O-Phenylisourea Synthesis and Deprotonation: Carbodiimide Elimination Precludes the Reported Chapman Rearrangement

Article abstract of DOI:10.1002/ejoc.201600386

The kinetics of the addition of phenol to diisopropylcarbodiimide, and reaction of the resulting N,N′-diisopropyl-O-phenylisourea with hydroxide, are reported. The isourea is generated by a slow overall termolecular equilibrium process, inhibited by isourea–phenol salt generation. In contrast to an earlier report, reaction of the isourea with hydroxide does not induce a synthetically useful 1,3-O–N (Chapman) rearrangement. Instead, deprotonation results in solvolysis by carbodiimide elimination.

Full text of DOI:10.1002/ejoc.201600386

DOI: 10.1002/ejoc.201600386
Full Paper
Reaction Mechanisms
O-Phenylisourea Synthesis and Deprotonation: Carbodiimide
Elimination Precludes the Reported Chapman Rearrangement
Joseph A. Tate,[a] George Hodges,[b] and Guy C. Lloyd-Jones*[a]
Abstract: The kinetics of the addition of phenol to diisopropyl- ited by isourea–phenol salt generation. In contrast to an earlier
carbodiimide, and reaction of the resulting N,N′-diisopropyl-O- report, reaction of the isourea with hydroxide does not induce a
phenylisourea with hydroxide, are reported. The isourea is gen- synthetically useful 1,3-O–N (Chapman) rearrangement. Instead,
erated by a slow overall termolecular equilibrium process, inhib- deprotonation results in solvolysis by carbodiimide elimination.
Introduction
The direct,[1] or catalysed[2] 1,3-O–N rearrangement of imidates
(1) to amides (2) has been substantially developed (Scheme 1).
The Chapman rearrangement (1 → 2; R = Ar)[3] provides a syn-
thetic route to aniline derivatives from readily available phenols.
However, this process has been far less developed than the
analogous rearrangement where R = allyl.[1,2]
Scheme 2. Rearrangement of O-arylisoureas 3 to N-arylureas 4. Top: thermal
rearrangement (only when Z is strongly electron-withdrawing). Bottom: base-
catalysed rearrangement, reported to proceed with a wide range of Z.[7]
The overall second-order kinetics were found to correlate
with the pKaH of the corresponding phenol, and a mechanism
involving equilibrium N–H deprotonation of 3, followed by
Scheme 1. Thermal 1,3-O–N rearrangement of imidates 1 to amides 2; known
as the Chapman rearrangement when R = Ar.
rate-limiting intramolecular rearrangement (Z = H; ΔS‡
=
–13.4 cal K–1 mol–1) was proposed (Scheme 3). Given that a
broad substrate scope rearrangement would provide substan-
tial sythetic utility, we were surprised to find there have been
no reported applications.[8] We initially suspected that this was
due to the reported use of potentially hazardous[9] picrate salts
([5][OPic]), prepared by fusion of the phenol with diisopropyl-
carbodiimide (6a), then addition to a cold picric acid solution.
The isoureas were liberated in situ for rearrangement ([5][OPic]
→ 3 → 4).[7]
The Chapman rearrangement proceeds by intramolecular
generation of a zwitterionic Meisenheimer-like transition state
or intermediate.[4] Although this process is accelerated by aryl
groups bearing electron-withdrawing substituent(s), in nearly
all cases the Chapman rearrangement of O-arylimidates (R = Ar;
Y/Z = Ar′; Scheme 1) requires high temperatures (200–300 °C)
to effect useful conversions.[3,4] The analogous thermal 1,3-O–
N rearrangement of O-arylisoureas (3 → 4; Scheme 2) has also
been reported, but only with examples where Ar is (poly)-
nitrated and thus highly electron-deficient.[5] Less strongly acti-
vated systems resist rearrangement.[6] In 1983, Suttle and Willi-
ams reported that the isourea rearrangement is catalysed by
hydroxide, at ambient temperature, even with relatively neutral
aryl substituents (Z; Scheme 2).[7]
[a] EaStChem, University of Edinburgh
Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK
E-mail: guy.lloyd-jones@ed.ac.uk
www.lloyd-jones.chem.ed.ac.uk
[b] Syngenta, Jealott's Hill International Research Centre
Bracknell, Berkshire, RG42 6EY, UK
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600386.
Scheme 3. Reported deprotonation/rearrangement of isourea 3a, liberated in
situ from [5a][OPic]; OPic = [2,4,6-(O2N)3C6H2O–].[7]
Eur. J. Org. Chem. 2016, 2821–2827
2821
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
We have now re-investigated the process[7] in some detail CDCl3 at 21 °C was studied in situ by 1H NMR spectroscopy; see
and herein report on (a) the generation of O-phenylisourea 3a data (A) in Figure 1.
from PhOH and diisopropylcarbodiimide (6a), and (b) the reac-
tion of [5a][OPic] and related salts with excess base. We show
why the kinetics for direct generation of isourea 3a from PhOH
and 6a is synthetically disadvantageous. Moreover, we show
that O-phenylisourea 3a does not rearrange under the reported
conditions[7] but instead undergoes elimination and solvolysis.
