Reactions of a series of bis(α-amino acidato)copper(II) complexes with formaldehyde and benzamide: Aldol-type condensation versus Mannich aminomethylation

Article abstract of DOI:10.1039/b202955c

In the reactions of bis(α-amino acidato)copper(II) with formaldehyde and benzamide, competing processes occur and the preferred pathway depends on the nature and number of the α-carbon substituents of the chelated amino acid, and the pH of the reaction me

Full text of DOI:10.1039/b202955c

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Reactions of a series of bis(ꢀ-amino acidato)copper(II)
complexes with formaldehyde and benzamide: aldol-type
condensation versus Mannich aminomethylation
Chew Hee Ng,*a Thiam Seong Chong,a Siang Guan Teoh,b Farook Adamsb and Seik Weng Ngc
a School of Arts and Science, Tunku Abdul Rahman College, 53300 Kuala Lumpur, Malaysia.
E-mail: ngch@mail.tarc.edu.my
b School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
c Institute of Postgraduate Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia
Received 25th March 2002, Accepted 25th June 2002
First published as an Advance Article on the web 2nd August 2002
In the reactions of bis(α-amino acidato)copper() with formaldehyde and benzamide, competing processes occur
and the preferred pathway depends on the nature and number of the α-carbon substituents of the chelated amino
acid, and the pH of the reaction medium. Aldol-type condensation yields complexes with oxazolidine ring(s) while
Mannich aminomethylation results in the formation of complexes with N-methylbenzamido pendant arm(s). The
crystal structure determination of bis(3-methylbenzamido-5-methyloxazolidine-4-carboxylato)copper() dihydrate
establishes its formation from a combination of both processes, in which aldol condensation occurs first. The
chemistry of these reactions is rationalized with a proposed reaction scheme. The synthesized compounds are
characterized by infrared spectroscopy and microanalysis.
1
Introduction
2
Experimental
Mannich aminomethylation,1 an organic reaction involving
a substrate having active hydrogen, formaldehyde/aldehydes
and an amine/ammonia functionality, also encompasses the
analogous reaction of metal complexes of amino acids for
which the metal amino acetate replaces the amine reagent. This
‘inorganic’ Mannich reaction involves chelated amino acids
reacting as an amine component2,3 or as a substrate with active
hydrogen since the amino protons are labile.4,5
Glycine (gly), -alanine (-ala), C-phenylglycine (C-ꢀgly),
-threonine (-threo) and -serine (-ser) were supplied by
Sigma. Hydroxymethylserine (OHMe-ser) was prepared by a
previously reported procedure.8 Benzamide and 37% aqueous
formaldehyde solution were obtained from Merck. Cu(aa)2
were prepared as reported previously.9
The infrared spectra of the complexes were recorded on a
Perkin-Elmer 2000 FT-IR spectrophotometer from 4000–
400 cmϪ1 as KBr discs. Elemental analyses were carried out
on a Perkin-Elmer 2400 in the School of Chemical Sciences,
Universiti Sains Malaysia.
To develop further the chemistry of this reaction type, we
investigated the reactions of bis(amino acidato)metal(),
M(aa)2, with formaldehyde and amides.6,7 The first study shows
that bis[N,N-di(N-methylacetamido)glycinato]metal(), MII-
[DMeA-gly]2, were formed from the reactions of bis(glycinato)-
metal() with formaldehyde and acetamide.6 Subsequently,
we discovered that pH and the nature of the metal() cations
influences the type of product formed from the reactions of
bis(β-alaninato)metal(), M(β-ala)2, with formaldehyde and
benzamide.7 In basic medium, reactions of Cu(β-ala)2 yielded
bis[N-methyl-N-(N-methylbenzamido)-β-alaninato]copper(),
CuII[Me-MeB-β-ala]2 through both Canizzaro-type methyl-
ation and Mannich aminomethylation, while those involving
other M(β-ala)2 (M = Zn, Ni, Co) resulted in the formation
of bis[N,N-di(N-methylbenzamido)-β-alaninato]metal() com-
plexes, MII[DMeA-β-ala]2. In the absence of base, only the
Cu(β-ala)2 reacted with formaldehyde and benzamide to form
CuII[DMeA-β-ala]2. To acquire further understanding of this
Mannich reaction involving amide, this paper reports the reac-
tion of a series of bis(α-amino acidato)copper(), Cu(aa)2 1,
with formaldehyde and benzamide to investigate the effect of
pH and different α-substituents of the α-amino acid.
