 and −20.5 ppm, respectively. The difference is therefore beneath the margin of error (estimated at Δδ±0.4 ppm). Likewise, trifluoroanisole and difluoroanisole are separated by only Δδ=4.8 ppm, in spite of the proximity of the fluorine atoms with respect to the oxygen atom (Figure 3). Thus, the CF3 and CF2H groups have a surprisingly similar impact on the shielding of proximal oxygen atoms.

In conclusion, the 17O NMR spectrum of TFE and especially that of HFIP shows a strong shielding effect of the β−CF3 functional groups, in comparison to the non‐fluorinated analogues (Δδ=−29.6 and −51.0 ppm, respectively). In the case of HFIP, the severely increased shielding on the oxygen atom may in part be linked to its efficiency as a solvent in terms of high polarity and ability to stabilize charged transition states. Perfluoro‐tert‐butyl alcohol [(CF3)3COH] displays the largest β−CF3 shielding effect of the study (Δδ=−63.1 ppm).9 A propos perfluoro‐tert‐butyl alcohol, Larossa very recently demonstrated the use of the corresponding potassium salt, (CF3)3COK, as a privileged base in a frontier C−H arylation reaction of benzoic acids catalyzed by a Ru catalyst.10, 11 The β−CCl3 effects were also found to be pronounced, which indicates that oxochlorinated solvents may also have interesting properties for cross‐dehydrogenative coupling reactions. In general, this study shows the importance of the relative position of the CF3 group and related functional groups on the shielded or deshielded character of neighboring oxygen atoms. These effects might impact solvent design in the development of future chemical reactions. Furthermore, 17O NMR spectroscopy of organic compounds can be utilized on a routine basis, with relatively short acquisition times. The large span of 17O NMR shifts allows for the rapid and unambiguous recognition of all the typical functional groups of organic chemistry. Moreover, the strong sensitivity of 17O to remote steric, electronic, H‐bonding, and even isotopic alterations make this characterization technique indispensable for organic chemistry.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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