The overall reaction involves the slow attainment of an equi-
librium mixture of product 3a and reactants. However, this oc-
curs by a two-stage process, the second stage being many or-
ders of magnitude slower than the first one. In the first stage
of the reaction (up to 50 % conversion of 6a) the major product
is not the isourea (3a), but the salt [5a][OPh]. As a consequence,
the reaction becomes extremely slow as the PhOH concentra-
tion is almost completely depleted. Accordingly, introduction of
further 6a at this point has minor impact on the rate (B; Fig-
ure 1). In contrast, introduction of a second equivalent of PhOH
induces further conversion (C; Figure 1). The kinetics can be
satisfactorily simulated (see solid lines through datasets A, B, C;
Results and Discussion
Synthesis of O-Phenylisourea 3a
The preparation of a range of O-arylisoureas from phenols Figure 1) by an overall third-order initial reaction: –d[6a]/dt =
(ArOH) and carbodiimides has been documented.[10] Most pro- obs[PhOH]2[6a]. This is consistent with two phenol molecules
k
cedures use an excess of the phenol, but common to all is the adding to carbodimide (6a), either stepwise, e.g. via
use of high reaction concentrations (usually by fusion of neat [6aH][(PhO)2H] to directly generate the salt [5a][OPh], or in a
reactants) at high temperatures. To the best of our knowledge, concerted manner, e.g. reaction of a phenol dimer with 6a to
the mechanistic origins for the requirement of such conditions generate 3a, via 7a. In either pathway, the overall third-order
have not been elucidated.[10] The kinetics of the reaction of kinetics, exacerbated by phenol sequestration through salt for-
diisopropylcarbodiimide (6a; 0.24
M) with PhOH (0.25 M
) in mation account for the forcing conditions.[7,11]
Figure 1. Temporal concentration of [6a] during the reaction with PhOH (0.25
according to model shown; k1 = 6.2 × 10–5 –2 s–1; K1 = 2 × 103 –2; K2 = 63
(C) additional PhOH (0.25 ) added; (D) full equilibrium for standard conditions (as A) attained by catalysis (20 mol-% CuCl; sparingly soluble).
M
) in CDCl3, 21 °C. Open circles: data (in situ 1H NMR); solid lines: simulation
–1; (A) standard reaction; (B) additional 6a (0.24
) added at point indicated;
M
M
M
M
M
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2822
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Reaction of O-Phenylisourea Salts with KOH
Reaction of PhOH with diisopropyl- (6a) or dicyclohexylcarbodi-
imide (6b), followed by silica-gel adsorption, extraction of resid-
ual 6a,b and PhOH, elution with diethyl ether, concentration,
and trituration, gave crude isoureas 3a,b. A variety of isourea
salts were prepared by addition of the corresponding acids.
Those most amenable to handling (crystalline, non-hygro-
scopic) were found to be [5a][OTs] and [5b][OTf]. For reasons
of safety,[9] we did not initially prepare samples of the picrate
salt [5a][OPic].[7]
The isourea rearrangement (3 → 4) reported by Suttle and
Williams[7] employed low concentrations of [5a][OPic] (10–6 to
10–7
M, in 30 % EtOH/H2O), at unspecified KOH concentrations.
The product (4a) having been identified by HPLC and UV analy-
ses, was referenced against independently prepared samples.[7]
In initial reactions we employed [5a][OTs] (10–3
M
, in 30 % EtOH/
H2O) and tested for rearrangement on addition of 0.1 and
0.01 KOH. However, no trace of 4a could be detected
[≤ 10–5
(1 %)]. Instead, the reaction mixture consisted solely
M
M
of solvolysis products (Scheme 4) identified (NMR, MS, IR) as
PhOH, N,N′-diisopropylurea 8a (major) and the transesterified
isourea 9a (minor). Analogously, [5b][OTf] gave 8b/9b, and no
4b.
Scheme 4. Reaction of salts [5a] and [5b] with KOH to give N,N′-dialkylureas
8a,b plus small amounts (6–8 %) of the isourea ethanolysis product (9a,b).
No trace of 4a,b was detected by 1H NMR analysis (detection threshold ca.
1 %).
At this stage we suspected that either the presence of picrate
ions is essential for the rearrangement (3 → 4),[7] for example
to facilitate an electron-transfer process, or that intermolecular
association of the isourea (e.g. as an H-bond dimer)[12] may be
diverting (3a)n towards solvolysis. However, addition of picric
Figure 2. Top: selected UV spectra showing key changes in the absorbance
(A) centred at 242 and 290 nm during the reaction of [5a][OPic] (10–4
M) with
KOH (0.1
M) in 30 % EtOH/H2O at 25 °C. Bottom: kinetics determined at
290 nm, initial [5a][OTs] concentration 10–4
M, path length 1 cm. Data: closed
circles; fit: A = ae–kt + b, where a and b are fitting parameters, and k = kobs
[s–1]. Inset: first-order dependence on KOH; –d[3a]/dt = [3a](kOH[OH] + k0);
kOH = 4.48 × 10–3 –1 s–1. The uncatalysed reaction is slow: k0 ≤ 0.9 × 10–5 s–1
M .
acid (10–3
M) had no impact on the outcome, nor did conduct-
Table 1. Solvolysis rate constants for 3a,b (KOH in 30 % EtOH/H2O, 25 °C).
