Determining the predominant tautomeric structure of iodine-based group-transfer reagents by 17O NMR spectroscopy

Article abstract of DOI:10.3762/bjoc.14.203

Cyclic benziodoxole systems have become a premier scaffold for the design of electrophilic transfer reagents. A particularly intriguing aspect is the fundamental I^I–I^III tautomerism about the hypervalent bond, which has led in certain cases to a surprising re-evaluation of the classic hypervalent structure. Thus, through a combination of ¹⁷O NMR spectroscopy at natural abundance with DFT calculations, we establish a convenient method to provide solution-phase structural insights for this class of ubiquitous reagents. In particular, we confirm that Shen’s revised, electrophilic SCF₃-transfer reagent also adopts an "acyclic" thioperoxide tautomeric form in solution. After calibration, the approach described herein likely provides a more general and direct method to distinguish between cyclic and acyclic structural features based on a single experimental ¹⁷O NMR spectrum and a computationally-derived isotropic shift value. Furthermore, we apply this structural elucidation technique to predict the constitution of an electrophilic iodine-based cyano-transfer reagent as an NC–I–O motif and study the acid-mediated activation of Togni's trifluoromethylation reagent.

Full text of DOI:10.3762/bjoc.14.203

Determining the predominant tautomeric structure
of iodine-based group-transfer reagents
by 17O NMR spectroscopy
Nico Santschi*, Cody Ross Pitts, Benson J. Jelier and René Verel
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2289–2294.
Eidgenössische Technische Hochschule (ETH) Zürich, Department of
Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 1/2, 8093
Zürich, Switzerland
doi:10.3762/bjoc.14.203
Received: 14 February 2018
Accepted: 23 July 2018
Email:
Published: 30 August 2018
Nico Santschi* - snico@inorg.chem.ethz.ch
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
* Corresponding author
Keywords:
Guest Editor: T. Wirth
electrophilic; hypervalent iodine; 17O NMR spectroscopy;
trifluoromethylation; trifluoromethylthiolation
© 2018 Santschi et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Cyclic benziodoxole systems have become a premier scaffold for the design of electrophilic transfer reagents. A particularly
intriguing aspect is the fundamental II–IIII tautomerism about the hypervalent bond, which has led in certain cases to a surprising
re-evaluation of the classic hypervalent structure. Thus, through a combination of 17O NMR spectroscopy at natural abundance with
DFT calculations, we establish a convenient method to provide solution-phase structural insights for this class of ubiquitous
reagents. In particular, we confirm that Shen’s revised, electrophilic SCF3-transfer reagent also adopts an "acyclic" thioperoxide
tautomeric form in solution. After calibration, the approach described herein likely provides a more general and direct method to
distinguish between cyclic and acyclic structural features based on a single experimental 17O NMR spectrum and a computation-
ally-derived isotropic shift value. Furthermore, we apply this structural elucidation technique to predict the constitution of an elec-
trophilic iodine-based cyano-transfer reagent as an NC–I–O motif and study the acid-mediated activation of Togni's trifluoro-
methylation reagent.
Introduction
The remarkable stability and reactivity of Togni's hypervalent afforded an isolable and powerful electrophilic SCF3 source,
iodine-based trifluoromethylation reagents (e.g., 4a) [1] have which was used, for example, in α-ketone functionalizations
inspired the development of analogous compounds, including a among other reactions [2,3]. While at the time the proposed
well-known SCF3-transfer reagent 5 in 2013 by Shen and cyclic hypervalent iodine structure 5a appeared reasonable in
co-workers [2,3]. In the presence of AgSCF3, chloroiodane 2a analogy to other well-established transfer reagents, it was
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unequivocally demonstrated to exist as the acyclic thioperoxide tandem with gauge-independent atomic orbital (GIAO) calcula-
tautomer 5b by Buchwald and co-workers in 2014 [4]. The tions may be a viable approach to establishing the predominant
structural reassignment was prompted by a series of remarkable, tautomer in solution.