Reaction and synthesis
Each reaction of Cu(aa)2 (aa = gly, -ala, C-ꢀgly, -ser, -threo,
OHMe-ser) with formaldehyde and benzamide was initially
carried out in the absence of base. The pH of the reaction
mixtures of subsequent reactions were raised with the addi-
tion of aqueous NaOH solution or aqueous NaHCO3. The
pH ranges were from pH ≈3.0 to pH ≈10.0. All reactions
required the addition of 95% ethanol to help dissolve the
benzamide.
Bis[N,N-di(N-methylbenzamido)glycinato]copper(II), 2a.
A
reaction mixture consisting of cis-Cu(gly)2ؒH2O (0.5 g,
2.4 mmol), formaldehyde (10 ml, 0.12 mol), benzamide (1.2 g,
10 mmol) and 95% ethanol was stirred thoroughly. Within the
same day, the resultant solution yielded a blue solid which was
filtered off, washed with cold ethanol and finally dried in vacuo
for 5 h. Yield 1.48 g, 78%. IR (cmϪ1): 3360, 3288, 3067, 2976,
2944, 1634, 1577, 1545, 1490, 1442, 1421, 1406, 1366, 1332,
1305, 1244, 1192, 1166, 1135, 1080, 1054, 1000, 983, 954,
931, 855, 829, 810, 755, 711, 696, 655, 620, 496, 452, 409. 3360s;
νOH(water) 3302s; νNH(amide) 3067w; νCOOϪ(asym, sym) 1634vs,
1367s. Elemental analysis calculated for C36H36N6O8Cuؒ
2.5H2O: C, 55.42; H, 5.13; N, 10.78. Found: C, 55.37; H, 4.86;
N, 10.46%. This complex could be synthesized between pH 3.6
and 9.0. IR spectroscopy shows that the same complex was
DOI: 10.1039/b202955c
J. Chem. Soc., Dalton Trans., 2002, 3361–3366
This journal is © The Royal Society of Chemistry 2002
3361

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formed when trans-Cu(gly)2 was used in the reactions. Poor
yields were obtained at higher pH values or at higher temper-
atures (e.g. 80 ЊC, 20% yield).
(Dihydro-1H,3H,5H-oxazolo[3,4-c]oxazole-7a-carboxylato)-
copper(II), 6a. When the reactions of Cu(-ser)2 with formalde-
hyde and benzamide were conducted at pH > 10, the compound
obtained has an IR spectrum identical to that of 6a reported
previously.11 This complex is also formed when the reactions
of Cu(OHMe-ser)2 with formaldehyde and benzamide were
carried out in the absence or presence of base (pH range
≈3.0–9.5) and a high yield was obtained for each reaction
(≈80%). A mixture of Cu(OHMe-ser)2 (0.1 g, 0.3 mmol), form-
aldehyde (10 ml, 0.12 mol), benzamide (0.08 g, 0.64 mmol) and
95% ethanol was stirred thoroughly. The pH of the resultant
solution was raised to pH 7.5 by addition of aqueous NaOH
solution. The solution was filtered and upon standing at room
temperature yielded a blue crystalline solid after a day. This was
filtered off, washed with ethanol and dried in vacuo for 5 h.
Yield, 0.09 g, 79%. IR(cmϪ1): 3429, 2904, 2868, 1638, 1611,
1540, 1510, 1491, 1474, 1381, 1283, 1240, 1191, 1183, 1144,
1120, 1111, 1183, 1090, 1058, 1007, 965, 929, 904, 818, 806,
775, 756, 666, 553, 492, 435. νCOOϪ(asym, sym) 1638vs, 1381s;
ν(triplet, oxazolidine) 1183, 1090, 1058s. Elemental analysis
calculated for C12H16N2O8Cu: C, 37.95; H, 4.22; N, 7.38.
Found: C, 38.37; H, 4.27; N, 7.08%.