Conc.[a]
[M]
[KOH][b]
[M]
kobs [s–1
]
kOH
[M ]
–1 s–1
[c]
[d]
Entry
Salt
1
2
[5a][OPic]
[5a][OPic]
[5a][OPic]
[5a][OTs]
[5a][OTs]
[5b][OTf]
[5b][OTf]
[5a][OTs]
[5a][OTs]
[5a][OTs]
1 × 10–4
1 × 10–5
–
1.0 × 10–1
1.0 × 10–1
4.6 × 10–4
4.1 × 10–4
4.6 × 10–3
4.1 × 10–3
5.7 × 10–3[e]
4.6 × 10–3
4.9 × 10–3
4.1 × 10–3
3.9 × 10–3
4.8 × 10–3
4.8 × 10–3
1.1 × 10–2[i]
[f]
[g]
[g]
3[e]
4
–
–
1 × 10–4
1 × 10–5
1 × 10–4
1 × 10–5
1 × 10–4
1 × 10–4
1 × 10–4
1.0 × 10–1
1.0 × 10–1
1.0 × 10–1
1.0 × 10–1
5.0 × 10–2
2.5 × 10–2
1.0 × 10–1
4.6 × 10–4
4.9 × 10–4
4.1 × 10–4
3.9 × 10–4
2.4 × 10–4
1.2 × 10–4
1.1 × 10–3
5
6
7
8
9
10[h]
[a] O-Arylisourea 3 liberated in situ from the salt. The product is a mixture (approximately 13:1) of 8/9. [b] Ionic strength 1.0
M (KOH/KCl). [c] Empirical pseudo
first-order rate constant (UV; 290 nm). [d] Second-order rate constant. [e] From ref.[7]; product is reported as 4a. [f] 10–6 to 10–7. [g] Not specified. [h] Reaction
in 30 % EtOD/D2O. [i] Solvent kinetic isotope effect (KIE) = 0.42.
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2823
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ing the reaction at a 100-fold dilution (10–5
M
), or using the Mechanism of Solvolysis
pure picrate salt [5a][OPic]. Rather perplexed, we measured the
rates of solvolysis (3 → 8/9) to compare with the kinetic data
reported for the rearrangement (3 → 4).[7] Suttle and Williams
determined reaction rates by UV spectroscopy, monitoring the
temporal change in absorption (A) at 290 nm.[7] As shown in
To investigate whether the solvolysis of 3a proceeds by an addi-
tion/elimination or an elimination/addition mechanism, the re-
1
action of [5a][OTs] with KOD was monitored by H NMR spec-
troscopy in 30 % [D6]EtOD/D2O. Deprotonation of the salt (k1)
to generate 3a was instantaneous, after which two distinct
steps for the conversion of 3a into 8a/9a (in constant ratio)
were identified: elimination of phenolate, followed by slow sol-
volysis of the resulting carbodiimide 6a (Figure 3).
Figure 2 (top), the reaction of [5a][OPic] (10–4
M) with 0.1 M KOH
did indeed give temporal changes centred at 242 and 290 nm.
However, the reaction products, identified by NMR spectro-
scopy, were still 8a/9a (as Scheme 4).
Curve fitting of A (λ = 290 nm) vs. t, gave kobs [s–1] (Table 1,
The kinetics was satisfactorily simulated by inclusion of base-
Entry 1). The same empirical rate constant, within experimental catalysed solvolysis (k3 + k4) of 6a and an inverse solvent kinetic
error, was obtained at lower substrate concentration (10–5
M
;
isotope effect (kD/kH = 2.4) for the elimination (k2), confirmed
Entry 2) and with [5a][OTs] (Entries 4 and 5; lower section of by UV (Table 1, Entry 10). The solvolysis of diisopropylcarbodi-
Figure 2). The cyclohexyl system ([5b][OTf]) reacted at a very imide 6a in 30 % [D6]EtOD/D2O was measured independently
similar rate (Entries 6 and 7). Reactions of [5a][OTs] conducted by 1H NMR, see inset to Figure 4, confirming hydroxide catalysis
at lower [KOH] concentrations but at the same ionic strength (kobs = kOR[KOD]; where kOR = k3 + k4). The inverse isotope effect
(Entries 8 and 9) confirmed that the reaction is first order in for phenolate elimination is indicative that deprotonation of N–
KOH (inset; Figure 2), allowing extraction of the second-order H/D in 3a is not rate-limiting (E2), but is consistent with that
rate constants (kOH; Table 1). All of the reactions led to solvoly- expected[13] for an E1cb mechanism. The negligible entropy of
sis, not rearrangement.
activation (ΔS‡ = –3.5 cal K–1 mol–1)[7,14] possibly arises from the
Figure 3. In situ analysis of the reaction of 3a, liberated in situ (k1) from [5a][OTs], with KOD in 30 % [D6]EtOD/D2O, 25 °C, by 1H NMR spectroscopy. Data:
circles. Model: solid lines. k1 = 1 × 103 –1 s–1 (nominal lower threshold); k2 = 1.13 × 10–2 –1 s–1; (k3 + k4) = 4.95 × 10–4 –1 s–1; k3/k4 = 13; EtO is C2D5O. Inset
shows analysis of KOD-catalysed solvolysis of pure diisopropylcarbodiimide 6a (0.01
) in 30 % [D6]EtOD/D2O (filled circles; kOR = 4.81 × 10–4 –1 s–1), and
comparison with the value employed in the model (open circles; k3 + k4) for solvolysis of in situ liberated 6a.