detailed inspections of 1H NMR spectra of precursors and
congeners. A final structural corroboration came about by suc- Results and Discussion
cessfully encapsulating 5b, an oil under ambient conditions, in a Arguably, the most common methods for structural elucidation
metal-organic framework (5b@MOF). This non-trivial protocol of small organic molecules are one-dimensional 1H and
rendered it amenable to X-ray diffraction studies confirming the 13C NMR spectroscopic techniques in combination with suit-
aforementioned structural reassignment. From a theoretical able two-dimensional experiments (COSY, HMBC, NOESY,
standpoint, acyclic isomer 5b is predicted to be thermodynami- etc.) [7]. However, in many cases (e.g., 5a versus 5b) these may
cally favored over the cyclic form 5a by more than 10 kcal/mol only provide limited information, as neither nucleus is a prima-
by DFT calculations [5]. However, this type of computational ry constituent of the central iodine(III) (a, X–I–O) or iodine(I)
analysis is in general still not decisive. For example, while (b, O–X) motif of interest. In stark contrast, changes in the
Togni reagent 4a is thermodynamically less favorable than its oxygen ligand's environment should be readily traceable upon
acyclic isomer 4b by over 50 kcal/mol, a high kinetic barrier oxidation from alcohol 1 to chloroiodane 2a (Figure 1, maroon),
suppresses the [a → b] isomerization (Figure 1) [5,6].
as well as during ensuing ligand substitutions, for example to
fluoroiodane 3a. In particular, whether oxygen is covalently
With SCF3 reagent 5a/5b, structure determination was notably bound to iodine or another element may heavily influence its
challenging and solely provides a solid-state structural perspec- shielding and thereby provide structural information by means
tive. Thus, we wondered whether a correct structural assign- of 17O NMR spectroscopy.
ment of reagent 5a/b would have been feasible without having
to resort to the preparation of crystalline congeners and/or the While natural abundance 17O NMR has been employed previ-
preparation of 5b@MOF. Importantly, establishing a reliable ously, including the analysis of hypervalent iodine compounds
way to differentiate cyclic (a) from acyclic (b) isomers in solu- [8-10], this spectroscopic method has not yet found its entry
tion would facilitate future structure determination of similar into the organic chemist's standard NMR toolbox. This, in large
iodine-based group-transfer reagents and provide greater mech- part, may be attributed to the extremely low natural abundance
anistic insight into reactivity of these reagents (Figure 1). Ac- of the 17O isotope (<0.04%) [11,12]. Consequently, the experi-
cordingly, we describe herein how 17O NMR spectroscopy in ment requires high sample concentrations and relatively long
Figure 1: Tautomerism in iodine-based group-transfer reagents probed by 17O NMR spectroscopy (A) and key structures investigated herein (B).
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experimental times, and ultimately fairly broad signals are ob- systematic and therefore, be accounted for by the abovemen-
served. Yet, due to the large chemical shift range available tioned referencing to experimentally determined values.
(>1000 ppm), the technique may still prove diagnostic, espe-
cially when paired with calculated oxygen isotropic shift values. We found that the calculated δiso-values for the two isomers
In order to substantiate this working hypothesis, five pairs of 2a/b and 4a/b differ by ∆δiso ≈ 20; these differences are signifi-
cyclic (a) vs acyclic (b) structural isomers 2–6 were investigat- cantly larger for 3a/b (∆δiso = −399.1), 5a/b (∆δiso = 81.2) and
ed initially by DFT at the ωB97XD/aug-cc-pVDZ 6a/b (∆δiso = 52.7). Given that the larger the difference ∆δiso,
(aug-cc-pVDZ-PP basis set for iodine [6,13]) level of theory the more likely a successful structural assignment based on
using Gaussian 09 [14,15]. The ωB97XD functional was chosen 17O NMR spectroscopy becomes, this technique may indeed
as a reasonably cost-effective way to include long-range disper- prove useful for the identification of the isomeric pairs 2–6. Ac-
sion [14].