Bis[{N-hydroxymethyl-N-(N-methylbenzamido)}glycinato]-
copper(II), 3a. By using a Cu(gly) to C6H5CONH2 mol ratio of
1 : 1, the above reaction (in the absence of a base) led to the
isolation of 3a in ≈60% yield: a reaction mixture consisting of
Cu(gly)2 (0.5 g, 2.4 mmol), formaldehyde (10 ml, 0.12 mol),
benzamide (0.3 g, 2.5 mmol) and 95% ethanol was stirred
thoroughly. The solution was filtered and allowed to stand at
room temperature. A light blue solid which was formed within
the same day, was filtered off, washed with cold ethanol
and dried in vacuo for 5 h. Yield 0.86 g, 61%. IR(cmϪ1):
3301, 3067, 2974, 2945, 1633, 1577, 1547, 1491, 1439, 1424,
1378, 1333, 1310, 1246, 1161, 1139, 1082, 1048, 1013, 964,
952, 928, 859, 830, 810, 754, 708, 654, 622, 498, 465, 410.
νOH(water) 3301s; νNH(amide) 3067w; νCOOϪ(asym, sym) 1633vs,
1378s. Elemental analysis calculated for C22H26N4O8Cuؒ3H2O:
C, 44.63; H, 5.41; N, 9.47. Found: C, 44.77; H, 5.09; N,
9.27%.
Bis[N,N-di(N-methylbenzamido)-L-alaninato]copper(II), 2b.
A mixture of Cu(-ala)2 (0.5 g, 2.1 mmol), formaldehyde
(10 ml, 0.12 mol), benzamide (0.5 g, 4.1 mmol) and 95% ethanol
was stirred thoroughly and filtered. (filtrate pH ≈4). After 1 day,
a blue solid had formed. It was filtered off, washed with ethanol
and dried in vacuo for 5 h. Yield 1.38 g, 75%. IR(cmϪ1): 3851,
3413, 3266, 3066, 2941, 1630, 1603, 1578, 1548, 1492, 1464,
1446, 1383, 1351, 1314, 1157, 1133, 1078, 1047, 998, 949, 875,
839, 806, 779, 707, 618, 522, 460. νOH(water) 3413s; νNH(amide)
3066w; νCOOϪ(asym, sym) 1630vs, 1383s. Elemental analysis
calculated for C38H40N6O8Cuؒ6H2O: C, 51.84; H, 5.95; N, 9.55.
Found: C, 51.87; H, 5.38; N, 9.79%. Poor yields (< 10%) of 2b
were obtained at higher pH values. Optimum yield (50–75%) for
2b was obtained in the pH range 5.5–6.0 and with a Cu(-ala)2
to benzamide mole ratio > 1 : 2.
Bis(3-methylbenzamido-5-methyloxazolidine-4-carboxylato)-
copper(II), 5b. A mixture of Cu(-threo)2 (0.6 g, 2 mmol), form-
aldehyde (10 ml, 0.12 mol), benzamide (0.5 g, 4 mmol) and 95%
ethanol was stirred thoroughly. Blue crystalline needles formed
after 3 days and were filtered off, washed with cold ethanol and
dried in vacuo for 5 h. Yield: 0.46 g, 37%. IR(cmϪ1): 3579, 3434,
3225, 3064, 2982, 2928, 1623, 1666, 1576, 1546, 1522, 1489,
1455, 1385, 1361, 1335, 1315, 1291, 1276, 1260, 1170, 1124,
1079, 1068, 967, 936, 899, 882, 862, 799, 842, 762, 719, 691,
560, 510, 484, 428. νOH(water), 3579; νNH(amide) 3064w;
νCOOϪ(asym, sym) 1623vs, 1385s; ν(triplet, oxazolidine) 1170,
1124, 1079s. Elemental analysis calculated for C26H30N4O8Cuؒ
2H2O: C, 49.88; H, 5.47; N, 8.95. Found: C, 50.10; H, 5.42;
N, 8.67%. This complex could be synthesized between pH ≈ 4
and 8.0, but the yield was less than 40% for each reaction. At
pH > 8.0, lower yields (< 25%) were obtained, decomposition
occurred and copper was deposited.
Bis(4-methyl-oxazolidine-4-carboxylato)copper(II), 4a.