M
M
M
M
M
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2824
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
phenolate expulsion (+ΔS) being compensated by increasing
rigidity in the nascent carbodiimide (–ΔS), although accompa-
nying changes in anion solvation will also contribute.
Scheme 5. Top: reported[7] hydroxide-catalysed Chapman rearrangement of
O-phenylisourea 3a, liberated in situ from [5a][OPic] in 30 % EtOH/H2O. Bot-
tom: revised mechanism in which PhOK elimination generates diisopropyl-
carbodiimide 6a, precluding Chapman rearrangement.
summary, in basic aqueous ethanol, the rate of solvolysis of O-
phenylisourea 3a precludes what would be a synthetically use-
ful Chapman rearrangement to 4a. However, it is of note that
cyclic N-arylguanidines do undergo an analogous anionic Chap-
man-type rearrangement on deprotonation with KOtBu in
DMSO.[8b] Presumably, elimination of a strained cyclic carbodi-
imide is strongly disfavoured;[16] however, our attempts to in-
duce anionic rearrangement of cyclic O-arylisoureas have so far
been unsuccessful.
Figure 4. Comparison of reference UV spectra (10–4
30 % EtOH/H2O, 25 °C) with the endpoint of reaction of [5a][OPic] (10–4
with 0.1 KOH (Table 1, Entry 1). During the reaction, the concentration of
picrate anion (the strongest UV-absorbing component) is constant. Urea 4a
has a very weak UV signal at 290 nm. Reference [isourea 3a + KOPic] liberated
in situ from [5a][OPic].
M in 0.1 M KOH, 0.9 M KCl,
M)
M
Experimental Section
CAUTION! Picric acid and its salts are not only toxic, but also ther-
mally and shock-sensitive, particularly when dry. These compounds
should be used with great caution, on as small a scale as feasible,
and with the appropriate level of physical and chemical protection
in place.
Conclusions
We have re-investigated a process reported by Suttle and Willi-
ams for the preparation and rearrangement of O-arylisourea
picrate salts [5][OPic] to N-arylureas 4 (Scheme 3).[7] The genera-
tion of O-phenylisourea 3a from PhOH and diisopropylcarbodi-
imide (6a) proceeds as reported, albeit by overall termolecular
kinetics that suffer from strong product inhibition through salt
formation ([5a][OPh]). However, in our hands, the reaction of
Preparation of Isourea Salts [5a][OTs] and [5a][OPic]: Phenol
(0.47 g, 5 mmol) and diisopropylcarbodiimide (6a; 2.32 mL,
15 mmol) were heated at 100 °C under N2 with stirring for 16 h.
Once cooled, the reaction mixture was diluted with CH2Cl2 (5 mL)
and loaded onto a short column of silica gel. CH2Cl2 was passed
through the column until the elution of phenol had halted (as de-
termined by TLC, ca. 400 mL of CH2Cl2). Et2O (ca. 100 mL) was used
to flush the remaining material off the column, and the eluate was
concentrated in vacuo. The residue was dissolved in petroleum
ether (b.p. 40–60 °C; 20 mL) and filtered. The filtrate was concen-
trated in vacuo to yield crude isourea (3a; 0.71 g, 3.2 mmol), which
was dissolved in CH2Cl2 (20 mL) and p-toluenesulfonic acid (mono-
hydrate; 0.61 g, 3.2 mmol) added portionwise with rapid stirring
over 5 min. After 1 h, the mixture was diluted with CH2Cl2 (10 mL)
and washed with water (3 × 20 mL). The organic phase was dried
(MgSO4), filtered and concentrated in vacuo. Trituration of the re-
sulting oil with Et2O (10 mL) caused it to solidify. The solid was
collected by Büchner filtration, washed with Et2O (3 × 10 mL) and
air-dried. Recrystallisation from tert-butyl methyl ether afforded
[5a][OTs] (0.52 g, 1.3 mmol, 26 %) as colourless needles. 1H NMR
(400 MHz, CDCl3): δ = 10.30 (br. s, 2 H), 7.83 (app d, JHH = 8.2 Hz, 2
H), 7.46 (m, 2 H), 7.28 (m, 1 H), 7.20 (app d, JHH = 8.2 Hz, 2 H), 7.09
[5a][OPic] (10–5 to 10–3
M) with excess KOH in 30 % EtOH/H2O
results solely in carbodiimide elimination, not rearrangement. It
is salient that N-phenylurea 4a was reportedly identified in situ
by UV/HPLC, but not isolated, and that all other N-arylureas 4
were assumed to be generated analogously.[7] The kOH value for
the reported rearrangement[7] (Table 1, Entry 3) is identical,
within experimental error, to that for elimination. Moreover, as
4a has a very weak UV signal at 290 nm (Figure 4), the only
species present that can induce a significant change in absorp-
tion (A) at the wavelength employed for the determination of
[7]
kOH is PhOK.