cordingly, spectral data on 1, 2a, 3a, 4a, 5 (assuming no assign-
ment ), and 6 (unassigned) were acquired and further supple-
Geometry optimizations of both cyclic and acyclic isomers were mented with values from some additional, structurally well-
followed by calculation of oxygen isotropic shift values (δiso) characterized hypervalent iodine compounds available in the lit-
using the GIAO method (Table 1) [8-10]. Furthermore, these erature (see Table 1 and Supporting Information File 1). Thus, a
computed isotropic shift values (δiso) were not referenced, for data set with a total of 11 entries was obtained.
example to water, since they were directly correlated to experi-
mentally determined 17O NMR shifts (vide infra). In addition, To obtain experimental 17O NMR shifts, we used samples pre-
note that the calculations did not include treatment of spin- pared in chloroform-d at a concentration of approximately
orbit-induced heavy-atom effects [16]. While undoubtedly im- 1.3 M. The obtained resonances typically featured a full-width
portant in the framework of classical bonding paradigms, they at half maximum of around 1000–1500 Hz (Figure 2A). There-
will only have a negligible effect on oxygen shifts derived for fore, the uncertainties of the determined 17O chemical shift
hypervalent iodine species. Specifically, spin-orbit effects values δobs are rated at a minimum of ±10 ppm, and thus, a reli-
heavily depend on and propagate through s-character rich able structural assignment should become feasible if predicted
bonds. However, within classical bonding theory the hyperva- shift differences between the constitutional isomers a and b are
lent bond about iodine comprises purely of p-orbitals (Rundle- greater. The observed 17O NMR chemical shifts ranged from
Pimentel model) and most recently, this notion was corrobo- 32 ppm (5) to 137 ppm (a C2F5-transfer reagent). Compounds
rated for structure 4a in a computational study [17]. Hence, 2a and 4a resonate at similar frequencies, with respective chem-
effects on oxygen isotropic shifts will be minor at best and ical shifts of 116 ppm and 130 ppm. For compound 5, an
Table 1: Compilation of δiso, δobs and δcalc values.
entry
tautomer
δisoa
δobsb [ppm]
δcalcc [ppm]
|δcalc – δobs|
1
–
a
b
a
b
a
b
a
b
a
b
249.7
192.7
203.6
236.2
−162.9
180.1
203.8
173.6
254.8
186.3
239.0
67
116
–
42
25
0
–
1
–
2
–
–
4
9
–
2 (X = Cl)
116
102
60
3 (X = F)
59
–
575
132
101
140
36
4 (X = CF3)
5 (X = SCF3)
6 (X = CN)
130
–
–
32
115
–
124
56
aδiso: computed isotropic shift value; bδobs: observed (experimental) chemical shift; cδcalc: calculated (predicted) chemical shift.
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approximately 100 ppm smaller chemical shift value was ob-
served with δobs = 32 ppm, and for unassigned structure 6 we
measured 115 ppm. It is noteworthy to indicate that under
certain circumstances the absolute 17O NMR shift alone may be
misleading in structure determination. For instance, the experi-
mental value of 59 ppm for the known cyclic fluoroiodinane 3a
is closer to the observed values of acyclic 1 (67 ppm) and 5b
(32 ppm) than it is to cyclic 2a and 4a. However, assessment of
the DFT-calculated isotropic shift values (δiso) in tandem with
experimental 17O NMR data (δobs) lends credence to the afore-
mentioned structural assignment. Specifically, for the "unas-
signed" compounds mentioned above, the best R2-value for a
linear relationship δobs ~ δiso is obtained when 5 and 6 are
assigned as 5b and 6a, where the additional known compounds
serve as calibration (Figure 2B) [18]. Based on the thus derived
equation, 17O NMR chemical shifts δcalc can be predicted for
both isomers. A notable exception is the free alcohol 1, which is
not part of the linear relationship and consequently displays a
large residual value (Table 1). Conceivably, this may be due to
intermolecular hydrogen bonding with the solvent or other
alcohol molecules in the concentrated solution. In fact, includ-
ing a methanol solvent molecule as a hydrogen-bond donor in
the DFT calculation will shift the δcalc in the right direction for
1 (i.e., to δcalc = 47 ppm based on δiso = 245.8, although
|δcalc – δobs| is still 20 ppm).