A
mixture of Cu(-ala)2 (1 g, 4.2 mmol), formaldehyde (10 ml,
0.12 mol), benzamide (1 g, 8.2 mmol) and 95% ethanol was
stirred thoroughly and filtered. The filtrate was heated in a
water bath at 80 ЊC. A blue solid formed after 2 weeks and was
filtered off, washed with ethanol and dried in vacuo for
5 h. Yield 0.12g, 14%. IR(cmϪ1): 3734, 3461, 3176, 2992,
2919, 2877, 1634, 1606, 1575, 1494, 1457, 1398, 1380, 1366,
1259, 1197, 1184, 1157, 1115, 1077, 1047, 1013, 944, 924,
825, 789, 766, 722, 585, 483. νOH(water) 3461s; νNH(amino)
3176s; νCOOϪ(asym, sym) 1607vs, 1398s; ν(triplet, oxazolidine)
1184, 1115, 1077s. This complex has an IR spectrum
identical to that of bis(4-methyl-oxazolidine-4-carboxylato)-
copper() synthesized previously.10 Elemental analysis calcu-
lated for C10H16N2O6Cuؒ2H2O: C, 33.38; H, 5.56; N, 7.79.
Found: C, 33.77; H, 5.25; N, 7.47%. In the pH range 9.0–10.0,
a mixture of 4a (≈10% yield) and 2b (≈1–2% yield) was
obtained.
Bis[N,N-di(N-methylbenzamido)-C-phenylglycinato]copper(II),
2c. A mixture of Cu(C-ꢀgly)2 0.5 g, 1.4 mmol), formaldehyde
(10 ml, 0.13 mol), benzamide (0.6 g, 2.8 mmol) and 95% ethanol
was stirred thoroughly. The pH of the solution was raised to pH
6.0 with NaOH solution. The light blue solid, which formed
after one day, was washed with ethanol and dried in vacuo for
5 h. Yield: 0.62 g, 44%. IR(cmϪ1): 3510, 3400, 3235, 3063, 1665,
1647, 1626, 1603, 1576, 1553, 1524, 1490, 1452, 1421, 1367,
1306, 1186, 1162, 1119, 1080, 1054, 1033, 975, 948, 910, 984,
824, 784, 753, 693, 643, 605, 508. νOH(water) 3400; νNH(amide)
3063w; νCOOϪ(asym, sym) 1626vs, 1367. Elemental analysis
calculated for C48H44N6O8Cuؒ6H2O: C, 57.39; H, 5.62; N,
8.37. Found: C, 57.88; H, 5.20; N, 8.45%. This complex was
formed between pH ≈3.0 and 8.0, and the yield ranges from
36–50%. At pH > 8, lower yields (< 25%) were obtained. At
pH ≈ 9, bis(4-phenyloxazolidine-4Ј-carboxylato)copper(), 4b,
was isolated as evidenced by its infrared spectrum.10
Bis(3-methylbenzamidooxazolidine-4-carboxylato)copper(II),
5a. A mixture of Cu(-ser)2 (0.5 g, 1.6 mmol), formaldehyde
(10 ml, 0.12 mol), benzamide (0.5 g, 4 mmol) and 95% ethanol
was stirred thoroughly. The blue solid which formed after 9
days was filtered off, washed with cold ethanol and dried in
vacuo for 5 h. (Copper was also deposited.) Yield 0.28 g, 31%.
IR(cmϪ1: 3598, 3435, 3222, 3060, 2878, 1646, 1578, 1539, 1487,
1452, 1397, 1376, 1315, 1291, 1215, 1185, 1154, 1115, 1089,
1059, 1041, 999, 969, 950, 927, 850, 797, 760, 711, 590, 557, 499.
νOH(water) 3435s; νNH(amide) 3060w; νCOOϪ(asym, sym) 1646vs,
1376s; ν(triplet, oxazolidine) 1185, 1154, 1059s. Elemental
analysis calculated for C24H26N4O8Cuؒ0.5H2O: C, 50.48; H,
4.77; N, 9.81. Found: C, 50.31 7; H, 4.53; N, 9.91%. This com-
plex was formed between pH ≈4 and 9.