The process monitored (UV; λ = 290 nm) by Suttle and Willi-
ams cannot therefore be the rearrangement, and it appears that
the kinetics of carbodiimide elimination were misinterpreted[15]
as those corresponding to rearrangement[7] (Scheme 5).
In light of this, it is unsurprising that the second-order rates
(of solvolysis) were found to correlate with the pKaH of the leav-
ing group (ArOH).[7] The extraordinarily large Brønsted coeffi-
cient (ꢀL = –2.3)[7] is now readily interpreted as arising from
3
(m, 2 H), 3.68 (br. m, 2 H), 2.37 (s, 3 H), 1.20 (d, JHH = 6.6 Hz, 12 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 156.9, 153.2, 142.3, 140.1,
130.9, 128.9, 126.12, 126.07, 115.8, 46.3, 22.6, 21.5 ppm. IR (neat):
νmax = 3177 (w, NH), 2979 (w), 2872 (w), 1668 (m, C=N), 1572 (m),
˜
1487 (m), 1382 (m), 1219 (m), 1177 (m), 1123 (m), 1035 (m), 1012
rate-limiting phenolate elimination, in an E1cb mechanism. In (m), 815 (m), 754 (m), 679 (s), 561 (m) cm–1. HRMS (EI+): calcd. for
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2825
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
C13H21N2O [M]+ 221.16484, found 221.16450. M.p. 91–92 °C.
[5a][OPic] was prepared by dropwise addition of a solution of crude
isourea 3a (0.76 g, 3.5 mmol), obtained as described above, in 2-
propanol (5 mL) to a solution of picric acid (0.8 g, 3.5 mmol) in 2-
propanol (75 mL) with rapid stirring over a period of 5 min. A yellow
precipitate formed throughout the addition. The suspension was
stirred for a further 30 min, then the yellow solid was isolated by
Büchner filtration, washed with 2-propanol (3 × 10 mL) to ensure
all picric acid was removed, and then air-dried. [5a][OPic] (0.99 g,
(101 Hz, [D6]DMSO): δ = 156.8, 40.7, 23.3 ppm. IR (neat): νmax
=
˜
3341 (w, NH), 2967 (w), 2873 (w), 1616 (m, C=O), 1556 (m), 1464
(w), 1384 (w), 1360 (w), 1325 (w), 1244 (m), 1166 (m), 1129 (m), 628
(m) cm–1. MS (EI+): calcd. for C7H16N2O [M]+ 144.13, found 144.1.
O-Ethyl-N,N′-diisopropylisourea (9a):[18] Diiisopropylcarbodiimide
(6a; 155 μL, 1 mmol) was added with stirring to a suspension of
copper(I) chloride (5 mg, 0.05 mmol) in EtOH (1 mL). After 21 h, the
mixture was diluted with brine (10 mL) and extracted with Et2O
(3 × 10 mL). The combined organic fractions were dried (MgSO4),
filtered and carefully concentrated in vacuo (750 mbar, 40 °C; note:
product volatile) to approx. 5 mL. The remaining solvent was re-
moved by passing a stream of nitrogen over the solution. The title
compound 17 (26 mg, 0.15 mmol, 15 %) was obtained as a pale
yellow oil that darkened to a pale green/blue colour over time,
1
2.2 mmol, 44 %) was obtained as a bright yellow powder. H NMR
(400 MHz, [D6]DMSO): δ = 8.98 (br. s, 2 H), 8.58 (s, 2 H), 7.53 (app t,
JHH = 7.6 Hz, 2 H), 7.36 (app t, JHH = 7.6 Hz, 1 H), 7.29 (app d, JHH
=
7.6 Hz, 2 H), 3.96 (br. s, 2 H), 1.20 (br. s, 12 H) ppm. 13C{1H} NMR
(126 Hz, [D6]DMSO): δ = 160.8, 155.4, 151.8, 141.8, 130.54, 126.4,
125.1, 124.1, 118.7, 45.4 (br. app d), 21.7 (br. app d) ppm. IR (neat):
indicative of minor quantities of copper-based contaminants. 1H
νmax = 3196 (w, NH), 3063 (w), 2978 (w), 1677 (m, C=N), 1633 (m),
˜
3
NMR (400 MHz, [D6]DMSO): δ = 4.84 (br. s, 1 H), 3.93 (q, JHH
=
1535 (m), 1463 (m), 1317 (m), 1271 (m), 1192 (m), 1164 (m), 1129
(m), 1077 (w), 926 (w), 912 (w), 804 (w), 742 (m), 709 (w), 685 (w)
cm–1. HRMS (EI+): calcd. for C13H21N2O [M]+ 221.16484, found
221.16435.