For the pair 5a/b a difference ∆δcalc of 104 ppm is obtained and
a value of 68 ppm results for 6a/b (Figure 2). Both figures are
significantly larger than the 17O chemical shift's lower-bound
uncertainty estimate of ±10 ppm. While 5a/b indeed has been
shown to exist as the thioperoxide 5b (vide infra), a crystallo-
graphic study on 6a/b is required to corroborate our prediction
as 6a.
Figure 2: Assignment of acyclic (b) and cyclic (a) structures to 5 and
6, respectively, based on computed isotropic shift values (δiso) and ex-
perimental 17O NMR chemical shifts (δobs).
To further gauge the utility of this approach, the activation of
Togni reagent 4a was studied, in particular its protonation with
a strong acid [1]. This brings about a significant elongation of
the I–O bond from 2.203(5) Å in 4a to 2.4991(13) Å in the fully
protonated form 4c [1,19]. Most recently, Toste and co-workers
studied this activation strategy too and demonstrated that in the
presence of an equivalent of gaseous HCl compound 4a
afforded an isolable iodonium-type structure [20]. Although this
activation can be conveniently followed by 19F NMR spectros-
copy with 4a resonating at −40.1 ppm and the fully protonated
“iodonium” congener 4c at −20 ppm [1], this technique
provides no indication on how to best represent 4c in solution.
Does the compound resemble the molecular structure obtained
in the solid state with oxygen still coordinated to iodine or
would a free alcohol be a more accurate representation? In order
to generate 4c, reagent 4a was treated with five equivalents of
trifluoroacetic acid (TFA) and then subjected to spectroscopic
analysis. A 19F NMR chemical shift of −23.2 ppm was ob-
tained, thereby confirming the presence of 4c. However, under
these strongly acidic and activating conditions, the compound is
unstable over a prolonged period of time (12 h). During the
acquisition of the 17O NMR data, approximately 36% of 4c had
decomposed to the corresponding α-methylstyrene derivative as
indicated by 1H NMR spectroscopy (see Supporting Informa-
tion File 1). As this byproduct is 17O NMR silent, the spectral
data acquisition was unhampered and a chemical shift
δobs = 77 ppm was measured. This value is larger than the
chemical shift obtained for the free alcohol 1 (67 ppm) and at
the same time, also significantly smaller than the value ob-
tained for the native reagent 4a (130 ppm). Structure 4c was
computed in the gas phase in absence of a counter anion and ge-
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ometry optimization furnished a minimum reminiscent of the Acknowledgements
pictographic representation of 4c with an intact but significant- This work was generously supported by the Swiss National
ly elongated I–O bond of 2.55 Å (Figure 3) and qualitatively, Science Foundation (N. S., P3P3P2_167744), ETH Zürich Post-
the NMR data are in support of this notion. From a quantitative doctoral Fellowship Program (C. R. P.) and the National
point of view, the data points (δiso, δobs) for 1, 4b, and 4c Science and Engineering Research Council of Canada (B. J. J.).
afforded a perfect linear correlation with R2 = 1, thus lending The authors gratefully acknowledge the support of Prof. Dr. D.
further credence to the representation of the protonated form 4a Günther and Prof. Dr. A. Togni (ETH Zürich).
in solution as 4c (see Supporting Information File 1).
ORCID® iDs
Nico Santschi - https://orcid.org/0000-0003-3839-778X
Cody Ross Pitts - https://orcid.org/0000-0003-1047-8924
Benson J. Jelier - https://orcid.org/0000-0002-5531-0431
René Verel - https://orcid.org/0000-0003-1575-2232
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