Structure determination of 5b
The 21,658 room-temperature intensities for a selected crystal
of size 0.50 × 0.46 × 0.28 mm were collected to θ = 29.17Њ at
293 K on a Siemens CCD area-detector diffractometer that was
equipped with Mo-Kα radiation (λ = 0.71073 Å). The structure
was solved by direct methods and refined on F 2 to R = 0.053 for
5277 (I ≥ 2σ(I )) reflections.12 The carbon- and nitrogen-bound
hydrogen atoms were generated geometrically; the water hydro-
gen atoms were found by the HYDROGEN option13 in the
WinGX suite,14 but these were not refined. The structure is
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Table 1 Selected bond distances (Å) and angles (Њ) for 5b
second set comprises Cu(-ser)2, Cu(-threo)2 and Cu(OHMe-
ser)2 complexes which are α-hydroxyalkyl substituted copper()
chelated glycine.
Cu(1)–O(1)
Cu(1)–N(3)
Cu(1)–O(5)
1.953(2)
2.060(3)
1.950(2)
Cu(1)–N(1)
2.046(3)
2.293(3)
3.379(4)
Cu(1)–O(4)
All the related synthesized complexes 2a, 2b, 2c, 3a, 5a, and
5b, obtained from the reactions of various Cu(aa)2 with form-
aldehyde and benzamide, exhibit typical coordinated carboxyl-
ate asymmetric and symmetric stretching frequencies at ≈1600
cmϪ1 and ≈1400 cmϪ1 respectively. Peaks attributed to Cu–N
stretching between 500 and 400 cmϪ1 observed for unreacted
chelated amino acids are similarly observed for the above
complexes.20 Their infrared spectra also possess an amide NH
peak at ≈3060 cmϪ1, which is similarly observed for (i)
MII[DMeA-gly]2 complexes6 and (ii) CuII[Me-MeB-β-ala]2 and
MII[DMeB-β-ala]2 complexes.7 These IR data indicate that the
above series of complexes are the result of the reactions of their
corresponding chelated amino acids, Cu(aa)2, with formalde-
hyde and benzamide. Furthermore, microanalytical data
supports the postulated formulae of these complexes.
Cu(1) ؒ ؒ ؒ O(8)i
O(1)–Cu(1)–O(4)
O(1)–Cu(1)–N(1)
O(4)–Cu(1)–O(5)
O(4)–Cu(1)–N(3)
O(5)–Cu(1)–N(3)
99.3(1)
84.9(1)
96.8(1)
92.3(1)
85.3(1)
O(1)–Cu(1)–O(5)
O(1)–Cu(1)–N(3)
O(4)–Cu(1)–N(1)
O(5)–Cu(1)–N(1)
N(1)–Cu(1)–N(3)
163.6(1)
96.5(1)
88.7(1)
93.1(1)
178.2(1)
Symmetry transformation: i: 1 Ϫ x, ½ ϩ y, 1½ Ϫ z.
The first series of Cu(aa)2, comprising Cu(gly)2 1a (R1 = R2 =
H), Cu(-ala)2 1b (R1 = H, R2 = CH3), and Cu(C-ꢀgly)2 1c
(R1 = H, R2 = C6H5), reacted with formaldehyde and benzamide
to give 2a, 2b and 2c respectively (Scheme 1). Their infrared
Scheme 1
spectra also has an absence of the amino proton peak at ≈3160
cmϪ1 and this indicates both amino protons have been substi-
tuted. Hence, 1a, 1b and 1c are postulated to have undergone
N,N-diaminomethylation to yield two N-methylbenzamido
substituents. These complexes are shown as 2. Nevertheless, the
oxazolidine-containing complex 4a is also recovered together
with 2b from the reactions of Cu(-ala)2 with formaldehyde and
benzamide at pH 9.0–10.0 (Scheme 2); similarly, 4b was formed
Fig. 1 Molecular structure of 5b showing all non-hydrogen atoms at
50% probability level and the atom numbering scheme. The two lattice
water molecules are not shown.
illustrated as an ORTEP plot15 in Fig. 1. Selected bond lengths
and angles are given in Table 1.