7.0 Hz, 2 H), 3.64 (br. m, 1 H), 3.34 (br. m, 1 H), 1.13 (t, 3JHH = 7.0 Hz,
3
3
3 H), 1.04 (br. d, JHH = 6.4 Hz, 6 H), 0.95 (br. d, JHH = 6.1 Hz, 6 H)
ppm. 13C{1H} NMR (101 Hz, [D6]DMSO): δ = 150.4, 59.5, 44.4 (br),
42.7 (br), 24.7 (br), 23.4 (br), 14.5 ppm. IR (neat): νmax = 2964 (m,
˜
Reaction of Isourea Salts with KOH: [5a][OPic] (22.5 mg,
0.05 mmol) in EtOH (6 mL) was added with rapid stirring to a solu-
tion of KOH (28.1 mg or 281 mg, 0.5 or 5 mmol) in water (35 mL)
and EtOH (9 mL). After 44 h, the reaction mixture was extracted
with EtOAc (2 × 25 mL). To the organic phase was added [D6]DMSO
(1 mL) and the mixture then carefully concentrated by passing a
stream of air over the solution whilst it was rapidly stirred. The
resulting solution was analysed by 1H NMR spectroscopy (400 MHz)
without further purification. Phenol, picric acid, N,N′-diisopropyl-
isourea (8a) and O-ethyl-N,N′-diisopropylisourea (9a) were the only
species detected. N,N′-diisopropyl-N-phenylisourea (4a) could not
be detected (<1 %, by reference to 13C satellites of the 1H signals
of the phenol). Samples of 4a, 8a and 9a, prepared as outlined
NH), 2931 (w), 2871 (w), 1659 (s, C=N), 1464 (w), 1448 (w), 1366 (m),
1311 (s), 1169 (m), 1123 (w), 1085 (m), 1026 (w), 711 (w), 609 (w),
577 (w), 494 (w) cm–1. HRMS (EI+): calcd. for C9H20N2O [M]+
172.15701, found 172.15763.
Isourea Synthesis Kinetics by 1H NMR Spectroscopy: Figure 1.
Phenol (94.1 mg, 1 mmol) was dissolved in CDCl3 (4 mL) under N2;
6a (150 μL, 0.97 mmol) was added (t = 0) and the resulting mixture
very briefly stirred. An aliquot of this solution (0.6 mL) was then
transferred to each of four J. Young valve NMR tubes (Samples A,
B, C, D). The tube for sample D also contained copper(I) chloride
1
(3.0 mg, 0.03 mmol). The H NMR spectra (400 MHz) of these sam-
ples were repeatedly recorded between t = 20 min to t = 520 h. At
t = 288 h, to sample B was added additional 6a (23 μL, 0.15 mmol),
and to sample C was added additional phenol (14.1 mg, 0.15 mmol).
Values for [6a]t were extracted from 1H NMR spectra using Mes-
tReNova. DynoChem was used to fit the mechanistic model de-
scribed in Figure 1 to this data by allowing freedom in k1, k–1 and
1
below, were used to reference the H NMR ([D6]DMSO) spectra.
N,N′-Diisopropyl-N-phenylisourea (4a):[7] Isopropyl isocyanate
(0.20 mL, 2 mmol) was diluted with Et2O (2 mL) under N2. N-Iso-
propylaniline (0.29 mL, 2 mmol) was then added dropwise with
stirring over 2 min. After 30 min, the reaction mixture was diluted
with EtOAc (10 mL) and washed with HCl (10 % aqueous; 10 mL)
and water (2 × 10 mL). The organic layer was dried (MgSO4), filtered
k
–2. The value of k2 was arbitrarily fixed at 1 × 103 –1 s–1. NMR
M
spectroscopic data for N,N′-diisopropyl-O-phenylisourea (3a): 1H
NMR (400 MHz, CDCl3): δ = 7.31 (app t, JHH = 7.5 Hz, 2 H), 7.07 (app
and concentrated in vacuo. The resulting crude solid was recrystal- t, JHH = 7.5 Hz, 1 H), 7.01 (app d, JHH = 7.5 Hz, 2 H), 3.74 (sept,
3
lised from petroleum ether (b.p. 60–80 °C) to afford 4a (127 mg,
3JHH = 6.4 Hz, 2 H), 1.11 (d, JHH = 6.4 Hz, 12 H) ppm.
1
0.58 mmol, 29 %) as colourless needles. H NMR (400 MHz, CDCl3):
Solvolysis Kinetics by UV Spectroscopy: Table 1. Stock solutions
were prepared using volumetric glassware, and a single stock solu-
tion of a given concentration of reagent was used throughout. Di-
δ = 7.45–7.36 (m, 3 H), 7.16–7.13 (m, 2 H), 4.88 (sept, 3JHH = 6.8 Hz,
3
3
1 H), 3.93 (sept, JHH = 6.5 Hz, 1 H), 3.62 (br. s, 1 H), 1.04 (d, JHH
=
6.8 Hz, 6 H), 0.99 (d, JHH = 6.5 Hz, 6 H) ppm. 13C{1H} NMR (101 Hz,
3
lute stock solutions of isourea salts (0.2 and 0.02 mM) were prepared
CDCl3): δ = 156.5, 138.2, 131.4, 129.6, 128.3, 46.3, 42.4, 23.5, 21.8
by sequential dilution. Volumes of stock solutions were measured
using Gilson pipettes. Background spectra were recorded after com-
bining a stock solution of EtOH/water (6:4; 1 mL) with an aqueous
KOH/KCl stock solution (1 mL) of the appropriate concentration.