Crystal data/refinement data. C26H34N4O10Cu, M = 626.11,
orthorhombic, P212121, a = 12.2944(2), b = 12.4471(1), c =
19.7477(3) Å, ρ = 1.376 g cmϪ3, V = 3021.98(7) Å3, Z = 4,
µ = 0.781 mmϪ1, N = 21 658, No (I ≥ 2σ(I )) = 5277, R = 0.053,
Rw = 0.123.
CCDC reference number 180977.
See http://www.rsc.org/suppdata/dt/b2/b202955c/ for crystal-
lographic data in CIF or other electronic format.
3
Results and discussion
Chemistry of Cu(aa)2 ؉ HCHO ؉ C6H5CONH2 reactions
In the Mannich aminomethylation of chelated amino acids by
formaldehyde and a third substrate, there exists possible com-
petition from aldol-type condensation. This is because chelated
α-amino acids with α-hydroxyalkyl substituents have under-
gone aldol-type condensation with formaldehyde alone, in the
absence of base, to yield complexes containing oxazolidine
rings.11,16,17 However, M(gly)2 and chelated α-alkyl substituents
need a base to react similarly to yield such oxazolidine-
containing complexes.10,16–19
In the present investigation, the series of Cu(aa)2 1 can thus
be grouped into two categories: the first group comprises
Cu(gly)2, Cu(-ala)2 and Cu(C-ꢀgly)2, in which the latter two
are α-alkyl substituted copper() chelated glycine; and the
Scheme 2
from the corresponding reactions of Cu(C-ꢀgly)2 at pH ≈ 9
(Scheme 3).
In one of the reactions of Cu(gly)2 1a with formaldehyde and
benzamide (see Experimental section), we managed to isolate
an intermediate complex bis[{N-hydroxymethyl-N-(N-methyl-
benzamido)}glycinato]copper() 3a. In its infrared spectrum,
there is an absence of the peak at ≈3160 cmϪ1; this shows the
absence of amino protons and that both amino protons of 1a
J. Chem. Soc., Dalton Trans., 2002, 3361–3366
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Scheme 5
Scheme 6 is proposed to help rationalize the various results
obtained. Cu(aa)2 complex, 1, is easily N-hydroxymethylated
by formaldehyde in basic and non-basic media5,7,21 to yield a
N-hydroxymethyl derivative, 7 (a carbinolamine). Subsequent
elimination of a water molecule results in the formation of an
exo-imine intermediate, 8. Similar imine intermediates have
been isolated and the imine carbon atom is known to be par-
tially activated towards attack by nucleophiles.22 Benzamide is
weakly acidic (pKa ≈14.5); both itself and its conjugate base are
nucleophilic.23 The oxygen atom of the α-hydroxyalkyl sub-
stituent of Cu(aa)2 is also nucleophilic due to lone pairs of
electrons. As a consequence, two competing processes occur
and the ensuing reaction of 8 can proceed along two different
pathways, Ia and Ib. When R2 is a hydroxyalkyl substituent
[1 is then Cu(-ser)2 1d, Cu(-threo)2 1e or Cu(OHMe-ser)2 1f],
pathway Ia is preferred and the oxazolidine ring in complex 4 is
formed from the cycloaddition of the α-hydroxyalkyl substitu-
ent of 8 to its own imine. When R2 is a proton or an alkyl
substituent [1 is 1a, 1b or 1c], the reaction proceeds along path-
way Ib where the deprotonated benzamide attacks each imine
group to yield the N-methylbenzamido derivative 9. Path-
ways Ia and Ib can be viewed as an intramolecular cyclization
and intermolecular condensation pathway respectively. Subse-
quently, both 9 and 4 are again N-hydroxymethylated by form-
aldehyde and an iminium intermediate with an uncoordinated
nitrogen is believed to be formed prior to further reaction.7 The
second N-methylbenzamido substituent in 2 is thus formed
from 9 in a manner similar to that reported for the formation of
MII[DMeB-β-ala]2 from the reaction of M(β-ala)2 with form-
aldehyde and benzamide.7 Though the iminium intermediate
has not been isolated, iminium salts have been utilized as
Mannich reagents in aminomethylation of various substrates.24
However, under suitable conditions (e.g. sufficiently high pH),
the intermediate 8 for Cu(-ala)2 1b seems to undergo parallel
reactions to yield both the aldol condensation complex 4 and
the Mannich aminomethylation complex 2. The formation of
both oxazolidine-complexes 4a (4, R1 = H, R3 = CH3) and 4b
(4, R1 = phenyl, R2 = H) at higher pH necessitates the prior
α-hydroxymethylation of Cu(-ala)2 1b and Cu(C-ꢀgly)2 1c by
formaldehyde via abstraction of an α-carbon proton by base;
this is consistent with earlier studies of M(-ala)2 reactions with
formaldehyde.10
Scheme 3
have been substituted. An amide peak at 3067 cmϪ1 confirms
the formation of at least one N-methylbenzamido substituent.