Background spectra were subsequently subtracted from the UV/Vis
absorption spectra of analytes in solutions of the same composi-
tion. Reference UV/Vis absorption spectra were recorded immedi-
ately after combining stock solutions of the reference compounds
ppm. IR (neat): νmax = 3438 (w, NH), 2964 (w), 2930 (w), 2876 (w),
˜
1647 (m, C=O), 1489 (m), 1466 (m), 1452 (m), 1321 (m), 1267 (m),
1254 (m), 1170 (m), 1116 (m), 760 (m), 709 (m), 585 (m) cm–1. HRMS
(EI+): calcd. for C13H20N2O [M]+ 220.15701, found 220.15596. M.p.
66–67 °C.
N,N′-Diisopropylisourea (8a):[17] Glacial acetic acid (150 μL,
2.6 mmol) was added dropwise over 2 min, with rapid stirring, to a
solution of diisopropylcarbodiimide (6a; 155 μL, 1 mmol) in petro-
leum ether (b.p. 40–60 °C; 4 mL). A colourless precipitate formed
throughout the addition. After 1 h, the solid was isolated by Büch-
(2 × 10–7 mol) in EtOH/water (6:4; 0.2 m
KOH/KCl (0.2/1.8 stock, 0.2 mmol/1.8 mmol; 1 mL). The stock solu-
tion of 6a in EtOH/water (6:4) was used immediately after prepara-
M stock; 1 mL) with aqueous
M
ner filtration, washed with petroleum ether (b.p. 40–60 °C; 3 × 5 mL) tion. The following procedure for kinetic analysis is typical: Stock
and air-dried. Recrystallisation from EtOH afforded 9a (100 mg,
solutions were pre-heated to 25 °C. Aqueous KOH/KCl (0.2/1.8
stock, 0.2 mmol/1.8 mmol; 1 mL) was added to [5a][OPic] (2 × 10–
8 mol) in EtOH/water (6:4; 0.02 m
stock solution; 1 mL) in a cuvette
(1 cm pathlength). The cuvette was sealed with a stopper and
M
0.69 mmol, 69 %) as colourless needles. 1H NMR (400 MHz,
3
3
[D6]DMSO): δ = 5.47 (d, JHH = 7.6 Hz, 2 H), 3.63 (dsept, JHH = 7.6
M
3
and 6.5 Hz, 2 H), 1.00 (d, JHH = 6.5 Hz, 12 H) ppm. 13C{1H} NMR
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2826
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
d) G. J. Mercer, J. M. Yang, M. J. McKay, H. M. Nguyen, J. Am. Chem. Soc.
2008, 130, 11210–11218.
briefly shaken before being placed in a thermostatted cell holder.
The UV/Vis spectrum of the solution was recorded at 20 s time
intervals for 10000 s with an Ocean Optics USB4000 detector and
data processed (Kinetic Studio; TgK Scientific) to afford the temporal
absorbance (A) at 290 nm. The Microsoft Excel Solver Add-in was
used to fit d(A)/dt = k[3a][KOH] (where A = absorbance), by assum-
[3] O. Mumm, H. Hesse, H. Volquartz, Ber. Dtsch. Chem. Ges. 1915, 48, 379–
391; A. W. Chapman, J. Chem. Soc. Trans. 1925, 127, 1992–1998.
[4] a) K. B. Wiberg, B. I. Rowland, J. Am. Chem. Soc. 1955, 77, 2205–2209; b)
H. M. Relles, J. Org. Chem. 1968, 33, 2245–2249; c) H. M. Relles, G. Pizzo-
lato, J. Org. Chem. 1968, 33, 2249–2253; d) O. H. Wheeler, F. Roman, O.
Rosado, J. Org. Chem. 1969, 34, 966–968.
ing [KOH] = 0.1
M +
remains constant and solving k: A = –B × e(–k)
C (where B and C are arbitrary fitting variables).
[5] a) M. Busch, G. Blume, E. Pungs, J. Prakt. Chem. 1909, 79, 513–546; b) E.
Vowinkel, Chem. Ber. 1963, 96, 1702–1711; c) A. C. Piñol, M. M. Mañas,
Chem. Commun. (London) 1967, 229a–229a; d) M. Allen, R. Y. Moir, Can.
J. Chem. 1963, 41, 252–262.
Solvolysis Kinetics by 1H NMR Spectroscopy: Figure 3. Stock solu-
tions were prepared immediately prior to performing kinetic reac-
tions and were only used once. A pellet of KOH was weighed under
N2, and then the appropriate volume of D2O added to afford a stock
solution of the desired concentration. The following procedure is
typical: A sample of [5a][OTs] (6.0 × 10–3 mmol, 2.36 mg) was dis-
solved in [D6]EtOH (0.18 mL) and added to a 5 mm NMR tube. KOH
[6] F. Stewart, Aust. J. Chem. 1968, 21, 477–482.
[7] N. A. Suttle, A. Williams, J. Chem. Soc. Perkin Trans. 2 1983, 1369–1372.
[8] To the best of our knowledge there are five citations of ref.[7] In none
of these is the rearrangement (3 → 4) applied or reproduced: a) A. L.
Chimishkyan, N. D. Gulyaev, T. V. Leonova, Zh. Org. Khim. 1988, 24, 2047–
2051; b) F. Esser, K. Brandt, K.-H. Pook, H.-J. Förster, H. Köppen, J.-M.
Leger, A. Carpy, J. Chem. Soc. Perkin Trans. 1 1988, 3311–3316; c) S. Y.