Elemental analysis supports the postulated N-hydroxymethyl-
ation and Mannich aminomethylation of 1a. The isolation of
3a supports our contention that 2 has to be formed from this
complex and thus lend support to the reaction mechanism to be
outlined latter.
In contrast, the second series of Cu(aa)2 1, consisting of
Cu(-ser)2 1d (R1 = H, R2 = CH2OH), Cu(-threo)2 1e,
Cu(OHMe-ser)2 1f, yielded different types of complexes. Under
all pH values investigated 1f (which has two α-hydroxymethyl
substituents) merely reacted with formaldehyde, i.e. it has
undergone an aldol-type condensation, to yield 6a which con-
tains two oxazolidine rings; no Mannich reaction has occurred
(Scheme 4). The Cu(-ser)2 1d reacted with formaldehyde and
Scheme 4
For Cu(-threo)2 1e reactions, the intermediate 10a (R1 = H,
R3 = CH3) undergoes further reaction with benzamide to give
the final complex 5b (R1 = H, R3 = CH3); an intermediate 10a
(R1 = H, R3 = CH3 in 10) has previously been isolated.21 Com-
plex 10a (synthesized by directly reacting 1e with formalde-
hyde), when treated with formaldehyde and benzamide in a
separate reaction, yields the same product 5b; this result sup-
ports the proposed formation of 5b from 10a. For the Cu-
(-ser)2 1d reactions, the subsequent reaction of 10b (R1 = R3 =
H in 10) can proceed along pathway IIa or IIb, depending on
pH. At pH > 10, pathway IIa is preferred and the bis(oxo-
zolidine)copper() complex, 6a (R3 = H in 6), is formed. No
such competitive reaction has been observed for the reactions
involving 1e; this can be explained on the basis of the inability
of the base to abstract the α-carbon proton in 10 (R1 = H, R3 =
CH3) and thereby allow α-hydroxymethylation by formalde-
hyde.
benzamide to produce the complex 5a which has an infrared
spectrum showing an amide NH peak (3060 cmϪ1) and a triplet
in the 1200–1050 cmϪ1 region characteristic of an oxazolidine
ring system.16,19,21 This suggests that 5a has one N-methyl-
benzamido pendant arm and one oxazolidine ring per chelated
serine moiety. Microanalytical results support the postulated
structure. The infrared spectrum of 5b obtained from the
reaction of Cu(-threo)2 1e, formaldehyde and benzamide
shows similar features, i.e. the amide and oxazolidine peaks.
The structures of both reaction products are therefore similar.
The crystal structure determination of 5b (Fig. 1) confirms the
postulated structure. Thus, 5a and 5b are depicted as structure
5 in Scheme 5. Finally, for the reactions of 1d at pH > 10,
the recovery of only 6a, a bis(oxazolidine) complex, shows
that aldol-type condensation occurs without Mannich amino-
methylation.
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J. Chem. Soc., Dalton Trans., 2002, 3361–3366

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Scheme 6
In the above overall reaction scheme, both series of reaction
steps (i) 1 4 and (ii) 4 10 6, which yield
oxazolidine-containing complexes, constitute aldol-type con-
densation. The other series of reaction steps (iii) 1
9, (iv) 9 2 and (v) 4 10 5, which yield complexes
with N-methylbenzamido substituents, constitute Mannich
aminomethylation. As such, the present findings have shown
that both the nature of the α-carbon substituent of the
Cu(aa)2 and the pH predisposes the choice of reaction path-
way – aldol-type condensation or Mannich aminomethyl-
ation. For the special case involving Cu(OHMe-ser)2 1f, the
isolation of only 6a shows aldol condensation is the pre-
ferred reaction and both α-hydroxymethyl substituents in
1f have successfully competed with the benzamide and this
result supports our proposal that 5 is formed via an initial
aldol condensation and a subsequent Mannich aminomethyl-
ation.
is orientated upwards while its oxazolidine ring, having an
7
8
envelope conformation, bends downwards in relation to the
N2O2 plane. The N-methylbenzamido substituent and the oxa-
zolidine ring of each threonine moiety in 5b are likewise simi-
larly orientated. This suggests that 4c is formed first and it then
reacts with more formaldehyde and benzamide to yield 5b
(Scheme 7); in this postulated sequence, the reaction occurs on
the same side as the amino proton and the N-methylbenzamido
group substitutes the amino proton of the threonine moiety in
4c, i.e. the substitution is stereospecific. A similar conclusion is
suggested in the N-hydroxymethylation of chelated amino
7
8
3
acids.25 Further evidence for this postulated pathway 1e
10a 5b and this stereospecificity is obtained when two
4c
separate reactions, (i) 4c with formaldehyde and benzamide and
(ii) 10a with formaldehyde and benzamide, yield the same com-
plex 5b.
The copper atom in 5b is five-coordinate in a distorted square
pyramidal geometry (81% along the trigonal bipyramidal–
square pyramid Berry pseudorotation pathway). The two
anionic ligands chelate through their carboxyl oxygen and ter-
tiary nitrogen atoms such that the N2O2 donor atoms forming
the basal plane (which is non-planar with a mean deviation
of 0.120 Å) has a trans-configuration. Characteristically, the
copper atom lies 0.157 Å out of the N2O2 basal plane in the
direction of the apical atom (apical bond length, 2.293(3) Å).
The benzamido oxygen atom of the second anion interacts with
an adjacent molecule [Cu ؒ ؒ ؒ O = 3.379(4) Å] to furnish a
linear chain along the c-axis of the orthorhombic unit cell as
shown in Fig. 2. Steric repulsion prevents further approach of
this benzamido oxygen atom and hexa-coordination for copper
is not achieved. The N3–Cu1–N1 basal angle (178.2Њ) could
have been straightened due to steric interaction as such angles
Description of the crystal structure of 5b
This complex 5b (Fig. 1, Table 1) is formed from the reaction
of Cu(-threo)2 with formaldehyde and benzamide. Each
threonine moiety has an oxazolidine ring and one N-methyl-
benzamido substituent. The oxazolidine ring arises from
an aldol-type condensation of the threonine moiety with
formaldehyde as has been found to occur in the reaction of
Cu(-threo)2 with formaldehyde alone.21 The N-methylbenz-
amido substituent is formed from a Mannich reaction between
the threonine moiety, formaldehyde and benzamide.
The structure of 5b bears close resemblance to that of bis-
(5-methyloxazolidine-4-carboxylato)copper() dihydrate,21 4c.
In the latter, the single amino proton in each threonine moiety
J. Chem. Soc., Dalton Trans., 2002, 3361–3366
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α-hydroxymethylation by formaldehyde and thus hinder
Mannich aminomethylation.
Acknowledgements
We thank Tunku Abdul Rahman College (01–1404), the
Universiti Sains Malaysia (304/PKIMIA/63306) and University
of Malaya (PJP 0717/2002A) for supporting this work. The
X-ray diffraction measurements were carried out by Professor
Hoong Kun Fun of the School of Physics, Universiti Sains
Malaysia.
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Fig. 2 Diagram showing the polymeric nature of the 5b molecules.
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4
Conclusion
Competing processes occur in the reactions of Cu(aa)2 with
formaldehyde and benzamide. The nature of the α-carbon sub-
stituent of the chelated amino acid and the pH determine the
preferred pathway. For CuII[OHMe-ser]2, the two α-hydroxy-
methyl substituents successfully competed with the benzamide
to yield the intramolecular aldol condensation complex, a
bis(oxazolidine)copper(). For Cu(aa)2 with one reactive
α-hydroxyalkyl substituent per amino acid moiety, aldol
condensation occurs first prior to Mannich aminomethylation
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J. Chem. Soc., Dalton Trans., 2002, 3361–3366