Kim, G.-i. An, H. Rhee, Synlett 2003, 112–114; d) S. Y. Kim, G.-i. An, H.
Rhee, Tetrahedron Lett. 2003, 44, 2183–2186; e) J. Vicente, J.-A. Abad, M.-
J. López-Sáez, P. G. Jones, D. Bautista, Chem. Eur. J. 2010, 16, 661–676.
[9] CAUTION! Picric acid is toxic and thermally and shock-sensitive, particu-
larly when dry.
[10] a) E. Vowinkel, Chem. Ber. 1963, 96, 1702–1711; b) E. Vowinkel, C. Wolff,
Chem. Ber. 1974, 107, 907–914; diaryl carbodiimides react with aliphatic
alcohols at high temperatures or with added alkoxide catalysts, whereas
dialkylcarbodiimides do not: c) H. G. Khorana, Can. J. Chem. 1954, 32,
227–234; d) E. Däbritz, Angew. Chem. Int. Ed. Engl. 1966, 5, 470–477–490;
Angew. Chem. 1966, 78, 483.
(0.06 mmol) in D2O (0.143
M stock; 0.42 mL) was then added (t =
0) and the solution briefly shaken. The NMR tube was loaded into
the NMR spectrometer (probe temperature 25 °C), and 1H NMR
spectra (400 MHz) were recorded at regular time intervals. Values
for the concentrations of phenolate and 6a with respect to time
were extracted from the 1H NMR spectra using MestReNova. Dyno-
Chem was used to fit the kinetic model in Figure 3, allowing free-
dom in k2 and k(3+4). The rate of hydrolysis of 6a (inset in Figure 3)
was measured using the same procedure, but using N-phenylurea
(1.17 mg, 8.6 × 10–6 mol) as internal standard, and 6a (0.89 μL,
5.7 × 10–3 mmol; calculated relative to 4a by 1H NMR integral analy-
sis) dissolved in [D6]EtOH (0.18 mL) and adding KOH (0.058 mmol,
0.15 mmol and 0.232 mmol, in three separate experiments) in D2O
(0.42 mL stock). The Microsoft Excel Solver Add-in was used to fit
the following rate equation to this data: –d[6a]/dt = k[6a][KOH], by
assuming [KOH] remains constant and solving the following equa-
tion for k: [6a] = [6a]0 × e–kt + C (where C is an arbitrary fitting
variable).
[11] Copper catalysis has been reported: G. Heinisch, B. Matuszczak, D. Rako-
witz, K. Mereiter, J. Heterocycl. Chem. 2002, 39, 695–702. Addition of acid
(20 mol-%, TsOH) or base (20 mol-%, Et3N or DMAP) does not catalyse
equilibration, instead they cause a reduction in rate.
[12] M. C. Stumpe, H. Grubmüller, J. Phys. Chem. B 2007, 111, 6220–6228, and
references therein.
[13] The isotope effect is approximately consistent with that predicted by
standard thermodynamic fractionation factors for D2O, OD–, and RNH–:
R. L. Schowen, J. Labelled Compd. Radiopharm. 2007, 50, 1052–1062.
[14] The activation parameters (ΔH‡
= ; =
19.4 kcal K–1 mol–1 ΔS‡
–3.4 cal K–1 mol–1) have been recalculated from the data reported (ref.[7]
,
Acknowledgments
Table 3) as it appears that the tabulated rate constants are one order of
magnitude lower than experimentally determined.
We thank Syngenta and the Engineering and Physical Sciences
Research Council (EPSRC) (iCASE award) for funding.
[15] One explanation for this outcome is that reference samples of PhOH and
4a, prepared for product analysis by UV and HPLC, may have become
inadvertently mislabelled or interchanged, leading to the conclusion that
“90.1 % of the original substrate had been converted into the urea (NN′-
diisopropyl-N′-phenylurea) and that a small proportion (2.7 %) was
phenol”.
Keywords: Ureas · Rearrangement · Elimination · Solvolysis ·
Reaction mechanisms
[16] Under these conditions [5a][OTs] and 3a still give carbodiimide 6a.
[17] J. Lee, A. J. Chubb, E. Moman, B. M. McLoughlin, C. T. Sharkey, J. G. Kelly,
K. B. Nolan, M. Devocelle, D. J. Fitzgerald, Org. Biomol. Chem. 2005, 3,
3678–3685.
[1] See for example: a) L. E. Overman, N. E. Carpenter, in Organic Reactions,
John Wiley & Sons, Inc., Hoboken, New Jersey, USA, 2004; b) A. El-Faham,
F. Albericio, Chem. Rev. 2011, 111, 6557–6602.
[18] E. Schmidt, F. Moosmüller, Justus Liebigs Ann. Chem. 1955, 597, 235–240.
[2] See for example a) F. Cramer, N. Hennrich, Chem. Ber. 1961, 94, 976–989;
b) T. G. Schenck, B. Bosnich, J. Am. Chem. Soc. 1985, 107, 2058–2066; c)
C. E. Anderson, L. E. Overman, J. Am. Chem. Soc. 2003, 125, 12412–12413;
Received: March 29, 2016
Published Online: May 23, 2016
Eur. J. Org. Chem. 2016, 2821–2827
www.eurjoc.org
2827
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim